FIELD OF THE INVENTION The present invention relates to chemical agents affecting levels of gene expression in cellular systems, including cancer cells. In particular, the present invention relates to derivatives of quinone moiety, processes for their preparation, their use as antitumor drugs and pharmaceutical compositions containing them as active ingredients.

BACKGROUND OF THE INVENTION Screening assays for novel drugs are based on the response of model cell based systems in vitro to treatment with specific compounds. Various measures of cellular response have been utilized, including the release of cytokines, alterations in cell surface markers, activation of specific enzymes, as well as alterations in ion flux and/or pH. Some such screens rely on specific genes, such as oncogenes or tumor suppressors.

Our approach to screening small molecule compounds as potential anticancer drugs is based on the idea that for each specific tumor type, a unique signature set of genes, that are differentially expressed in tumor cells if compared to corresponding normal cells, can be established. The relatively small signature set, containing 10-30 genes, allows for easy, high throughput screening for compounds that can reverse the gene expression profile from patterns typical for cancer cells to patterns seen in normal cells. As a part of our efforts to provide new diversified compounds for high throughput gene expression screening, we designed and synthesized a number of novel derivatives of quinones. Gene expression screening and subsequent cytotoxicity screening revealed that some of the compounds possess biological activity.

Consequent, more detailed structure-activity relationship studies led to the discovery of compounds of formula I as new small molecule agents having antineoplastic activity.

BRIEF SUMMARY OF THE INVENTION In one aspect, the present invention relates to novel organic compounds, derivatives of quinone, that have the ability to function as gene expression modulators for genes found in cancer cells, especially genes involved in misregulated signal transduction pathways typical for cancer such as colon and breast cancers.

In one embodiment of the present invention, the compounds disclosed herein are able to up regulate genes found to be up regulated in normal (i. e., non-cancerous) cells versus cancer cells, especially colon and breast cancer cells, thereby producing an expression profile for said gene (s) that more resembles the expression profile found in normal cells. In another embodiment, the compounds disclosed herein are found to down regulate genes found to be up regulated in cancer cells, especially colon and breast cancer cells, relative to normal (i. e. , non-cancerous) cells thereby producing

an expression profile for said gene (s) that more resembles the expression profile found in normal cells. Thus, in addition to activity in modulating a particular gene that may or may not have a major role in inducing or sustaining a cancerous condition, the agents disclosed herein also find value in regulating a set of gene whose combined activity is related to a disease condition, such as cancer, especially colon and breast cancer, including adenocarcinoma of the colon. Thus, while an overall set of genes is modulated, the effect of modulating any subset of these may be disproportionately large or small with respect to the effect in ameliorating the overall disease process. Consequently, different disease conditions may rely on different subsets of genes to be active or inactive as a basis for the overall disease process.

Thus, the present invention relates to novel organic compounds that have the ability to function as gene modulators for genes found in normal (i. e., non-cancer) cells and which genes are found to be up regulated or down regulated in normal cells, especially colon and breast cells. Such an effect may prevent a disease condition, such as cancer, from arising in those otherwise more susceptible to such a condition. In one such embodiment, administration of one or more of the agents disclosed herein may succeed in preventing a cancerous condition from arising.

In other embodiments, the agents disclosed herein find use in combination with each other as well as with other agents, such as where a mixture of one or more of the agents of the present invention are given in combination or where one or more of the agents disclosed herein is given together with some other already known therapeutic agent, possibly as a means of potentiating the affects of such known therapeutic agent or vice versa.

The present invention also relates to processes of preventing or treating disease conditions, especially cancer, most especially colon and

breast cancer, by administering to a subject, such as a mammal, especially a human, a therapeutically active amount of one or more of the agents disclosed herein, including where such agents are given in combination with one or more known therapeutic agents.

DEFINITIONS The following is a list of definitions for terms used herein.

"Acyl"or"carbonyl"is a radical formed by removal of the hydroxy from a carboxylic acid (i. e. , R-C (=O)-). Preferred acyl groups include (for example) acetyl, formyl, and propionyl.

"Alkyl"is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms."Alkene"is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms."Alkyne"is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. Alkyl, alkene and alkyne chains (referred to collectively as"hydrocarbon chains") may be straight or branched and may be unsubstituted or substituted.

Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e. g. , phenoxy), heteroaryloxy, acyloxy (e. g. , acetoxy), carboxy, aryl (e. g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano,

or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.

Also, as referred to herein, a"lower"alkyl, alkene or alkyne moiety (e. g.,"lower alkyl") is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne.

"Alkoxy"is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i. e.,-O-alkyl or-O- alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.

"Aryl"is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring. Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6-or 7-membered rings fused to 5-, 6-, or 7- membered rings. Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.

"Aryloxy"is an oxygen radical having an aryl substituent (i. e.,-O-aryl).

Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.

"Cycloalkyl"is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring.

Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-6-or 7-membered rings fused to 5-, 6-, or 7-membered rings.

Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.

"Halo"or"halogen"is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro, especially fluoro.

"Haloalkyl"is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are Cl-Cl2 haloalkyl ; more preferred are Cl-C6 haloalkyl ; still more preferred still are Cl-C3 haloalkyls.

Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.

"Heteroatom"is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.

"Heteroalkyl"is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent.

Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i. e.,-O-alkyl or-O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred

branched heteroalkyl have one or two branches, preferably one branch.

Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof. Where a group is described, for example, as an alkyl derivative, such as"-ethylpyridine"the dash"-"indicate point of attachment of the substituent. Thus,"-ethylpyridine"means attachment of ethylpyridine via the ethyl portion of the group whereas"ethylpyridine-"means attachment via the pyridinyl ring.

"Heteroaryl"is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise 5-, 6-or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include, but are not limited to, the following:

H H H t Q Furan Thiophene H s s N U Isothiazole 1, 2, 5-Thiadiazole 1, 2, 3-Triazole 1, 3, 4-Thiadiazole Furazan H N\) s N 1, 2, 3-Thiadiazole 1, 2, 4-Thiadiazole 1, 2, 4-Triazole Tetrazol O S N-N N-N N-N N 1, 2, 4-Oxadiazole 1, 3, 4-Oxadiazole 1, 2, 3, 4-Oxatriazole 1, 2, 3, 4-Thiatriazole 1, 2, 3, 5-Thiatriazole O NtsNN \-/I 1 1 (ir 1, 2, 3, 5-Oxatriazole 1, 2, 3-Triazine 1, 2, 4-Triazine 1, 2, 4, 5-Tetrazine Dibenzofuran H N I N N N^N N N1// (N N'z'N Pyridine Pyridazine Pyrimidine Pyrazine 1, 3, 5-Triazine Indolizine H H 0 \NH / /NN N N Isoindole Benzofuran Benzothiophene 1 Purine Quinoline H N N N N N N N. H Benzimidazole Pteridine Carbazole N N_ Isoquinoline 1, 8-Napthypyridine \ N Acridine Phenazine

N) () NX"Heteroaryloxy"is an oxygen radical having a heteroaryl substituent (i. e.,-O-heteroaryl). Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene) oxy, (oxazol) oxy, (thiazole) oxy, (isoxazole) oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.

"Heterocycloalkyl"is a saturated or unsaturated ring containing carbon atoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring.

Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms.

Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6-or 7- membered rings fused to 5-, 6-, or 7-membered rings. Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to, the following : H O CNH -, I_I Oxirane Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 3H-Indole S O O NH '// 1, 3-Dioxolane 1, 2-Dithiolane 1, 3-Dithiolane 4, 5-Dihydroisoxazole 2, 3-Dihydroisoxazole H U Pyrazolidine 2H-Pyran 3, 4-Dihydro-2H-pyran Tetrahydropyran 2H-Chromene

w 0 o (X) 11 0 H Chromone Chroman Piperidine Morpholine 4H-1, 3-Oxazine 6H-1, 3-Oxazine H J \ \ \ J N L U. 5, 6-dihydro-4H-1, 3-oxazine 4H-3, 1-benzoxazine Phenothiazine 1, 3-Dioxane H M c < i \ 0 c LO U J Cepham Piperazin Hexahydroazepine 1, 3-Dithiane 1, 4-Dioxane Penem H NH . S O NH2 Coumarin Thiomorpholine Uracil Thymine Cytosine Thiolane H H s C S 2, 3-Dihydro-1H-lsoindole 1, 4-Oxathiane 1, 4-Dithiane hexahydro-Pyridazine /NU ASZ p O 1, 2-Benzisothiazoline Benzylsultam NHWhile alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention: Enols (OH attached to a carbon bearing a double bond).

Amino groups attached to a carbon bearing a double bond (except for vinylogous amides).

More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring).

Hydroxy, amino, or amido attached to a carbon that also has a heteroatom attached to it.

A''pharmaceutically-acceptable salt"is a cationic salt formed at any acidic (e. g., carboxylic acid) group, or an anionic salt formed at any basic (e. g. , amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987 incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like.

Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice.

A"solvate"is a complex formed by the combination of a solute (e. g., a metalloprotease inhibitor) and a solvent (e. g. , water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).

Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e. g. , water, ethanol, acetic acid, N, N- dimethylformamide and others known or readily determined by the skilled artisan).

The terms"optical isomer", "stereoisomer", and"diastereomer"have the accepted meanings (see, e. g., Hawley's Condensed Chemical Dictionary, 11th Ed. ). The illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.

DETAILED SUMMARY OF THE INVENTION The present invention relates generally to a compound having the structure: Formula I wherein W, X, Y and Z are each selected from a bond, CH, C-R8, C-Rg, C-Rio, C- Ru, 0 (oxygen), N (nitrogen) and S (sulfur) and no more than two of W, X, Y and Z are simultaneously 0, N and S; and wherein, R8, R9, Rio, Rll each may be hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NR14CONR12R13 ;

wherein R12, R13 and R14 are hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl ; NRi2Ri3 may form a substituted or unsubstituted, mono or bicyclic rings, with one to four heteroatoms selected from N, O and S; and wherein, R12 and R14 may form a 4,5, 6 or 7- membered cyclic ring system; and wherein Ri, R2, R3, R4, and R5 are each selected from: hydrogen, alkyl, substituted or unsubstituted phenyl or polyaromatic rings, substituted or unsubstituted heteroaromatic, with hetero atom (s) as N, O, S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon and mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms as N, O, or S; and wherein said substitutions are selected from hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, N02, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NR14CONR12R13 ; wherein R12, R13 and R14 are each selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl ; NR12R13 is also substituted or unsubstituted, mono or bicyclic rings with one to four heteroatoms selected from N, O and S; and wherein R12 and R14 may, in one embodiment, form a 4,5, 6 or 7-membered cyclic ring system; and wherein R1, R4, R5, R6 and R7 may also be selected from:

wherein n is 2,3 or 4 and R15, R16, R17, R18 and Rig are selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted alkylaryl ; and NR17R18 may also be a substituted or unsubstituted, mono or bicyclic ring with one to four heteroatoms selected from N, O and S; and wherein Riy and Rie may form a 4,5, 6 or 7-membered cyclic ring system; and wherein R4 is also selected from -COR13, -SO2R13, - CONR12R13, and-C (=NR19) NRi7Ris ; wherein R6 and R7 may also each be selected from: alkyl, substituted and unsubstituted phenyl or polyaromatic,

substituted and unsubstituted heteroaromatic rings with hetero atoms selected from N, O and S, substituted and unsubstituted aralkyl, substituted and unsubstituted, cyclic or polycyclic hydrocarbon and mono or polyheterocyclic rings, each of 3- 8 atoms, said heterocycle having one to four hetero atoms selected from N, O and S; and wherein substitutions are selected from hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, NR14CONR12R13 ; wherein R12, R13 and R14 are each selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl ; NR12R13 is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S; and wherein NR4R5 and NR6R7 may each form a substituted or unsubstituted, mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S and wherein said N may also be substituted or unsubstituted, and including salts of any of the above-recited structures.

In another preferred embodiment, Ri, R2, R3, R4, and R5 are each selected from hydrogen, alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted polyaromatic, and substituted or unsubstituted heteroaromatic comprising one or more hetero atom (s) selected from N, O and S.

In another preferred embodiment, R1, R2, R3, R4, and R5 are each selected from substituted or unsubstituted aralkyl, substituted or unsubstituted

cyclo or polycyclo hydrocarbon or mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms selected from N, O and S.

In any of these preferred embodiments, substitutions are selected from hydroxyl, sulfhydryl, lower alkoxy (1-6 carbon), lower thioalkoxy (1-6 carbon), lower alkyl (1-6 carbon), halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NRi4CONRi2Ri3, wherein R12, R13 and R14 are hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl. In a further preferred embodiment of the foregoing, R12 and R14 form a 4,5, 6 or 7-member cyclic ring system.

In a further preferred embodiment, NR12R13 forms a substituted or unsubstituted mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S.

In one preferred embodiment, Ri, R4, R5, R6 and R7 are each selected from:

wherein n is 2,3 or 4 and R15, R16, R17, Pis and Rio are selected from hydrogen, lower alkyl, cycloalkyl, substituted and unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkylaryl. In a preferred embodiment thereof, NR17R18 is forms a substituted or unsubstituted, mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S. In another preferred embodiment thereof, R17 and R19 form a 4,5, 6 or 7-membered cyclic ring system.

In a preferred embodiment of the compounds of Formula I, W and Z are each selected from C-R8, C-RI, and N, and X and Y are each selected from C-R9 and C-R10. In another preferred embodiment, X and Y are each selected from C-R9, C-R10 and N and wherein W and Z are each selected from C-R8 and C-R11. In another preferred embodiment, W is C-R8 or N, and X, Y and Z are each selected from C-R9, C-R10 and C-R11.

Where a position in a structure, such as W, X, Y or Z, or a substituent, such as an R group, as recited above, is described as selected from, it means

that each of W, X, Y and Z, or R, can be selected from the indicated group of structures or atoms and each is selected independently of the others unless it is expressly stated herein to be otherwise. By"independent"is meant that the selection of one substituent does not limit the range of selection for another substituent, unless expressly stated as such. For example, where X and Y are selected from a range of atoms, such as N, O and S, then X and Y may be the same or different and the selection of one does not limit the range of the other. Thus, if X is nitrogen then Y can still be N, O or S.

Where a position, for example, in a ring, is described as being selected from"a bond"etc. , this means that the position is not occupied by an atom.

Thus, if in Formula I, X is a bond, then the ring with W, X, Y and Z is a 5 membered ring instead of a 6 membered ring.

In a preferred embodiment, NR4R5 and/or NR6R7 of Formula I form (s) a piperazine ring, preferably an N-acetylpiperazinyl group.

In a preferred embodiment,--NR4R5 and/or--NR6R7 of Formula I is a substituted or unsubstituted morpholinyl group. In a highly preferred embodiment thereof, R6 and R7 are both hydrogen. In a most preferred embodiment, R2 and R3 are both hydrogen and--NR4R5 forms an unsubstituted morpholinyl group.

In a preferred embodiment, NR4R5 and/or NR6R7 of Formula I is a piperidine ring, preferably a substituted piperidine ring, most preferably 4- hydroxypiperidine.

In a highly preferred embodiment of any of the structures of the present invention, Ri, R6 and R7 of Formula I are each methyl.

In another preferred embodiment of the compounds of the invention, Z is C-riz or N and W, Y and Z are each selected from C-R8, C-R9 and C-Rio. In one embodiment of the latter, X is C-R9 or N and W, Y and Z are each

selected from C-R8, C-Rio and C-R11 In a preferred embodiment of the latter Y is C-Rio or N and W, X, and Z are each selected from CH, C-R8, C-R9 and C-RII. In a most preferred embodiment thereof, W, X, Y and Z are each selected from CH, C-R8, C-R9, C-Rio and C-R11, most preferably where W X, Y and Z are each CH (thereby forming a phenyl ring).

In another preferred embodiment of the compounds of the invention, R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) or aryl. In a further preferred embodiment of the compounds of the invention, Ri is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl,-methylpyridine,-ethylpyridine,- methylindole,-ethylindole, alkoxyethyl-, hydroxyethyl-, N, N-dialkyl-ethyl, N, N- <BR> <BR> <BR> dialkyl-propyl,-methylpyrrole,-ethylpyrrole,-methylfuran,-et hylfuran,- alkylmorpholine,-alkylpiperizine,-alkypiperidine, and-alkylpyrrolidine and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbons) and aryl.

In another preferred embodiment of the compounds of the invention, R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl,-methylpyridine,- ethylpyridine,-methylindole,-ethylindole, alkoxyethyl-, hydroxyethyl-, N, N- dialkyl-ethyl-, N, N-dialkyl-propyl-,-methylpyrrole,-ethylpyrrole,-methylfuran, - ethylfuran,-alkylmorpholine,-alkylpiperizine,-alkypiperidine , and- alkylpyrrolidine, and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl.

In another preferred embodiment of the compounds of the invention, R6 and R7 are selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl,-methylpyridine,-ethylpyridine,- methylindole,-ethylindole, alkoxyethyl-, hydroxyethyl-, N, N-dialkyl-ethyl, N, N- <BR> <BR> <BR> dialkyl-propyl,-methylpyrrole,-ethylpyrrole,-methylfuran,-et hylfuran,-

alkylmorpholine,-alkylpiperizine,-alkypiperidine, and-alkylpyrrolidine, and R2 and R3 are each selected from hydrogen, lower alkyl (1-6 carbons) and aryl.

In other preferred embodiments, R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl, wherein Ri, R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl,-methylpyridine,-ethylpyridine,- methylindole,-ethylindole, alkoxyethyl-, hydroxyethyl-, N, N-dialkyl-ethyl-, N, N- <BR> <BR> <BR> <BR> dialkyl-propyl-,-methylpyrrole,-ethylpyrrole,-methylfuran,-e thylfuran,- alkylmorpholine,-alkylpiperizine,-alkypiperidine, and-alkylpyrrolidine, and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) or aryl and wherein R6 and R7 are selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl,-methylpyridine,- ethylpyridine,-methylindole,-ethylindole, alkoxyethyl-, hydroxyethyl-, N, N- dialkyl-ethyl, N, N-dialkyl-propyl,-methylpyrrole,-ethylpyrrole,-methylfuran,- ethylfuran,-alkylmorpholine,-alkylpiperizine,-alkypiperidine , and- alkylpyrrolidine.

In another preferred embodiment of the compounds of the invention having Formula 1, R2 and R3 are each selected from hydrogen and alkyl, and wherein R4 and R6 are each selected from alkyl and wherein n is 2, 3 or 4 and wherein one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula I, Ri is alkyl while R2 and R3 are each selected from hydrogen and alkyl, and R4 and R6 are each selected from alkyl and

wherein n is 2,3 or 4 and one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl while R4 and R6 are each selected from alkyl and where n is 2,3 or 4 and one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl, wherein R4 and R6 are each selected from alkyl and

where n is 2,3 or 4 and at least one of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl, and R4 and R6 are each selected from alkyl and

where n is 2,3 or 4 and at least one of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl, and R4 and R6 are each selected from alkyl and

wherein n is 2,3 or 4 and wherein one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.

In another preferred embodiment of Formula 1, R2 and R3 are each be hydrogen or alkyl, R4 and R6 are each selected from alkyl and

where n is 2,3 or 4 and one or both of R5 and R7 is alkyl, and in either case most preferably wherein the alkyl is methyl.

In separate embodiments, the present invention encompasses compounds having a structure found in Table 1 including salts thereof, a compound having a structure of Table 2 including salts thereof, a compound having a structure of Table 3 including salts thereof, a compound having a structure of Table 4 including salts thereof, a compound having a structure of Table 5 including salts thereof, a compound having a structure of Table 6 including salts thereof, a compound having a structure of Table 7 including salts thereof, a compound having a structure of Table 8 including salts thereof, a compound having a structure of Table 9 including salts thereof, a compound having a structure of Table 11 including salts thereof, a compound having a structure of Table 12 including salts thereof, a compound having a structure of Table 13 including salts thereof, a compound having a structure of Table 14 including salts thereof, a compound having a structure of Table 15 including salts thereof, a compound having a structure of Table 16 including salts thereof, a compound having a structure of Table 17 including salts thereof, and a compound having a structure of Table 18 including salts thereof, and in each case most preferably pharmaceutically acceptable salts thereof. It is to be understood that each of the structures defined in each of these tables is considered to be a separate and preferred embodiment of the present invention.

In another aspect, the present invention relates to compositions of any of the compounds of the invention, preferably wherein such compound is

present in a pharmaceutical acceptable carrier and in a therapeutical effective amount. Such compositions will generally comprise an amount of such compound that is not toxic (i. e. , an amount that is safe for therapeutic uses).

In accordance with the foregoing, the present invention is directed to use of the compounds of the invention as active ingredients for medicaments, in particular for medicaments useful for the treatment of tumors. The compounds of the invention will thus be present in pharmaceutical compositions containing compounds of formula I as active ingredients, in admixture with pharmaceutical acceptable vehicles and excipients, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutical acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol, and the like, including carriers useful in forming sprays for nasal and other respiratory tract delivery or for delivery to the ophthalmic system. A thorough discussion of pharmaceutical acceptable carriers, diluents, and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co. , N. J. current edition). Use of such carriers is well known to those skilled in the art and will not be discussed further herein.

Also in accordance with the foregoing, the present invention relates to a method for preventing or treating a disease associated with a change in levels of expression of particular sets of genes in a mammal comprising administering to said mammal an effective amount of a compound of the invention.

In another aspect, the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, wherein the disorder is selected from the group consisting of cancer, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal

disease and skin disorders, comprising administering to a mammal in need of such treatment or prevention a therapeutical effective amount of a compound of the invention.

In a preferred embodiment thereof, the disorder is cancer, more preferably colon cancer, most preferably adenocarcinoma, and the treatment prevents, arrests or reverts tumor growth, metastasis or both.

The compounds of the invention will commonly exert a therapeutic effect by modulation of one or more genes found in a cell, especially a mammalian cell, such as a cancer cell, preferably colon cancer and most preferably adenocarcinoma. Thus, a compound, or compounds, of the invention can be used to determine or demarcate a set of genes by determining modulation of such set of genes by one or more compounds of the invention. For example, where a set of genes is found to be up-regulated in cancer cells versus otherwise normal cells, especially normal cells of the same tissue or organ as the cancer cells, a set of genes can be determined by their common property of being modulated (based on a change in expression of the genes, such as a change in rate or amount of RNA transcribed or the amount of polypeptide produced by said expression) by contacting such genes, or a cell containing such genes, with one or more of the compounds of the invention. The extent of such modulation may, of course, be related to the amount of said compound, or compounds, used in the contacting. Such modulation may include the increased expression of all the determined genes (i. e. , the genes of the set), the decreased expression of all genes of the set, or the increase in expression of some of the genes of the set and decreased expression of others. Thus, a gene not modulated by the test compound (the compound used in contacting the genes or cell containing them) is not considered a member of the set.

Thus, the present invention relates to a gene set wherein expression of each member of said gene set is modulated as a result of contacting said

gene set with a compound of the invention. In specific embodiments, expression of each member of said gene set is increased as a result of said contacting or is decreased as a result of said contacting. In another preferred embodiment, the gene set is present in a cell. Such a gene set will commonly be related to a specific disease process, such as a set of genes all of which are modulated by a compound of the invention wherein such compound has a specific therapeutic effect, such as being an anti-neoplastic agent.

In another aspect, the present invention relates to a method for identifying an agent that modulates the expression of a gene set of the invention, comprising: (a) contacting, or otherwise using, a compound, such as a test compound, a test system, such as a source of genes or polynucleotides, for example, those found to be related to a given disease or disorder, or a set that is modulated by a given compound, or group of compounds, especially where these are found in a cell, so that the cell represents the test system, containing one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said treatment; wherein said change in expression of step (b) indicates modulation of the members of said gene set by the test compound thereby identifying a test compound that modulates the expression of said gene set.

In one embodiment, the cell is a naturally derived cell that contains genes of a gene set or may be a recombinant cell engineered to comprise the genes or polynucleotides of the gene set. In an alternative embodiment, the test system may comprise the genes or polynucleotides in a cell-free system.

In a related aspect, the present invention provides a method for identifying a test compound that modulates the expression of a gene set, such as a gene set of the invention, comprising: (a) contacting a test compound with one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said contacting; wherein said change in expression of step (b) indicates modulation of the members of said gene set thereby identifying a test compound that modulates the expression of said gene set.

As used herein, "corresponding genes"or"corresponding polynucleotides"or"polynucleotides corresponding to genes"refers to polynucleotides and/or genes that encode an RNA that is at least 90% identical, preferably at least 95% identical, most preferably at least 98% identical, and especially identical, to an RNA encoded by one of the genes disclosed herein in Table 19. Such genes will also encode the same polypeptide sequence, but may include differences in such amino acid sequences where such differences are limited to conservative amino acid substitutions, such as where the same overall three dimensional structure, is maintained. A"corresponding gene"includes splice variants thereof.

Because a polynucleotide or gene used in the methods of the invention "corresponds to"a gene present in one of the gene sets of the invention, such as genes identified in Table 19, such polynucleotide or gene encodes an RNA (processed or unprocessed, including naturally occurring splice variants and alleles) that is at least 90% identical, preferably at least 95% identical, most preferably at least 98% identical to, and especially identical to, an RNA that would be encoded by, or be complementary to, such as by hybridization with, a gene of Table 19, or genes of any gene set identified according to the invention. Polynucleotides encoding the same proteins as any of these genes,

regardless of the percent identity of the sequences of such genes and/or polynucleotides, are also specifically contemplated by any of the methods of the present invention. The polynucleotides used in the methods of the invention also include any open reading frames, as defined herein, present therein. As used herein, the term"open reading frame" (or ORF) means a series of triplets coding for amino acids without any termination codons and is a sequence (potentially) translatable into protein.

The polynucleotides useful in the methods of the invention may be genomic in nature and thus represent the sequence of an actual gene, such as a human gene, or may be a cDNA sequence derived from a messenger RNA (mRNA) and thus represent contiguous exonic sequences derived from a corresponding genomic sequence, or they may be wholly synthetic in origin for purposes of practicing the processes of the invention. Because of the processing that may take place in transforming the initial RNA transcript into the final mRNA, the sequences disclosed herein may represent less than the full genomic sequence. They may also represent sequences derived from ribosomal and transfer RNAs. Consequently, the gene as present in the cell (and representing the genomic sequence) and the polynucleotide transcripts disclosed herein, including cDNA sequences, may be identical or may be such that the cDNAs contain less than the full genomic sequence. Such genes and cDNA sequences are still considered"corresponding sequences" (as defined elsewhere herein) because they both encode the same or related RNA sequences (i. e., related in the sense of being splice variants or RNAs at different stages of processing). Thus, by way of non-limiting example only, a gene that encodes an RNA transcript, which is then processed into a shorter mRNA, is deemed to encode both such RNAs and therefore encodes an RNA complementary to (using the usual Watson-Crick complementarity rules), or that would otherwise be encoded by, a cDNA (for example, a sequence as disclosed herein). Thus, the sequences disclosed herein correspond to genes contained in the cancerous cells (here, breast cancer) and are used to determine gene activity or expression because they represent the same

sequence or are complementary to RNAs encoded by the gene. Such a gene also includes different alleles and splice variants that may occur in the cells used in the methods of the invention, such as where recombinant cells are used to assay for anti-neoplastic agents and such cells have been engineered to express a polynucleotide as disclosed herein, including cells that have been engineered to express such polynucleotides at a higher level than is found in non-engineered cancerous cells or where such recombinant cells express such polynucleotides only after having been engineered to do so.

Such engineering includes genetic engineering, such as where one or more of the polynucleotides disclosed herein has been inserted into the genome of such cell or is present in a vector.

Such cells, especially mammalian cells, may also be engineered to express on their surfaces one or more of the polypeptides of the invention for testing with antibodies or other agents capable of masking such polypeptides and thereby removing the cancerous nature of the cell. Such engineering includes both genetic engineering, where the genetic complement of the cells is engineered to express the polypeptide, as well as non-genetic engineering, whereby the cell has been physically manipulated to incorporate a polypeptide of the invention in its plasma membrane, such as by direct insertion using chemical and/or other agents to achieve this result.

In a preferred embodiment of such method, the determined change in expression is a decrease in expression of said one or more polynucleotides, or a decrease in said expression. In other preferred embodiments, the determined change in expression is a change in transcription of said one or more polynucleotides or a change in activity of a polypeptide, or expression product, encoded by said polynucleotide, including a change in the amount of said polypeptide synthesized, such as by a cell. The term"expression product" means that polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid (s).

In additional preferred embodiments, said one or more polynucleotides are present in a cell, preferably a cancer cell, more preferably a colon and breast cancer cell, and most preferably where the coloncancer cell is an adenocarcinoma cancer cell. In another preferred embodiment of the invention, the cell is a recombinant cell engineered to contain said set of genes.

Such methods serve to identify other compounds that have like activity, including expected therapeutic activity, as the compounds of the invention and thus serve as the basis for large scale screening assays for therapeutic compounds. As a result, one or more compounds of the invention can be utilized to determine the presents of gene sets and subsets within the genome of a cell. Thus, the set of all genes modulated by a group of structurally related compounds of the invention can form a gene set while the different sets of genes regulated by each compound of a group will form a subset. By way of non-limiting example, where a structurally related group of 5 of the compounds of the invention (all having generally the structure of Formula I) modulate (by increasing or decreasing) expression of determined genes 1-20, this latter group of genes forms a gene set. Further examination then determines that genes 1-6 are modulated by compound A, genes 7-10 are modulated by compound B, genes 2-4 and 9-12 are modulated by compound C, genes 10-20 are modulated by compound D and the even numbered genes are modulated by compound E. Each of these groups of genes, such as the genes modulated by compound C, is considered a subset of the gene set of genes 1-20. In an analogous manner, the genes modulated by compound E can be themselves further subdivided into at least 2 subsets wherein one subset is made up of the genes whose expression is increased by compound E while the other subset is made up of genes whose expression is decreased by compound E, thus yielding subsets of subsets. It should be noted that within the context of the present invention, it is not necessary to identify subsets and that each so-called subset is, in its own right, a gene set

as used in the invention. The identification of sets and subsets is thus a function of the extent that a user of the methods of the invention wishes to determine modulation of genes resulting from contacting of one or more compounds of the invention. Thus, the genes modulated by a single compound form a gene set and it is not necessary, in carrying out the methods of the invention, to compare different groups of genes for modulation by more than one compound but this may, of course, be done.

In accordance with the foregoing, the present invention relates to a set of genes comprising a plurality of subsets of genes wherein each subset of said plurality is a gene set identified by the methods of the invention. The present invention also relates to compounds identified as having activity using the methods of the invention, such as novel compounds not specifically described herein by structure but which have been identified by their ability to modulates one or more gene sets modulated by compounds of the invention.

In a preferred embodiment, the present invention encompasses the gene sets and subsets of the genes identified in Table 19.

The present invention comprises also processes for the preparation of compounds of formula 1, and the relative key intermediates.

Compound Preparation: The compounds of the invention can be prepared using a variety of procedures known in the art. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes.

Scheme 1: The dichloro compound 1 is either commercially available or can be synthesized using methods known in the literature.

1. Shaikh I. A. et al, J. Med. Chem, 29 (8), 1329-1340, (1986) 2. Vlderrama el al, Syn. Comm. , 27 (12), 2143-2157, (1997) 3. Chu, Kwong-Yung; et al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1978) 4. Matsuhisa A. et al, Patent WO 01/60803 A1

The compound 1 is reacted with an amine in an appropriate solvent to provide the corresponding derivative 2. The compound 2 is then reacted with an appropriate 2-halo, 2-substituted acetyl halide to obtain the corresponding 3 derivatives. A reaction of crude or purified compound 3 with an amine gives compound 4. Compound 4 with or without isolation is treated with an amine in a suitable solvent at an appropriate temperature to afford compound 5.

In the same way, independent and selective modification of RI, R2, R3, R4, R5, R6, and R7 using methods known in the literature readily affords additional compounds of formula 1. Thus, compounds for which no separate preparation is provided herein are made by methods known in the literature or are of common knowledge to the skilled artisan.

The skilled artisan will recognize that some reactions are best carried out when another potentially reactive functionality on the molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often protecting groups are used to accomplish such increased yields or to avoid the undesired reactions. Such reactions are well within the ability of the skilled artisan. Some examples are found in T. Greene, Protecting Groups in Organic Synthesis.

In addition, it is to be appreciated that one optical isomer may have favorable properties over the other and thus the disclosure of a racemic mixture within the present invention may also include either optically active isomer if such isomer has advantageous physiological activity in accordance with the methods of the invention.

Example-A1<BR> <BR> 2-Chloro-3-methylamino-r 1, 4lnaphthoauinone

To a solution of 22.7g (100mol, 1equivalent) of 2, 3-dichloro- [1,4] naphthoquinone in 350 ml of anhydrous THF was added 200ml of 2. 0M methyl amine in THF (200mol, 2 equivalents). To the mixture was added 34 mi of N, N-diisopropylethylamine (200mmol, 2 equivalents) and it was shaken at room temperature for overnight (16-20 hours).

The red precipitates formed were filtered and washed with ether. The residue was again washed with water and ether. The solid was dried under vacuum. The filtrate was checked for the desired product, and then THF was evaporated. The residue was recrystallized with dichloromethane/ether. The titled compound was collected as a red solid (18g, Yield 74%).

In a process analogous to Example A1 using appropriate starting materials, the corresponding compounds are prepared as follows : Example Chemical Name A2 (3-Chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-ylamino)-acetic acid tert- butyl ester A3 2- (1-Benzyl-piperidin-4-ylamino)-3-chloro- [1, 4] naphthoquinone A4 2-(3-Chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-ylamino)-3-phenyl- propionic acid ter-butyl ester A5 2- (4-Acetyl-phenylamino)-3-chloro- [1, 4] naphthoquinone A6 2, 6-Dichloro-5, 8-dihydroxy-3- (3- 4- [3- (6-oxo-6H-2, 10b-diaza- aceanthrylen-5-ylamino)-propyl]-piperazin-1-yl}-propylamino) - [1,4] naphthoquinone A7 2-Chloro-3- (2-pyridin-4-yl-ethylamino)- [1, 4] naphthoquinone A8 2-Chloro-3- (3- {4- [3- (6-oxo-6H-2, 1 Ob-diaza-aceanthrylen-5-ylamino)- propyl]-piperazin-1-yl}-propylamino)- [1, 4] naphthoquinone A9 2-Chloro-3- (3-morpholin-4-yl-propylamino)- [1, 4] naphthoquinone A10 2-Chloro-3- (4-dimethylamino-benzylamino)- [1, 4] naphthoquinone A11 2-Chloro-3- (4-dimethylamino-phenylamino)- [1, 4] naphthoquinone A12 2-Chloro-3-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-[1, 4] naphthoquinone A13 2-Chloro-3-[2-(1, 2,2, 6, 6-pentamethyl-piperidin-4-yl)-ethylamino]- [1,4] naphthoquinone A14 2-Chloro-3- [3- (2-oxo-pyrrolidin-1-yl)-propylamino]- [1, 4] naphthoquinone A15 2-Chloro-3- [3- (methyl-phenyl-amino)-propylamino]- [1, 4] naphthoquinone A16 2-Chloro-3-{[(4-methyl-pyridin-2-yl)-phenyl-methyl]-amino}- [1,4] naphthoquinone A17 2-Chloro-3-phenylamino- [1, 4] naphthoquinone A18 2-Chloro-5, 8-dihydroxy-3- (3- {4- [3- (6-oxo-6H-2, 10b-diaza-aceanthrylen- 5-ylamino)-propyl]-piperazin-1-yl}-propylamino)-[1, 4] naphthoquinone A19 4- (3-Chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester

Example-B1 <BR> <BR> <BR> <BR> 2-Bromo-N-(3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-vl)-N-methyl- acetamide To a solution of 8g of 2-chloro-3-methylamino- [1, 4] naphthoquinone (36mmol) in 400 ml 1,4-dioxane was added 10g of potassium carbonate (72mmol). The mixture was heated until the starting material was completely dissolved. To the solution, 12. 5ml of bromoacetyl bromide (144mmol) was added and refluxed for 1 hour. Inorganic materials were filtered and washed thoroughly with dichloromethane. The filtrate was evaporated and the residue was purified by flash silica gel column using 75: 25- hexanes : ethyl acetate.

The compound was collected as yellow oil. (10g, Yield 80%).

In a process analogous to Example B1 using appropriate 2-chloro-3- substituted amino [1,4] naphthoquinone (Example A) and corresponding acid bromide following compounds are prepared.

2-Bromo-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-acetamide 2-Bromo-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N-methyl- acetamide 2-Bromo-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N-methyl- propionamide Example 1 (Compound 1, Table 1) 2-Dimethylamino-N-(3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N- methyl-acetamide

To a solution of 2.5g of 2-bromo-N- (3-chloro-1, 4-dioxo-1,4-dihydro- naphthalen-2-yl)-N-methyl-acetamide (7mmol, 1equivalent) in 200mi of ethyl acetate was added 28 ml of 2. 0M dimethylamine solution in tetrahydrofuran (56mmol, 8 equivalents). The amine solution was added in two portions stirring for 15 min after each addition. The solvent was then evaporated and then sample was purified on a silica gel column using initially ethyl acetate and then 10-20 % methanol in ethyl acetate. The solvent was evaporated and the residue was dissolved in DMSO. It was then purified further on preparative LCMS using 0. 1% NH40H in water/acetonitrile as mobile phase. (592mg, Yield 26%); H1 NMR (400MHz, CDCI3) 2.97 (s, 6H), 3.08 (s, 3H), 3.20 (s, 6H), 3.64 (s, 2H), 7.62 (m, 2H), 7.95 (t, 2H).

Compound 2-119 (Table 1) In a process analogous to Example 1 (Table 1) using appropriate chloro-bromo naphthoquinone (Example B) and the corresponding secondary amine, following compounds are prepared as shown in Table 1.

Example-C1 2-Chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N-methyl- acetamide

To a solution of 10g of 2-chloro-3-methylamino-[1, 4] naphthoquinone (45 mmol) in 250 mL of dioxane was added 172 mL of chloroacetyl chloride (48 equivalents). The reaction was heated at 85° C for 16 hours. The solvent was evaporated and the material was purified on silica gel using DCM and hexanes as solvents. The pure fractions were combined and the solvent was evaporated. The product was collected as a yellow/brown solid. (12.1g, Yield 90%).

In a process analogous to Example C1 using appropriate 2-chloro-3- substituted amino- [1, 4] naphthoquinone (Example A) and corresponding acid chloride following compounds are prepared. Example Chemical Name C2 2-Chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)- acetamide C3 2-Chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)- propionamide C4 2-Chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-2-phenyl- acetamide C5 2-Chloro-N-(3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N-methyl- propionamide C6 2-Chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N-methyl- 2-phenyl-acetamide

Example D1 2-Chloro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N- methyl-acetamide To a solution of 19g of 2-chloro-N- (3-chloro-1, 4-dioxo-1, 4-dihydro- naphthalen-2-yl)-N-methyl-acetamide (63 mmol) in 200 mL of ethyl acetate was added slowly 22 mL of N, N-diisopropylethylamine (2 equivalents). 70 mL of 2. 0M solution of dimethylamine in terahydrofuran (2.25 equivalents) was diluted with 100 mL of ethyl acetate. This amine solution was added slowly to the reaction mixture over one hour at room temperature. After stirring for an additional hour, the reaction was filtered and the solid material was washed with ethyl acetate. The filtrate was concentrated and purified using a normal phase column chromatography, and ethyl acetate and hexanes as solvents. The pure fractions were combined and the solvent was evaporated. The product was collected as a red solid. (10. 1 g, Yield-52%). H1 NMR (400MHz, CDC13) : 3.09 (s, 3H), 3.23 (s, 6H), 4.01 (q, 2H), 7.65-7. 77 (m, 2H), 8.03 (d, 1H), 8.08 (d, 1H).

In a process analogous to Example D1 using appropriate dichloro naphthoquinone derivatives (Example C) and corresponding secondary amine, the following compounds are prepared. Example Chemical Name D2 2-Chioro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)- acetamide D3 2-Chloro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)- propionamide D4 2-Chloro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-2- phenyl-acetamide D5 2-Chloro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N- methyl-propionamide D6 2-Chloro-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N- methyl-2-phenyl-acetamide

Example 2 (Compound 1, Table 2) 2-Diethylamino-N- (3-dimethylamino-1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-N- methyl-acetamide

To a solution of 0.54 g of 2-chloro-N- (3-dimethylamino-1, 4-dioxo-1,4- dihydro-naphthalen-2-yl)-N-methyl-acetamide (1.8 mmol) in 20 mL of ethyl acetate was added 2.2 mL of ethylamin (21. 6mmol, 12 equiv). The mixture was stirred at room temperature for two hours. The reaction mixture was then filtered and the solid was washed with ethyl acetate until all red material was dissolved. The red filtrate was concentrated and purified on a normal phase column chromatography using ethyl acetate. The pure fractions were combined and concentrated. The solid was then dissolved in 20mL of DCM and 12 equiv of 1. OM HCI in diethyl ether was added to produce hydrochloride salt. Organic solvents were evaporated and the product was dissolved in 5.0

mL of HPLC grade water. This material was freeze dried to give 0.42 g of final product as its hydrochloride salt. (Yield 62%). H1 NMR (400MHz, DMSO, D20) 1.14 (t, 6H), 2.97 (s, 3H), 3.08-3. 0 (m, 10H), 3.80 (d, 1H), 4.02 (d, 1H), 7.7-7. 9 (m, 2H), 7.89-8. 0 (m, 2H).

Compounds 2-119 (Table 2) In a process analogous to Example 2 using appropriate chloro naphthoquinone (Example D) and the corresponding secondary amine, compounds are prepared as shown in Table 2.

Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Gene No. Gene Identifier Gene Name 1 XM_011929 RTP801 2 NM 004864 prostate differentiation factor 3 NM 001657 amphiregulin (schwannoma-derived growth factor) 4 XM 033762 GRB10 5 NM 004083 DNA-damage-inducible transcript 3 6 XM 009097 PPP1 R15A 7 NM 005542 insulin induced gene 1 8 XM 032884 MGC11324 9 XM_052673 VEGF 10 NM 007235 exportin, tRNA (nuclear export receptor for tRNAs) 11 NM 000179 mutS homolog 6 (E. coli) 12 NM 005194 CCAAT/enhancer binding protein (C/EBP), beta 13 XM_043412 CDKN1A 14 NM004448 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma de 15 NM004526 MCM2 minichromosome maintenance deficient 2, mitotin (S. cerevisiae) 16 XM_035627 UHRF1 17 L24498 GADD45A 18 NM005915 MCM6 minichromosome maintenance deficient 6 (MIS5 homolog, S. pombe) (S. cerevis 19 NM 004642 CDK2-associated protein 1 20 NM 004629 Fanconi anemia, complementation group G 21 NM 022119 protease, serine, 22 22 XM 002003 STMN1 23 NM_014736 KIAA0101 gene product 24 NM 002691 polymerase (DNA directed), delta 1, catalytic subunit 125kDa 25 XM_034901 MSH2 26 XM 001284 MDM4 27 XM_018276 FLJ13782 28 NM 004707 APG12 autophagy 12-like (S. cerevisiae) 29 NM 004836 eukaryotic translation initiation factor 2-alpha kinase 3 30 XM_008618 CBX4 31 NM 003504 CDC45 cell division cycle 45-like (S. cerevisiae) 32 Xm_002242 HAT1 33 NM_014331 solute carrier family 7, (cationic amino acid transporter, y+ system) member 11 34 NM 003467 chemokine (C-X-C motif) receptor 4 35 XM 002899 CDC25A 36 NM 006349 putative cyclin G1 interacting protein 37 XM 056035 PCNA 38 XM_003511 EREG 39 XM_031515 RAD51 40 XM 017925 EIF4E 41 NM 001799 cyclin-dependent kinase 7 (MO15 homolog, Xenopus laevis, cdk- activating kinase) 42 NM 004990 methionine-tRNA synthetase 43 NM 057749 cyclin E2 44 NM_001540 heat shock 27kDa protein 1 45 NM005882 macrophage erythroblast attacher 46 XM 047059 SUV39H1 47 NM_006156 neural precursor cell expressed, developmentally down-regulated 8 48 NM_016395 butyrate-induced transcript 1 49 XM 012472 NPIP 50 NM_018518 MCM10 minichromosome maintenance deficient 10 (S. cerevisiae) 51 NM_000194 hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome) 52 NM002359 v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian) 53 XM_001589 DVL1 54 NM 003276 thymopoietin 55 XM 040103 DLC1 56 XM_010272 RBBP7 57 NM 001226 caspase 6, apoptosis-related cysteine protease 58 NM 013376 CDK4-binding protein p34SEI1 59 NM 001196 BH3 interacting domain death agonist 60 AF317391 BCL-6 interacting corepressor 61 NM_002435 mannose phosphate isomerase 62 NM_003503 CDC7 cell division cycle 7-like 1 (S. cerevisiae) 63 NM 001168 baculoviral IAP repeat-containing 5 (survivin) 64 XM_036462 ACLY 65 XM 009643 RBL1 66 NM 001424 epithelial membrane protein 2 67 AK057120 high-mobility group box 1 68 XM 051677 CDKN3 69 NM 001379 DNA (cytosine-5-)-methyltransferase 1 70 XM_001668 PDZK1 71 NM 001967 eukaryotic translation initiation factor 4A, isoform 2 72 XM_050297 XRCC3 73 NM 004428 ephrin-A1 74 AB037790 heme-regulated initiation factor 2-alpha kinase 75 NM 007306 breast cancer 1, early onset 76 NM004336 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) 77 NM031844 heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A) 78 XM 002943 POLQ 79 D21262 nucleolar and coiled-body phosphoprotein 1 80 XM_056165 YWHAH 81 NM 006609 mitogen-activated protein kinase kinase kinase 2 82 NM 013258 apoptosis-associated speck-like protein containing a CARD 83 NM 024602 hypothetical protein FLJ21156 84 NM 005080 X-box binding protein 1 85 NM 004050 BCL2-like 2 86 NM 014454 p53 regulated PA26 nuclear protein 87 W28438 chromosome 14 open reading frame 78 88 XM 008802 RBBP8 89 XM_053627 FGF4 90 NM 006727 cadherin 10, type 2 (T2-cadherin) 91 NM 005980 S100 calcium binding protein P 92 XM_050665 FH 93 NM 000432 myosin, light polypeptide 2, regulatory, cardiac, slow 94 D16815 nuclear receptor subfamily 1, group D, member 2 95 XM 044825 SUPT3H 96 NM 058179 phosphoserine aminotransferase 97 XM_018112 RBBP4 98 NM 020386 HRAS-like suppressor 99 AK057758 insulin receptor substrate 3-like 100 XM 044111 RIT1 101 NM 004313 arrestin, beta 2 102 L26584 Ras protein-specific guanine nucleotide-releasing factor 1 103 NM 005414 SKI-like 104 XM 031603 BUB1 B 105 XM_015963 SDFR1 106 NM002415 macrophage migration inhibitory factor (glycosylation-inhibiting factor) 107 NM 078487 cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) 108 XM 047707 KIAA1265 109 NM 001065 tumor necrosis factor receptor superfamily, member 1A 110 XM 045104 LGALS3BP 111 AI053741 Homo sapiens, clone IMAGE : 4826963, mRNA 112 NM 003600 serine/threonine kinase 6 113 NM 012112 chromosome 20 open reading frame 1 114 NM_000387 solute carrier family 25 (carnitine/acylcarnitine translocase), member 20 115 NM005587 MADS box transcription enhancer factor 2, polypeptide A (myocyte enhancer factor 116 NM 001892 casein kinase 1, alpha 1 117 NM 016277 RAB23, member RAS oncogene family 118 NM 003094 small nuclear ribonucleoprotein polypeptide E 119 NM 006623 phosphoglycerate dehydrogenase 120 NM 005441 chromatin assembly factor 1, subunit B (p60) 121 NM 002659 plasminogen activator, urokinase receptor 122 NM 000057 Bloom syndrome 123 NM 001202 bone morphogenetic protein 4 124 NM 003289 tropomyosin 2 (beta) 125 XM 003325 CCNA2 126 XM 032813 HUMGT198A 127 NM 006403 enhancer of filamentation 1 128 NM 006289 talin 1 129 NM003405 tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein, eta poly 130 NM 000368 tuberous sclerosis 1 131 BC008826 PAX3 132 NM 003908 eukaryotic translation initiation factor 2, subunit 2 beta, 38kDa 133 NM 004282 BCL2-associated athanogene 2 134 XM 010777 ICAP-1A 135 XM_034350 ANXA3 136 NM 004965 high-mobility group nucleosome binding domain 1 137 NM 001216 carbonic anhydrase IX 138 NM 006325 RAN, member RAS oncogene family 139 NM_006516 solute carrier family 2 (facilitated glucose transporter), member 1 140 NM003657 breast carcinoma amplified sequence 1 141 NM 004417 dual specificity phosphatase 1 142 M94362 LMNB2 143 XM 057994 SDHA 144 XM 043451 PIM1 145 NM 021005 nuclear receptor subfamily 2, group F, member 2 146 XM049928 CARD14 147 AA017553 ESTs 148 NM 004905 antioxidant protein 2 149 NM 001274 CHK1 checkpoint homolog (S. pombe) 150 NM002483 carcinoembryonic antigen-related cell adhesion molecule 6 (non- specific cross re 151 XM 045049 TNFSF10 152 XM 007770 FLJ20171 153 NM 015926 putative secreted protein ZSIG11 154 NM 005348 heat shock 90kDa protein 1, alpha 155 NM 003567 breast cancer anti-estrogen resistance 3 156 NM 002507 nerve growth factor receptor (TNFR superfamiiy, member 16) 157 XM 029216 APEX2 158 NM 005654 nuclear receptor subfamily 2, group F, member 1 159 XM 009873 MMP11 160 NM 002105 H2A histone family, member X 161 NM 001827 CDC28 protein kinase regulatory subunit 2 162 XM 050486 NOC4 163 XM_015513 SNRPG 164 AB037759 eukaryotic translation initiation factor 2 alpha kinase 4 165 NM000122 excision repair cross-complementing rodent repair deficiency, complementation gr 166 NM 006218 phosphoinositide-3-kinase, catalytic, alpha polypeptide 167 NM 003127 spectrin, alpha, non-erythrocytic 1 (alpha-fodrin) 168 NM 031265 mucin and cadherin-like 169 NM 016531 Kruppel-like factor 3 (basic) 170 NM 002629 phosphoglycerate mutase 1 (brain) 171 NM 003152 signal transducer and activator of transcription 5A 172 NM 002037 FYN oncogene related to SRC, FGR, YES 173 NM 002607 platelet-derived growth factor alpha polypeptide 174 XM 003560 MAD2L1 175 NM 052888 KIAA0563-related gene 176 NM 001348 death-associated protein kinase 3 177 NM 003883 histone deacetylase 3 178 NM 001659 ADP-ribosylation factor 3 179 NM 033379 CDC2 180 XM 031718 EHD4 181 NM 014977 apoptotic chromatin condensation inducer in the nucleus 182 NM 006570 Ras-related GTP-binding protein 183 NM 002466 v-myb myeloblastosis viral oncogene homolog (avian)-like 2 184 NM 001949 E2F transcription factor 3 185 XM 018149 SELT 186 NM 013277 Rac GTPase activating protein 1 187 NM 014060 MCT-1 protein 188 NM 003684 MAP kinase-interacting serine/threonine kinase 1 189 NM 031966 cyclin B1 190 XM 012601 MNT 191 NM 005657 tumor protein p53 binding protein, 1 192 XM 051583 RAF1 193 NM_001255 CDC20 cell division cycle 20 homolog (S. cerevisiae) 194 NM_030808 LIS1-interacting protein NUDEL; endooligopeptidase A 195 NM 032989 BCL2-antagonist of cell death 196 XM 011577 STK17A 197 NM 003925 methyl-CpG binding domain protein 4 198 NM_016587 chromobox homolog 3 (HP1 gamma homolog, Drosophila) 199 NM 006870 destrin (actin depolymerizing factor) 200 XM 008313 LOC146870 201 NM 006812 amplified in osteosarcoma 202 NM003183 a disintegrin and metalloproteinase domain 17 (tumor necrosis factor, alpha, con 203 XM 052798 CDC25C 204 NM 002626 phosphofructokinase, liver 205 NM033292 caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase) 206 XM_006961 CHD4 207 NM 000269 non-metastatic cells 1, protein (NM23A) expressed in 208 NM 004873 BCL2-associated athanogene 5 209 NM 001034 ribonucleotide reductase M2 polypeptide 210 NM_003070 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subf 211 NM 006595 apoptosis inhibitor 5 212 XM_040402 CPNE3 213 NM 007111 transcription factor Dp-1 214 NM 003597 TGFB inducible early growth response 2 215 NM 002741 protein kinase C-like 1 216 NM 021138 TNF receptor-associated factor 2 217 XM_054954 CCNF 218 NM 003879 CASP8 and FADD-like apoptosis regulator 219 NM 002089 chemokine (C-X-C motif) ligand 2 220 BC018118 Rho GTPase activating protein 1 221 XM 007070 TBC1 D4 222 NM 032094 protocadherin gamma subfamily A, 12 223 NM 003472 DEK oncogene (DNA binding) 224 XM036063 LOC204666 225 XM_006197 E21G4 226 NM 002198 interferon regulatory factor 1 227 NM003639 inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma 228 XM 010826 LOC150584 229 NM 006393 nebulette 230 NM 020436 sal-like 4 (Drosophila) 231 XM_038427 FES 232 NM032984 caspase 2, apoptosis-related cysteine protease (neural precursor cell expressed, 233 NM 002093 glycogen synthase kinase 3 beta 234 XM_043782 E2F4 235 XM_058230 JUND 236 XM 071388 PPFIA2 237 XM_056931 B3GNT1 238 NM 002357 MAX dimerization protein 1 239 NM 024320 hypothetical protein MGC11242 240 NM 006763 BTG family, member 2 241 NM 000244 multiple endocrine neoplasia 1 242 XM 017741 FSCN1 243 W02608 ESTs, Weakly similar to hypothetical protein FLJ20378 [Homo sapiens] [H. sapiens 244 XM 044910 SNRPB 245 NM 033339 caspase 7, apoptosis-related cysteine protease 246 NM001712 carcinoembryonic antigen-related cell adhesion molecule 1 (biliary . g1ycoprotein) 247 NM_031993 protocadherin gamma subfamily A, 1 248 NM002616 period homolog 1 (Drosophila) 249 XM 001357 MYCBP 250 NM 031295 Williams Beuren syndrome chromosome region 21 251 NM_001110 a disintegrin and metalloproteinase domain 10 252 NM 004359 cell division cycle 34 253 NM003667 G protein-coupled receptor 49 254 XM027651 TNFRSF10B 255 NM 012165 F-box and WD-40 domain protein 3 256 XM 009475 AHCY 257 XM_035145 LXN 258 NM 000365 TP11 259 NM 003994 KIT ligand 260 NM_004341 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase 261 XM 039754 RAB10 262 AF346509 NFAT5 263 XM 071453 YWHAE 264 NM 006701 similar to S. pombe dim1+ 265 NM 024854 hypothetical protein FLJ22028 266 NM 004964 histone deacetylase 1 267 NM 007194 CHK2 checkpoint homolog (S. pombe) 268 NM 007168 ATP-binding cassette, sub-family A (ABC1), member 8 269 XM_033064 ST5 270 NM_003841 tumor necrosis factor receptor superfamily, member 10c, decoy without an intrace 271 XM_031287 CXCL3 272 NM 003535 H3FJ 273 U82467 tubby homolog (mouse) 274 XM 017134 BRCA2 275 NM 014784 Rho guanine nucleotide exchange factor (GEF) 11 276 NM 005438 FOS-like antigen 1 277 NM 006107 acid-inducible phosphoprotein 278 NM_012323 v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (avian) 279 XM 002116 SFN 280 NM 006286 transcription factor Dp-2 (E2F dimerization partner 2) 281 XM_046643 NXT1 282 AA406526 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 2344436. 283 NM 020637 fibroblast growth factor 22 284 NM 005375 v-myb myeloblastosis viral oncogene homolog (avian) 285 NM012466 tetraspaninTM4-B 286 XM 002636 IGFBP2 287 AB037845 Rho-GTPase activating protein 10 288 NM 005983 S-phase kinase-associated protein 2 (p45) 289 AF308602 Notch homolog 1, translocation-associated (Drosophila) 290 NM 014318 apoptosis related protein 291 NM_000207 insulin 292 XM_043799 MPZL1 293 XM 010208 PIM2 294 XM 045613 EHD1 295 NM 018948 Gene 33/Mig-6 296 XM 015547 LATS1 297 NM 014248 ring-box 1 298 NM 003558 phosphatidylinositol-4-phosphate 5-kinase, type 1, beta 299 XM 033878 TIMP1 300 NM 007315 signal transducer and activator of transcription 1,91 kDa 301 NM 000679 adrenergic, alpha-1 B-, receptor 302 XM 036588 SDCCAG33 303 NM 004078 cysteine and glycine-rich protein 1 304 XM_050512 ACVR1 305 XM 028205 GLP1 R 306 XM 071498 E2F6 307 AA100736 hypothetical protein DKFZp434D0215 308 NM_005253 FOS-like antigen 2 309 XM 041335 SCAP2 310 AF110908 TNF receptor-associated factor 3 311 XM 058227 ZK1 312 XM_049776 DSCAM 313 XM_045802 PXN 314 XM 058125 UBF-fl 315 NM 005385 natural killer-tumor recognition sequence 316 NM 002745 mitogen-activated protein kinase 1 317 XM 031413 TIAF1 318 NM020249 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin typ 319 XM_046179 ID1 320 XM 007245 YY1 321 AI972873 SH3 domain binding glutamic acid-rich protein like 2 322 XM047494 UGDH 323 NM 022161 baculoviral IAP repeat-containing 7 (livin) 324 NM 004493 hydroxyacyl-Coenzyme A dehydrogenase, type 11 325 XM 009915 LIF 326 BF343776 glutathione reductase 327 NM004725 BUB3 budding uninhibited by benzimidazoles 3 homolog (yeast) 328 XM 008855 NR2F6 329 NM 018640 neuronal specific transcription factor DAT1 330 XM 013050 BIRC4 331 XM_003222 CTNNB1 332 NM 016316 REV1-like (yeast) 333 NM 012098 angiopoietin-like 2 334 XM 058285 CD24 335 NM 004040 ras homolog gene family, member B 336 XM_043785 NOL3 337 NM_032471 protein kinase (cAMP-dependent, catalytic) inhibitor beta 338 NM 022873 interferon, alpha-inducible protein (clone IFI-6-16) 339 XM 035114 KIAA1277 340 XM_007722 CHD2 341 NM 006054 reticulon 3 342 XM 054920 KIAA0828 343 NM 001895 casein kinase 2, alpha 1 polypeptide 344 NM 032365 PR02000 345 XM 010040 ARHGAP8 346 NM_005419 signal transducer and activator of transcription 2, 113kDa 347 NM 003299 tumor rejection antigen (gp96) 1 348 XM 042423 EMP1 349 AF207547 LATS, large tumor suppressor, homolog 2 (Drosophila) 350 NM 002878 RAD51-like 3 (S. cerevisiae) 351 XM 010914 PCAF 352 XM_038418 PRC1 353 Z18817 heat shock 70kDa protein 4 354 U70451 myeloid differentiation primary response gene (88) 355 NM 002957 retinoid X receptor, alpha 356 XM_046041 CCT2 357 XM 028620 HOXC9 358 XM_012894 ZNF14 359 NM 021979 heat shock 70kDa protein 2 360 NM 005163 v-akt murine thymoma viral oncogene homolog 1 361 XM_006299 API5 362 NM 001388 developmentally regulated GTP binding protein 2 363 NM 004992 methyl CpG binding protein 2 (Rett syndrome) 364 XM_016845 HHGP 365 AK054731 tubulin, alpha 1 (testis specific) 366 XM 003628 CCNG2 367 NM 000291 phosphoglycerate kinase 1 368 XM044653 EGFR 369 XM 046245 PIG8 370 NM 007229 protein kinase C and casein kinase substrate in neurons 2 371 NM 033637 beta-transducin repeat containing 372 XM 033862 ELK1 373 NM000638 vitronectin (serum spreading factor, somatomedin B, complement S-protein) 374 NM 018098 epithelial cell transforming sequence 2 oncogene 375 NM 001880 activating transcription factor 2 376 NM 003122 serine protease inhibitor, Kazal type 1 377 XM 008055 COX411 378 XM 046881 SLC9A1 379 NM 003860 barrier to autointegration factor 1 380 XM 003029 ITGB5 381 NM 005566 lactate dehydrogenase A 382 NM 019113 fibroblast growth factor 21 383 XM 030478 SVIL 384 NM 006167 NK3 transcription factor related, locus 1 (Drosophila) 385 NM007324 MAD, mothers against decapentaplegic homolog (Drosophila) interacting protein, r 386 NM 002342 lymphotoxin beta receptor (TNFR superfamily, member 3) 387 NM002909 regenerating islet-derived 1 alpha (pancreatic stone protein, pancreatic thread 388 XM 041552 RAD17 389 NM 030662 mitogen-activated protein kinase kinase 2 390 NM 022333 TIA1 cytotoxic granule-associated RNA binding protein-like 1 391 XM 037682 SMARCB1 392 XM_033932 FLJ20485 393 BC002513 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa 394 NM 003470 ubiquitin specific protease 7 (herpes virus-associated) 395 NM 001320 casein kinase 2, beta polypeptide 396 AA527919 Homo sapiens, clone IMAGE : 5285034, mRNA 397 NM 005167 hypothetical protein MGC19531 398 XM_045642 SF1 399 XM 029816 YWHAB 400 NM 006121 keratin 1 (epidermolytic hyperkeratosis) 401 NM 004843 class I cytokine receptor 402 NM 000450 selectin E (endothelial adhesion molecule 1) 403 NM 013374 programmed cell death 6 interacting protein 404 AK024858 hypothetical protein LOC221496 405 XM 006890 ELK3 406 NM 022870 myosin, heavy polypeptide 11, smooth muscle 407 XM 033910 TCP1 408 XM_030523 MAP3K8 409 NM 003821 receptor-interacting serine-threonine kinase 2 410 XM_002633 MYCN 411 NM 002087 granulin 412 NM 007019 ubiquitin-conjugating enzyme E2C 413 Al685200 DKFZP586G1517 protein 414 XM_009203 AKT2 415 NM 013986 Ewing sarcoma breakpoint region 1 416 NM 004208 programmed cell death 8 (apoptosis-inducing factor) 417 XM 011791 LAMC3 418 NM 022746 hypothetical protein FLJ22390 419 AL042759 NADPH oxidase organizer 1 420 NM 003808 tumor necrosis factor (ligand) superfamily, member 13 421 XM 002562 VAMP5 422 NM 005923 mitogen-activated protein kinase kinase kinase 5 423 NM 001315 mitogen-activated protein kinase 14 424 NM 007022 putative tumor suppressor 101 F6 425 XM_047007 PLAGL2 426 NM 005556 keratin 7 427 NM000454 superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) 428 AI8862326 hypothetical protein FLJ21195 similar to protein related to DAC and cerberus 429 NM 005917 malate dehydrogenase 1, NAD (soluble) 430 NM 002835 protein tyrosine phosphatase, non-receptor type 12 431 NM 005972 pancreatic polypeptide receptor 1 432 NM 016328 GTF21 repeat domain containing 1 433 NM 000860 hydroxyprostaglandin dehydrogenase 15- (NAD) 434 NM 003882 WNT1 inducible signaling pathway protein 1 435 XM 028817 ADCY6 436 NM_000955 prostaglandin E receptor 1 (subtype EP1), 42kDa 437 X68560 Sp3 transcription factor 438 NM 006443 putative c-Myc-responsive 439 NM 001090 ATP-binding cassette, sub-family F (GCN20), member 1 440 NM 002827 protein tyrosine phosphatase, non-receptor type 1 441 XM 034007 BCAR1 442 NM 005901 MAD, mothers against decapentaplegic homolog 2 (Drosophila) 443 NM 001963 epidermal growth factor (beta-urogastrone) 444 BM044930 neuronal guanine nucleotide exchange factor 445 NM 004701 cyclin B2 446 XM 002375 IL1 F8 447 NM001945 diphtheria toxin receptor (heparin-binding epidermal growth factor- like growth f 448 NM 000230 leptin (obesity homolog, mouse) 449 NM 001903 catenin (cadherin-associated protein), alpha 1,102kDa 450 NM 002220 inositol 1,4, 5-trisphosphate 3-kinase A 451 NM 020384 claudin 2 452 NM002734 protein kinase, cAMP-dependent, regulatory, type 1, alpha (tissue specific extin 453 NM 020243 translocase of outer mitochondrial membrane 22 homolog (yeast) 454 NM 004380 CREB binding protein (Rubinstein-Taybi syndrome) 455 XM 044659 CSK 456 NM 002875 RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae) 457 XM 033428 AK1 458 NM 005745 accessory protein BAP31 459 NM 030753 wingless-type MMTV integration site family, member 3 460 XM 034587 FLJ22174 461 NM 004920 AATK 462 NM 007065 CDC37 cell division cycle 37 homolog (S. cerevisiae) 463 NM 001239 cyclin H 464 XM 036323 TSG101 465 NM 001233 caveolin 2 466 XM_015956 CTBP2 467 XM_015505 AXL 468 NM 003749 insulin receptor substrate 2 469 XM_016033 DPF3 470 NM004889 ATP synthase, H+ transporting, mitochondrial FO complex, subunit f, isoform 2 471 XM_003213 NS 472 XM_033761 COBL 473 XM 047049 E2F1 474 NM 006572 guanine nucleotide binding protein (G protein), alpha 13 475 NM 006024 Tax1 (human T-cell leukemia virus type 1) binding protein 1 476 NM 016245 retinal short-chain dehydrogenase/reductase 2 477 XM_010339 GPC4 478 NM 002129 high-mobility group box 2 479 NM_006565 CCCTC-binding factor (zinc finger protein) 480 AL137667 MAPK8 481 XM 050236 LENG4 482 NM 005805 26S proteasome-associated pad1 homolog 483 XM_054928 CLN8 484 NM001350 death-associated protein 6 485 NM_016073 likely ortholog of mouse hepatoma-derived growth factor, related protein 3 486 XM 031926 NFKB2 487 NM 005085 nucleoporin 214kDa 488 NM 003904 zinc finger protein 259 489 NM 014397 NIMA (never in mitosis gene related kinase 6 490 XM 017096 ABR 491 XM_003477 FAT 492 NM001982 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) 493 NM_006705 growth arrest and DNA-damage-inducible, gamma 494 NM 004958 FK506 binding protein 12-rapamycin associated protein 1 495 XM_004713 FLNC 496 NM 021235 epidermal growth factor receptor substrate EPS15R 497 XM 030044 CSE1 L 498 Api685466 LOC90353 499 NM 003311 tumor suppressing subtransferable candidate 3 500 XM 039984 CNOT8 501 XM_001831 CYR61 502 XM 052827 CFL2 503 XM_007487 ASB2 504 XM 003405 HD 505 XM012723 C18orf1 506 NM 005564 lipocalin 2 (oncogene 24p3) 507 XM_010767 NCKAP1 508 NM 001324 cleavage stimulation factor, 3'pre-RNA, subunit 1,50kDa 509 NM 005658 TNF receptor-associated factor 1 510 NM_000168 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome) 511 XM 027639 DKFZP434J214 512 XM 033445 SLC7A7 513 NM 000852 glutathione S-transferase pi 514 NM 002097 general transcription factor IIIA 515 NM003243 transforming growth factor, beta receptor III (betaglycan, 300kDa) 516 XM_003444 FGF5 517 XM 035107 BRAF 518 D55886 adenylate cyclase 5 519 NM 005633 son of sevenless homolog 1 (Drosophila) 520 Al161049 voltage-dependent calcium channel gamma subunit-like protein 521 XM 045460 CDC25B 522 AA634799 Homo sapiens cDNA : FLJ22864 fis, clone KAT02164. 523 NM_004230 endothelial differentiation, sphingolipid G-protein-coupled receptor, 5 524 XM 040912 AMN 525 XM_056595 OTOF 526 XM 054160 VMD2 527 XM_049935 CTEN 528 NM 006365 transcriptional activator of the c-fos promoter 529 XM_027186 WNT2 530 NM 001067 topoisomerase (DNA) II alpha 170kDa 531 XM044785 KCNJ13 532 XM 007585 TJP1 533 XM 042940 UNC5C 534 XM_037408 BAP1 535 XM_005428 1-Dec 536 NM 014452 tumor necrosis factor receptor superfamily, member 21 537 NM 006645 serologically defined colon cancer antigen 28 538 XM_031972 CNNM2 539 XM 047561 ARHA 540 XM 046191 CGI-31 541 NM 003778 UDP-Gal : betaGIcNAc beta 1, 4- galactosyltransferase, polypeptide 4 542 XM 011713 COPS5 543 NM 032957 tumor necrosis factor receptor superfamily, member 6b, decoy 544 NM 006044 histone deacetylase 6 545 NM 021144 PC4 and SFRS1 interacting protein 1 546 AA531287 ESTs 547 XM_033355 ABL1 548 XM_008394 EZH1 549 XM 036570 TNFRSF12A 550 XM 031209 IL1 F9 551 XM_027311 BFAR 552 NM 006166 nuclear transcription factor Y, beta 553 XM 043103 HSD11 B2 554 XM 050735 ST14 555 NM 057159 endothelial differentiation, lysophosphatidic acid G-protein- coupled receptor, 2 556 NM 001702 brain-specific angiogenesis inhibitor 1 557 NM005312 guanine nucleotide-releasing factor 2 (specific for crk proto- oncogene) 558 NM 001042 solute carrier family 2 (facilitated glucose transporter), member 4 559 L41944 interferon (alpha, beta and omega) receptor 2 560 NM 000264 patched homolog (Drosophila) 561 XM 041744 IER3 562 NM 005967 NGFI-A binding protein 2 (EGR1 binding protein 2) 563 XM_009170 CEACAM7 564 NM 004231 ATPase, H+ transporting, lysosomal 14kDa, V1 subunit F 565 NM 004315 N-acylsphingosine amidohydrolase (acid ceramidase) 1 566 XM_008654 MAP2K4 567 XM 041847 TNF 568 XM 040448 RAD1 569 XM011068 MST1R 570 NM 000662 N-acetyltransferase 1 (arylamine N-acetyltransferase) 571 XM 001744 TNFRSF8 572 XM_028038 BMPR2 573 NM 006534 nuclear receptor coactivator 3 574 NM 005091 peptidoglycan recognition protein 575 NM 024426 Wilms tumor 1 576 AA290601 hypothetical protein LOC137075 577 AI810669 ESTs, Moderately similar to hypothetical protein FLJ20378 [Homo sapiens] [H. sap 578 NM 003550 MAD1 mitotic arrest deficient-like 1 (yeast) 579 NM 012415 RAD54B homolog 580 XM_033469 TGFBR2 581 XM 039779 CAPRI 582 XM 049512 TRIP13 583 NM 002969 mitogen-activated protein kinase 12 584 NM 005380 neuroblastoma, suppression of tumorigenicity 1 585 XM 029490 DPH2L1 586 AL136835 Toll-interacting protein 587 XM 034567 CCND2 588 NM032192 protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regu 589 NM000072 CD36 antigen (collagen type I receptor, thrombospondin receptor)