Field of the invention

The present invention relates to new 8-substituted and 6,8-disubstituted 2 -deoxyguano- sines and precursors for preparing these as well as methods for preparing said compounds and precursors. Moreover, the present invention is directed to the use of one or more of these compounds for preparing a medicament, preferably a medicament for the treatment and/or prevention of cancer, infections, autoimmune diseases, cardiovascular diseases, inherited genetic diseases, skin diseases and primary immunodeficiency diseases. In addition, the present invention concerns a pharmaceutical or diagnostic composition comprising the new 8-substituted and 6,8- disubstituted 2 -deoxyguanosines as well as diagnostic and medical methods involving these.

Background of the invention

Nucleoside derivatives and analogues are a family of biologically active compounds that can be used to treat viral infections, bacterial infections, parasites and cancer. Nucleoside derivatives that closely mimic the natural metabolites can act as enzyme inhibitors and can disrupt the function of undesired RNA and DNA activities during cycles of viral, parasitic, bacterial and/or cancer cell replication and respiration. Nucleoside drugs used to treat hemic malignancies and solid tumours include cytosine arabinoside, fludarabine, cladribine and gemcitabine. Common nucleoside drugs used to treat viral infections include penciclovir, stavudine, acyclovir, ganciclovir and famciclovir. These compounds share some general common characteristics in terms of their transport by means of specific membrane transporters, metabolism and interaction with intracellular targets, and, in particular, their incorporation into nucleic acids such as RNA and DNA. Nucleoside analogues and their derivatives can also inhibit the enzymes involved in the biosynthesis of nucleotides and can activate the caspase cascade leading to cell death.

The lack of efficient, economical and robust synthetic methods for preparing new nucleoside analogues is a limiting factor in the development of new drug candidates,

i CONFlRMATiON COPY especially for the development of biologically active guanosine analogues and derivatives.

Relevant patents in the area of nucleoside synthesis and use are, for example, US Patent No. 5,726,174 (Nucleoside analogues), US Patent No. 6,306,899 (Inhibition and treatment of Hepatitis B virus and Flavivirus by Helioxanthin and its analogs), US Patent No. 7,405,204 (Nucleoside compounds for treating viral infections) as well as US Patent No. 6,436,945 (Substituted O6-benzyl-8-aza-guanines).

It is the object underlying the present invention to provide new deoxyguanosine compounds having medical use, in particular for treating and/or preventing infections, cancer, autoimmune diseases, cardiovascular diseases, inherited genetic disorders, skin disorders or primary immunodeficiency diseases. It is a further object of the present invention to provide new deoxyguanosine compounds for use as fluorescent probes, diagnostic agents and chemosensors. Moreover, it is desired to provide a new method and new precursors for the preparation of 8- and 6,8-substituted deoxyguanosines. Last but not least, it is desired to provide diagnostic and medical uses for the above compounds as well as pharmaceutical and diagnostic compositions comprising said compounds.

Description of the invention

In a first aspect, the above objects are solved by new compounds of formula (I):

wherein R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle, R2 denotes independently of one another H, hydroxy I, thiol, seleno, azido, amino or a monovalent straight chain or cyclic radical ether (-OR1), thioether (-SR1), sulfate, phosphate, diphosphate, triphosphate, phosphate diester (-OPO ₃ RI), phosphate triester (-OPO ₃ (RI) ₂ ) or cyclic derivatives thereof, and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases.

In a second aspect, the above objects are solved by new compounds of formula (II):

wherein

R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle, R2 denotes independently of one another H, hydroxy I, thiol, seleno, azido, amino or a monovalent straight chain or cyclic radical ether (-OR1), thioether (-SR1), sulfate, phosphate, diphosphate, triphosphate, phosphate diester (-OPO ₃ RI), phosphate triester (-OPO ₃ (RI) ₂ ) or cyclic derivatives thereof, R3 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (-Si(RI) ₃ ) or alkylsilyl group, and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases

In another aspect, the present invention relates to precursors for preparing 8-substituted and 6,8-disubstituted 2 -deoxyguanosines containing at least a protecting group R3 at position 06 and an activating group R4 in the δ-position. Preferably, precursors of the invention may comprise additional protecting groups in the R5 and R6 position shown below.

Preferably, the precursors are compounds of formula (III)

(Hl), wherein R3 denotes a protecting group, preferably a linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (- Si(RI) ₃ ) or alkylsilyl group, R4 denotes an activating group, preferably a halogen, ethynyl, boronic acid, boronic acid ester (-B(ORI) ₂ ), stannane (-Sn(RI) ₃ ), triflate, sulfonate (-OSO ₂ RI) or phosphate triester (-OPO ₃ (RI) ₂ ), R5 denotes an amine or a protecting group, preferably an amide (-NHC(O)-RI), carbamate (-NHC(O)-ORI), thiocarbamate (-NHC(O)-SRI), urea (-NHC(O)-NHRI), thiourea (-NHC(S)-NHRI) or sulphonamide (-NHS(O ₂ )-R1), R6 denotes a protecting group, preferably a linear or branched silyl (-Si(RI) ₃ ), alkylsilyl, ester (-C(O)-RI), carbamate (C(O)-NHRI), sulfonyl (- SO ₂ RI) or triflate, and wherein R1 denotes a linear or branched, substituted or non- substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle, and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases.

Precursor compounds of formula (III) can be chemically transformed into preferred precursor compounds of formula (IV):

(IV), wherein R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle. R3 denotes a protecting group, preferably a linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (-Si(RI) ₃ ) or alkylsilyl group, R5 denotes an amine or a protecting group, preferably an amide (-NHC(O)-RI), cabamate (-NHC(O)- 0R1), thiocarbamate (-NHC(O)-SRI), urea (-NHC(O)-NHRI), thiourea (-NHC(S)-NHRI) or sulphonamide (-NHS(O ₂ )-R1), R6 denotes a protecting group, preferably a linear or branched silyl (-Si(RI) ₃ ), alkylsilyl, ester (-C(O)-RI), carbamate (C(O)-NHRI), sulfonyl (- SO ₂ RI), or triflate (-SO ₂ CF ₃ ), and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases.

It is noted that when there is more than one R1 group in a substituent such as, e.g. in the above mentioned phosphate triester (-OPO ₃ (RI) ₂ ) or silyl (-Si(RI) ₃ ) groups, that each R1 is selected independently of one another from the above definitions.

In a most preferred embodiment the compound according to the invention is selected from the group consisting of 8-bromo-3 ^l ,5'-O-bis(te/t-butyldimethylsilyl)-2'-deoxy- guanosine (3), 8-bromo-3',5'-O-bis(terf-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (4), 8-(2-pyridyl)-3',5 ^I -O-bis(fert-butyldimethylsilyl)-O ⁶ -benzyl-2 ¹ -deoxyguanosine (5), 8- (3-pyridyl)-3',5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ -benzyl-2 ¹ -deoxyguanosine (6), 8-(4- pyridyl)-3',5 ^l -O-bis(teAt-butyldimethylsilyl)-O ⁶ -benzyl-2 ¹ -deoxyguanosine (7), 8-(2-pyridyl)- O ⁶ -benzyl-2'-deoxyguanosine (8), 8-(3-pyridyl)-O ⁶ -benzyl-2'-deoxyguanosine (9), and 8- (4-pyridyl)-3',5'-O ⁶ -benzyl-2'-deoxyguanosine (10), 8-bromo-3',5'-O-bis(fe/f- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (11), 8-(2-pyridyl)- 3',5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2 ^l -deoxyguanosine (12), 8-(3-pyridyl)-3 ¹ ,5'-O-bis(fert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2 ^I - deoxyguanosine (13), 8-(4-pyridyl)-3\5'-O-bis(terf-butyldimethylsilyl)-O ⁶ -(trimethylsilyl- ethylether)-2'-deoxyguanosine (14), 8-(2-furyl)-3',5'-O-bis(ferf-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (15), 8-(2-thiophenyl)-3',5'-O-bis(te/t- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (16), 8-(2-(phenyl-2- yl)vinyl)-3',5'-O-bis(ter/-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (17), 8-(2-pyridyl)-2'-deoxyguanosine (18), 8-(3-pyridyl)-2'-deoxyguanosine (19), 8-(4- pyridyl)-2'-deoxyguanosine (20) 8-(2-furyl)-2'-deoxyguanosine (21), and 8-(2-thiophyl)- 2'-deoxyguanosine (22), 8-(tributylstannanyl)-3 ^l ,5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (23), 8-(6-indolyl)-3',5'-O-bis(te/f- butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (24), 8-(6-indolyl)-2'- deoxyguanosine (25), 8-(trimethylsilyl-alkynyl)-3 ^I ,5'-O-bis(terf-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (26), 8-(alkynyl)-3',5'-O-bis(teAt- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (27), 8-(1-methyl-4- trizyl)-3',5'-O-bis(fe/f-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (28), 8-(1-methyl-4-trizyl)-2'-deoxyguanosine (29), 8-(boronic acid pinacol ester)-3',5'-O- bis(fe/t-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (30), 8-(3- thiophyl)-3',5 ^I -O-bis(teAf-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (31) and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases. The numbers in parenthesis refer to the corresponding chemical structures in the figures below.

Definitions

In the context of the present invention it is understood that antecedent terms such as linear or branched, substituted or non-substituted indicate that each one of the subsequent terms is to be interpreted as being modified by said antecedent term. For example, the scope of the term "linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, carbocycle" encompasses linear or branched, substituted or non-substituted alkyl; linear or branched, substituted or non-substituted alkenyl; linear or branched, substituted or non-substituted alkynyl; linear or branched, substituted or non- substituted alkylidene; and linear or branched, substituted or non-substituted carbocycle. For example, the term "C ₂ -C ₁₂ alkenyl, alkynyl or alkylidene" indicates the group of compounds having 2 to 12 carbons and alkenyl, alkynyl or alkylidene functionality. In all compounds disclosed herein, in the event that the nomenclature conflicts with the structure, it shall be understood that the compound is defined by the structure. The term "heteroatom", as used herein, shall be understood to mean atoms other than carbon and hydrogen such as and preferably O, N, S and P.

The terms alkyl, alkenyl, alkynyl, alkylidene, etc. shall be understood as encompassing linear as well as branched forms of carbon-containing chains where structurally possible. In these carbon chains one or more carbon atoms can be optionally replaced by heteroatoms, preferably by O ₁ S or N. If N is not substituted it is NH. The heteroatoms may replace either terminal or internal carbon atoms within a linear or branched carbon chain. Such groups can be substituted as herein described by groups such as oxo to result in definitions such as but not limited to alkoxycarbonyl, aery I, amido and thioxo.

The term "carbocycle" shall be understood to mean an aliphatic hydrocarbon radical containing from 3 to 20, preferably 3 to 12 carbon atoms, more preferably 5 or 6 carbon atoms. Carbocylces include hydrocarbon rings containing from 3 to 20, preferably 3 to 10 carbon atoms. These carbocycles may be either aromatic or non-aromatic systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl, and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably. The term "cycloalkyl" shall be understood to mean aliphatic hydrocarbon-containing rings having from 3 to 20, preferably 3 to 12 carbon atoms. These non-aromatic ring systems may be mono- or polyunsaturated, i.e. the term encompasses cycloalkenyl and cycloalkynyl. The cycloalkyl may comprise heteroatoms, preferably O, S or N, and be substituted or non-substituted. Preferred and non-limiting cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, benzocyclobutanyl, benzocycloheptanyl und benzocycloheptenyl.

The term "heterocyclic" refers to a stable non-aromatic, preferably 3 to 20-membered, more preferably 3 to 12-membered, most preferably 5 or 6-membered, monocyclic or multicyclic, preferably 8 to 12-membered bicyclic, heteroatom-containing cyclic radical, that may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur. The heterocyclic residue may be bound to the remaining structure of the complete molecule by any atom of the cycle, which results in a stable structure. Exemplary heterocycles include, but are not limited to, pyrrolidinyl, pyrrolinyl, morpho- linyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, 1-oxo-λ4-thiomorpholinyl, 13-oxa-11-aza- tricyclo[7.3.1.0-2,7]tridecy-2,4,6-triene, tetrahydropyranyl, 2-oxo-2H-pyranyl, tetrahydrofuranyl, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4-dioxanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, 2-thia-5-aza-bicyclo[2.2.1]heptanyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulphide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulphide, tetramethylene sulfoxide and tetramethylene sulfone.

The term "aryl" as used herein shall be understood to mean an aromatic carbocycle or heteroaryl as defined herein. Each aryl or heteroaryl unless otherwise specified includes its partially or fully hydrogenated derivative. For example, quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl; naphthyl may include its hydrogenated derivatives such as tetrahydronaphthyl. Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art. Naturally, the term encompasses aralkyl and alkylaryl, both of which are preferred embodiments for practicing the compounds of the present invention. For example, the term aryl encompasses phenyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl and decahydronaphthyl.

The term "heteroaryl" shall be understood to mean an aromatic C ₃ -C _2O , preferably 5 to 8- membered monoxyclic or preferably 8 to 12-membered bicyclic ring containing 1 to 4 heteroatoms such as N, O and S. Exemplary heteroaryls comprise aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3- bjpyridinyl, pyrazole[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-jb]pyridinyl and imidazo[4,5-

£>]pyridinyl.

Terms which are analogues of the above cyclic moieties such as aryloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to its respective group.

As used herein, the terms "nitrogen" and "sulphur" include any oxidized form of nitrogen and sulphur and the quaternized form of any basic nitrogen as long as the resulting compound is chemically stable. For example, for an -S-C _1-6 alkyl radical shall be understood to include -S(O)-Ci _-6 alkyl and -S(O) ₂ -Ci _-6 alkyl.

The compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, compounds having a 'dangling valency' or a 'carbanion' are not compounds contemplated by the inventive concept disclosed herein.

In a preferred embodiment, R1 is a linear or branched, substituted or non-substituted, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl or arylalkynyl group of preferably 1 to 20, more preferably 1 to 10 carbons, most preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, pyridyl, naphthyl, biphenyl, furanyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, aryl groups substituted with one, two or three substituents chosen from halogen, cyano, amino, guanidino, nitro, C _{1 to} io-alkyl, Cuoio-alkoxy, trifluoromethyl, alkoxycarbonyl, 4-chlorophenyl, 2-methylphenyl and 3-ethoxyphenyl

In another preferred embodiment R3 is a linear or branched, substituted or non- substituted alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, aryl or heteroaryl group, silyl (-Si(RI) ₃ ) or alkylsilyl group of preferably 1 to 20, more preferably 1 to 10 carbons.

Methods of preparation

The compounds and precursor compounds of the present invention can be prepared without any undue burden or inventive skill by any appropriate conventional synthetic strategy known to those of skill in organic chemistry and as demonstrated below and in the examples in combination with Figures 1 to 5.

The compounds of formula I and Il contain substitutions at the 8-position (R1) of guanosine alone (I) or in combination with variable groups at the 6 position (R3) (II).

In a further aspect the present invention relates to methods for preparing compounds of formula I, Il and IV. The two key features of this method are the addition of a protecting group (R3) to the 06-position of 2'-deoxyguanosine (dG) and the activation of the 8- position, e.g. by the addition of a halogen, boron, triflate, tin or the like to the 8-position of dG (R4). The resulting 8-activated, 06-protected 2'-deoxyguanosines are useful as precursors for highly efficient metal-catalysed carbon-carbon bond forming reactions to install new groups at the 8-position of dG. Using this approach, compound libraries of 8- substituted and 6,8-disubstituted 2'-deoxyguanosines can be prepared and have already demonstrated cytotoxic activity towards cancer tissues (see the examples in combination with Fig. 7).

In one embodiment, the method of the invention comprises the preparation of precursors by adding a protecting group to the 06-position and an activating group to the 8-position of 2'-deoxyguanosine (dG). More preferably, said method further comprises the use of said precursors in metal-catalyzed cross-coupling reactions to modify the 8-position of dG through carbon-carbon bond formation. Most preferably, said method comprises the (optionally selective) deprotection to furnish compounds either lacking (compounds of formula (I)) or still containing a group at the 06-position (compounds of formula (II) to provide 8-substituted and 6,8-disubstituted 2'-deoxyguanosines, respectively.

The term precursor as used herein is meant to refer to modified 2 -deoxyguanosines comprising both a protecting group R3 at 06 and an activating group R4 at the 8- position. An "activating group" refers to functional groups for use in carbon-carbon forming reactions including, but not limited to, halogens (e.g. Cl, Br, I), triflate (- OSO ₂ CF ₃ ), boronic acids (-B(OH) ₂ ), boronic acid esters (-B(ORI) ₂ ), stannanes (- Sn(RI) ₃ ) and the like. A "protecting group" refers to functional groups that do not participate directly in carbon-carbon forming reactions, but facilitate this reaction by preventing side reactions. The protecting groups may or may not be removed after the carbon-carbon forming reactions.

In a preferred embodiment the present invention is directed to a method for preparing compound IV as defined above, comprising the step of reacting compound III as defined above with an activated compound of the general structure R1-R4 in the presence of a suitable metal catalyst (cat.) to substitute the R4-group of said activated compound III for an R1 group, wherein R1 , R3, R4, R5 and R6 are as defined above, according to the following reaction:

(III) (IV).

Preferred metal catalysts for the above reaction are selected from the group consisting of phosphine palladium catalysts, preferably tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ), dichlorobis(triphenylphosphine)palladium(ll) (Pd(PPh ₃ ) ₂ CI ₂ ), dichlorobis- (tricyclohexylphosphine)palladium(ll) (Pd(PcHex ₃ ) ₂ CI ₂ ), dichloro-(1 ,2-bis(diphenyl- phosphino)ethane)palladium(ll) (Pd(dppe)CI ₂ ), dichloro-(1 ,2-bis(diphenylphosphino)- ferrocenyl)palladium(ll) (Pd(dppf)CI ₂ ); palladium(O) precursors such as Pd(OAc) ₂ used in combination with phosphine ligands, preferably tris(2,4-dimethyl-5-sulfophenyl)- phosphine trisodium salt or triphenylphosphine, but also including air-stable phosphine- free ligands such as C-based heterocyclic carbenes, C,N-based 2-aryl-2-oxazolines, aryloximes, arylimines, and Λ/,Λ/-based diazabutadienes, Pd(OAc) ₂ -amine complex, preferably /rans-Pd(OAc) ₂ (Cy ₂ NH) ₂ (DAPCy) and cyclopalladated ferrocenylimines; nickel catalysts such as nickel(ll) acetylacetonate (Ni(acac) ₂ ) used in combination with various phosphine ligands, such as triphenylphosphine (PPh ₃ ), tributylphosphine (Bu ₃ P), 1 ,1'-bis(diphenylphosphino)ferrocene (dppf), 1 ,3-Bis(diphenylphosphino)propane (dppp) and the like; copper catalysts such as copper iodide, copper bromide, copper chloride, copper cyanide, copper thiophene carboxylate; gold catalysts such as trinuclear triphenylphosphine 1 ,2-Au(I) complexes with the [N,N,O]-tridentate unsymmetrical Schiff bases such as -tert-Butyl-4-methyl-6-[({[(2S)-1-(2-naphthylmethyl)pyrrolid inyl])methyl}- imino)methyl]-phenol [(C2 ₈ H34N2)O(Au(PPh ₃ ) ₃ )][CI] ₂ ; [(C ₃ 2H ₂₈ N2)O(Au(PPh ₃ ) ₃ )]CI; and iron catalysts such as Fe(II) or Fe(III) precatalysts like iron(lll) chloride or iron(lll) acetylacetonate (Fe(acac) ₃ ) reduced in situ by organometallic nucleophilies.

In a more preferred embodiment the present invention is directed to a method for preparing compound I as defined above, comprising the step of removing R3, substituting R5 by NH ₂ and substituting R6 by R2 of compound IV, wherein R1 to R3 and R5 and R6 are as defined above, according to the following reaction:

(IV) (I).

The above method provides for the complete deprotection, i.e. deprotection of R6, R3 and R5 in order to provide compounds of formula (I).

However, this deprotection can also be performed selectively, i.e. by deprotecting R5 and R6 only and leaving R3 in the 06 position in order to arrive at compounds of formula (II).

Hence, in another more preferred the present invention concerns a method for preparing compound Il of the invention, comprising the step of selectively substituting R5 by NH ₂ and substituting R6 by R2 of compound IV as defined above, wherein R1 to R3 and R5 and R6 are as defined above, according to the following reaction:

(IV) (II)

In a most preferred embodiment the method for preparing compound I comprises preparing compound (IV) from compound (III) and then preparing compound I from compound (IV) as illustrated above.

In a further most preferred embodiment the method for preparing compound Il comprises preparing compound (IV) from compound (III) and then preparing compound Il from compound (IV) as illustrated above.

For illustrative purposes only, specific and non-limiting examples of the above methods will be provided further below in the example section with reference to the figures.

Medical use and pharmaceutical compositions

The invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and (II). A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formula (I) or (II). Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g. magnesium), ammonium and N-(C ₁ -C ₄ BIkYl) ₄ ⁺ salts. In addition, the scope of the invention also encompasses prodrugs of compounds of formula (I) and (II). Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.

In view of the above and because of the above-described compounds (I) and (II) demonstrate cytotoxicity in cancer cells as shown in the examples below, another aspect of the present invention relates to the use of one or more compounds of the invention for preparing a medicament.

In a preferred embodiment one or more compounds of the present invention are used for preparing a medicament for the treatment and/or prevention of a disease or medical condition selected from the group consisting of cancer, preferably hemic malignancies and solid tumours, infections, preferably viral, bacterial and parasitic infections, autoimmune diseases, preferably rheumatoid arthritis and multiple sclerosis, cardiovascular diseases, preferably atherosclerosis, inherited genetic diseases, preferably cystic fibrosis, skin diseases, preferably psoriasis, and primary immunodeficiency diseases, preferably Boder-Sedgwick syndrome.

In the above respect the present invention also relates to a pharmaceutical composition, comprising as active substance one or more compounds according to the invention or pharmaceutically acceptable derivatives or prodrugs thereof, optionally combined with conventional excipients and/or carriers.

Methods of use

In a further aspect the present invention relates to a method for the treatment and/or prevention of a disease or medical condition comprising the step of administering a pharmaceutical composition according to the invention to a patient in need thereof.

For therapeutic or prophylactic use the compounds of the invention may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intra- synovially, by infusion, sublingually, transdermally, orally, topically, or by inhalation. The preferred modes of administration are oral and intravenous. The compounds may be administered alone or in combination with adjuvants that enhance stability of the compounds, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase cytotoxic activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. The above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: U.S. patent application no. 09/902,822, PCT/US 01/21860 und US provisional application no. 60/313,527, each incorporated by reference herein in their entirety. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5 %, but more preferably at least about 20 %, of a compound of formula (I) or (II) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.

As mentioned above, dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Controlled release dosage forms with or without immediate release portions are also envisaged. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5 ^th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1 - 100 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. Reference in this regard may also be made to US provisional application no. 60/339,249. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific doses and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician. For example, the compounds of the present invention can be administered the same way as other cytotoxic nucleoside compounds. Preferably, they are administered orally, preferably as hydrochloride salts.

Compounds of the invention may be formulated into capsules the same way other modified nucleoside derivatives are formulated. Each capsule may contain 10 to 500, preferably 150 to 300, more preferably 200 to 250 mg of a compound of the invention. For example, non-medicinal ingredients in capsules for the compounds of the present invention are - capsule shell: D&C yellow No. 10, FD&C blue No. 1 , FD&C red No. 3, FD&C yellow No. 6, gelatin and titanium dioxide. Bottles of 100. (see also Martindale: the complete drug reference, 34 ^th Edition, 2005, Pharmaceutical Press, p 612.)

Diagnostic use, diagnostic compositions and methods

The compounds (I) and (II) of the invention exhibit substantial fluorescent properties that make them useful for preparing a fluorescent diagnostic substance or composition, preferably a diagnostic fluorescent probe for in vitro and/or in vivo use. For example, the compounds of the invention can be combined with specific marker substances, e.g. antibodies, diabodies, etc. that bind specifically to biological structures that are indicative of a healthy or diseased biology in a mammal, mammalian tissue or mammalian cell. The fluorescent action of the compounds will allow for specifically detecting, locating and quantifying target structures in a compound-bound or unbound state.

Preferably, a diagnostic composition comprising as active substance one or more compounds of the invention or pharmaceutically acceptable derivatives or prodrugs thereof, optionally combined with conventional excipients and/or carriers, is used in a method for the diagnosis of a disease or medical condition comprising the step of adding or administering a diagnostic composition of the invention to a diagnostic sample or a patient in need thereof. Last but not least, a further aspect of the invention relates to the use of the inventive compounds as optical sensors. Moreover, the inventive compounds can be used as metal ion sensors, preferably for detecting and/or quantifying Cd (II), Cu(II), Ni(II), Pd(II), Pt(II), Hg(II) and Zn (II), preferably in diagnostic kits as well as in other diagnostic equipment. Evidence for the suitability of the inventive compounds for said purpose is provided in example 6 below.

Brief description of the figures

Fig. 1 Synthesis and use of precursor 8-bromo-3',5'-O-bis(teff-butyldimethylsilyl)-O ⁶ - benzyl-2'-deoxyguanosine (4) in carbon-carbon bond forming reactions for preparing compounds (5 - 7). Removal of the TBDMS protecting group generates the corresponding 6,8-disubstituted 2'-deoxyguanosines (8 - 10).

Fig. 2 Synthesis and use of precursor 8-bromo-3',5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (11) in carbon-carbon bond forming reactions, Condition (A): aryl-tributylstannane, Pd(PPh ₃ ) ₄ , toluene, 110 ⁰ C for preparing compounds (12 -16) Condition (B): arylboronic acid pinacol ester, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , DME, toluene, 80 ⁰ C for preparing compound (17). Removal of the protecting groups generates the corresponding 8-substituted 2'-deoxyguanosines (18 - 22).

Fig. 3 Synthesis and use of precursor 8-tributylstannane-3',5'-O-bis(teff-butyldi- methylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (23).

Fig 4. Synthesis and use of precursor 8-alkynyl-3',5'-O-bis(te/Y-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (27).

Fig. 5 Synthesis and use of precursor 8-(boronic acid pinacol ester)-3',5'-O-bis(tert- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (30).

Fig. 6 lists the photophysical properties of selected 8-aryl-2'-deoxyguanosines. Where λ AbS _max indicates the wavelength of maximal absorbance; λ Em _max indicates the wavelength of maximal fluorescence emission; ε indicates the molar extinction coefficient (cm ¹ M ^"1 ) at the indicated λ Abs _max ; Φ (H ₂ O) indicates the quantum yield in water; Φ (CH ₃ CN) indicates the quantum yield in acetonitrile.

Fig. 7 lists the cytotoxic activities of selected 8-aryl-2'-deoxyguanosines. A standard viability assay was used to quantify metabolic activity of cancer cells (skMel28, MCF7, Mac, or B16-F10 cells) exposed to variable concentrations of 8-aryl-2'-deoxyguanosines for 24 hours. The EC50 values indicate the concentration of each compound needed to decrease the metabolic activity of each cell type by 50%. "N. D." = not determined.

In the following the present invention will be further illustrated with reference to the figures and specific examples, which are not intended to be restrictive to the scope of the claims as appended.

Examples

Example 1 - General synthetic route with reference to Fig. 1 In this example the 0(6) position of 2'-deoxyguanosine was protected with a benzyl group (R3) to furnish the precursor compound 8-bromo-3',5'-O-bis(te/f-butyldimethyl- silyl)-O ⁶ -benzyl-2'-deoxyguanosine (4) (Fig. 1) for use as a precursor for efficient metal- catalyzed cross-coupling reactions with tributylstannyl pyridines to furnish 8-(2-pyridyl)- 3\5'-O-bis(te/f-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (5), 8-(3-pyridyl)-3',5 ^I -O- bis(ferf-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (6), 8-(4-pyridyl)-3',5'-O-bis(terf- butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (7) in high yields (Fig. 1). In this example compounds (5), (6), and (7) were deprotected by addition of tetrabutyl- ammonium fluoride trihydrate (TBAF) to furnish the corresponding 6,8-disubstituted 2'- deoxyguanosines: 8-(2-pyridyl)-O ⁶ -benzyl-2'-deoxyguanosine (8), 8-(3-pyridyl)-O ⁶ - benzyl-2'-deoxyguanosine (9), and 8-(4-pyridyl)-3 ^I ,5'-O ⁶ -benzyl-2 ¹ -deoxyguanosine (10) in high yields (Fig. 1).

Example 2 - General synthetic route with reference to Fig. 2

In this example the 0(6) position of 2'-deoxyguanosine was protected with a trimethyl- silyl-ethylether group (R3) to furnish the precursor compound 8-bromo-3',5'-O-bis(feAf- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (11) (Fig. 2) for use as a precursor for efficient metal-catalyzed cross-coupling reactions with aryl tributylstannanes to furnish 8-(2-pyridyl)-3\5'-O-bis(fe/f-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (12), 8-(3-pyridyl)-3 ^I ,5'-O-bis(te/t- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (13), 8-(4-pyridyl)- 3 ^I ₁ 5 ^l -O-bis(te/t-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (14), 8-(2-furyl)-3 ¹ ,5 ^I -O-bis(fert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2 ¹ - deoxyguanosine (15), and 8-(2-thiophenyl)-3',5 ¹ -O-bis(tert-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethylether)-2'-deoxyguanosine (16) (Fig. 2). 8-bromo-3',5'-O-bis(fe/f- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (11) was also used as a precursor for efficient metal-catalyzed cross-coupling reactions with boronic acid esters to furnish 8-(2-(phenyl-2-yl)vinyl)-3\5'-O-bis(ferf-butyldimethylsilyl) -O ⁶ - (trimethylsilylethyl)-2'-deoxyguanosine (17) (Fig. 2). In this example compounds (12), (13), (14), (15), and (16) were deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosines: 8-(2- pyridyl)-2'-deoxyguanosine (18), 8-(3-pyridyl)-2'-deoxyguanosine (19), 8-(4-pyridyl)-2'- deoxyguanosine (20) 8-(2-furyl)-2'-deoxyguanosine (21), and 8-(2-thiophyl)-2'- deoxyguanosine (22) (Fig. 2).

Example 3 - General synthetic route with reference to Fig. 3

In this example 8-bromo-3',5 ^l -O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)- 2'-deoxyguanosine (11) was converted into precursor 8-(tributystannanyl)-3',5'-O- bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (23) using a metal-catalyzed cross-coupling reaction with 1 ,1 ,1 ,2,2,2-hexabutyl-distannane (Fig. 3). 8-(tributystannanyl)-3',5 ¹ -O-bis(te/f-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'- deoxyguanosine (23) was used as a precursor for efficient metal-catalyzed cross- coupling reactions with 6-bromoindole to furnish 8-(6-indolyl)-3',5'-O-bis(ferf- butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (24) (Figure 2). Also, compound (24) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(6-indolyl)-2'- deoxyguanosine (25) (Fig. 3).

Example 4 - General synthetic route with reference to Fig. 4 In another embodiment, 8-bromo-3 ¹ ,5 ^I -O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl- ethylether)-2'-deoxyguanosine (11) was converted into precursor 8-(alkynyl)-3',5'-O- bis(fert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (26) using a metal-catalyzed cross-coupling reaction with trimethylsilyl (TMS) acetylene followed by deprotection of TMS under basic conditions (Fig. 4). 8-(alkynyl)-3',5'-O-bis(fe/f- butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2 ¹ -deoxyguanosine (27) was used as a precursor for efficient metal-catalyzed reaction with azidomethane to furnish 8-(1-methyl- 4-trizyl)-3',5'-O-bis(terf-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (28) (Fig. 2). Also, compound (28) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(1- methyl-4-trizyl)-2'-deoxyguanosine (29) (Fig. 4).

Example 5 - General synthetic route with reference to Fig. 5

In this example 8-bromo-3',5'-O-bis(teAt-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)- 2'-deoxyguanosine (11) was converted into precursor 8-(boronic acid pinacol ester)-3',5'- O-bis(te/t-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2'-deoxyguanosine (30) using a metal-catalyzed cross-coupling reaction with diboron pinacol ester (Fig. 5). 8-(boronic acid pinacol ester)-3',5'-O-bis(teAt-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethylether)-2 ^I - deoxyguanosine (30) was used as a precursor for efficient metal-catalyzed reaction with 3-iodothiophene to furnish 8-(3-thiophyl)-3\5'-O-bis(terf-butyldimethylsilyl)-O ⁶ - (trimethylsilylethyl)-2'-deoxyguanosine (31) (Fig. 5). Also, compound (31) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(3-thiophyl)-2'-deoxyguanosine (29) (Fig. 5).

Example 6 - Fluorescent activities

In this example it was demonstrated that 8-substituted and 6,8-disubstituted 2'-deoxy- guanosines exhibit fluorescence properties that allow for their use as diagnostic agents and chemical sensors. The photophysical properties of these deoxyguanosines revealed high molecular extinction coefficients (ε= 25 ¹ OOO Cm ¹ M ¹ ), environmentally-sensitive quantum yields (Φ = 0.001 - 0.72), and large Stokes shifts (Δ= 140 nm) (Fig. 6).

The quantum yields of selected 8-substitued guanosines were measured in both water and acetonitrile according to the following equation:

_ _ 2 ' wherein Φ _R is the quantum yield of the reference; / and I _R are the integrated emission intensities of the probe and the reference respectively; OD and OD _R are the optical densities of the probe and the reference respectively; n and n _R the refractive indexes of the solvent for the probe and the reference respectively. 2-aminopyridine in 0.1 M H ₂ SO ₄ was used as a reference (Φ = 0.6).

8-aryl substituted 2' deoxyguanosines show relatively high molar extinction coefficients and emission maxima well into the visible range (Fig. 6). Many of these compounds exhibit high quantum yields in acetonitrile and are quenched by water, highlighting the promising environmentally-sensitive emission and ability to act as chemosensors.

The capability of these compounds to report the presence of metal ions in solution was determined by measuring the absorption and emission spectra 8-(2-pyridyl)-deoxy- guanosine (18) in the presence of Cd (II), Cu(II), Ni(II), Pd(II), Pt(II), Hg(II) and Zn (II). In one experiment, the addition of Zn(II), caused a dramatic (approximately 20-fold) increase in the quantum yield of compound (18) along with a 50 nm red-shift in its excitation and emission maxima.

Example 7 - Cytotoxic activities

In this example the medical utility, i.e. cytotoxicities of selected 8-substituted 2'-deoxy- guanosines in cancer tissues, was assessed using a standard assay (for details see Liu, D. Bull. Environmental Contamination Toxicology, 1981 , 26, 145-149; Strotmann, U. J., Butz, B., Bias, W-R. Ecotoxicology Environmental Safety, 1993, 25, 79-89) that evaluates metabolic activity as a function of compound concentration. The concentration of the compound needed to inhibit metabolic activity by 50% is defined as the EC50 value (Fig. 7). In this example, selected 8-substituted 2'-deoxyguanosines, in particular 8-(4-pyridyl)-2'-deoxyguanosine (20) and 8-(2-thiophyl)-2'-deoxyguanosine (22) were highly cytotoxic to cancer tissues.

Example 8 - Preparation of 8-(2-pyridyl)-3'.5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ -benzyl-2'- deoxyguanosine (5):

8-bromo-3',5 ^l -0-bis(tert-butyldimethylsilyl)-0 ⁶ -benzyl-2'-deoxyguanosine (4) (270 mg, 0.41 mmoles) and 2-tributylstannyl pyridine (441.6 mg, 1.2 mmoles) were dissolved in dry toluene (20 ml_) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 30 minutes and then tetrakis(triphenylphosphine) palladium (57.2 mg, 0.05 mmoles) was added all at once. The resulting solution was heated at 110 ⁰ C under argon for 24 hours. The solvents and other volatiles were then evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 85:15) to yield 664 mg (73 %) of a yellowish oil. ¹ H-NMR (400 MHz, O ₆ - DMSO) δ 8.69 (dd, J ₁ = 4.0 Hz, J ₂ = 0.8 Hz, 1H), 8.63 (dd, J ₁ = 4.8 Hz, J ₂ = 0.8 Hz, 1 H), 8.39 (dd, J ₁ = 7.9 Hz, J ₂ = 0.8 Hz, 1H), 8.08 (dd, J ₁ = 8.0 Hz, J ₂ = 0.8 Hz, 1 H), 7.95 (t, J = 7.7 Hz, 2H), 7.53-7.34 (m, 2H), 6.46 (s, 2H) ₁ 5.53 (s, 2H), 4.63 (t, J = 2.8 Hz, 1 H), 3.78 (br s, 1 H), 3.72-3.69 (m, 1 H) ₁ 3.62 (br s, 1H), 3.56-3.50 (m, 1 H), 2.17-2.14 (m, 1H), 0.90 (S, 9H), 0.82 (s, 9H), 0.12 (d, J = 3.3 Hz, 6H), 0.00 (s, 3H), -0.03 (s, 3H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₃₄ H ₅₀ N ₆ O ₄ Si ₂ , 686.2; found 686.0.

Example 9 - Preparation of 8-(3-pyridyl)-3'.5'-O-bis(teff-butyldimethylsilyl)-O ⁶ -benzyl-2'- deoxyguanosine (6):

8-bromo-3',5'-O-bis(terf-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (4) (200 mg, 0.30 mmoles) and 3-tributylstannyl pyridine (310.8 mg, 0.84 mmoles) were dissolved in dry toluene (14 mL) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 1 hour and then tetrakis(triphenylphosphine) palladium (40.2 mg, 0.04 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 24 hours. The solvents and other volatiles were then evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 65:35) to yield 175 mg (88 %) of a yellowish oil. ¹ H-NMR (400 MHz, cfe- DMSO) δ 8.87 (s, 1H), 8.71 (s, 1 H), 8.10 (d, J = 4.7 Hz, 1H), 7.57 (s, 1 H), 7.50 (s, 2H), 7.40-7.34 (m, 3H), 6.43 (s, 2H), 6.09 (t, J = 7.8 Hz, 1 H), 5.52 (s, 2H), 4.61 (s, 1 H), 4.04 (br s, 2H), 3.77 (br s, 1H), 3.65 (br s, 1 H), 3.47-3.45 (m, 1 H), 2.17-2.11 (m, 1H), 0.85 (s, 9H), 0.81 (s, 9H), 0.08 (s, 6H), -0.01 (s, 3H), -0.03 (s, 3H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₃₄ H ₅₀ N ₆ O ₄ Si ₂ , 686.2; found 686.5. Example 10 - Preparation of 8-(4-pyridyl)-3',5'-O-bis(terf-butyldimethylsilyl)-O ⁶ -benzyl- 2'-deoxyguanosine (7):

8-bromo-3 ^I ,5 ¹ -O-bis(terf-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (4) (200 mg, 0.30 mmoles) and 4-tributylstannyl pyridine (310.8 mg, 0.84 mmoles) were dissolved in dry toluene (14 mL) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 1 hour and then tetrakis(triphenylphosphine) palladium (40.2 mg, 0.04 mmoles) was added all at once. The resulting mixture was heated at 110 ⁰ C under argon for 24 hours. The solvents and other volatiles were then evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 8:2) to yield 159 mg (79 %) of a yellowish oil. ¹ H-NMR (400 MHz ₁ J ₆ -DMSO) δ 8.73 (S ₁ 2H), 7.71 (s, 2H), 7.50-7.35 (m, 5H), 6.47 (s, 2H), 6.16 (t, J = 9.2 Hz, 1 H), 5.53 (s, 2H), 4.67 (br s, 1H), 3.79 (br s, 2H), 3.70-3.68 (m, 1H), 3.51-3.46 (m, 1 H), 2.17-2.15 (m, 1H) ₁ 0.86 (d, J = 2.5 Hz ₁ 9H) ₁ 0.81 (d, J = 2.5 Hz ₁ 9H), 0.09 (d, J = 4.9 Hz ₁ 6H), -0.01 (s, 3H) ₁ -0.02 (s, 3H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₃₄ H ₅₀ N ₆ O ₄ Si ₂ , 686.2; found 685.5.

Example 11 - Preparation of 8-(2-pyridyl)-O ⁶ -benzyl-2'-deoxyguanosine (8):

8-(2-pyridyl)-3\5'-0-bis(terf-butyldimethylsilyl)-0 ⁶ -benzyl-2'-deoxyguanosine (5) (200 mg, 0.30 mmoles) was dissolved in anhydrous tetrahydrofuran (7.5 mL) and tetrabutylammonium fluoride trihydrate (234.4 mg, 0.74 mmoles) was added. The reaction was stirred at room temperature for 1 hour. The solvents and other volatiles were then evaporated in vacuo, and the crude was purified by column chromatography (DCM:MeOH 95:5 to 90:10) to yield 66 mg (50 %) of a yellowish oil. ¹ H-NMR (400 MHz, de-DMSO) δ 8.69 (d, J = 4.5 Hz ₁ 1 H) ₁ 8.09 (d, J = 7.8 Hz, 1 H), 7.95 (dt, J ₁ = 7.8 Hz, J ₂ = 1.7 Hz, 1H), 7.54-7.48 (m, 3H), 7.43-7.34 (m, 3H), 7.26 (t, J = 7.9 Hz, 1 H), 6.47 (s, 2H), 5.53 (S, 2H), 5.29 (dd, J ₁ = 7.6 Hz, J ₂ = 4.2 Hz, 1 H), 5.15 (d, J = 4.1 Hz, 1 H), 4.47 (s, 1H), 3.81 (s, 1 H), 3.72-3.67 (m, 1 H) ₁ 3.56-3.49 (m, 1H), 3.23-3.16 (m, 1H), 2.19-2.13 (m, 1H).

Example 12 - Preparation of 8-(3-pyridyl)-O ⁶ -benzyl-2'-deoxyguanosine (9):

8-(3-pyridyl)-3 ^I ₎ 5 ^I -O-bis(tert-butyldimethylsilyl)-O ⁶ -benzyl-2'-deoxyguanosine (6) (200 mg, 0.30 mmoles) was dissolved in anhydrous tetrahydrofuran (7.5 ml_) and tetrabutylammonium fluoride trihydrate (234.4 mg, 0.74 mmoles) was added. The reaction was stirred at room temperature for 1.5 hours. The solvents and other volatiles were then evaporated in vacu, and the crude was purified by column chromatography (DCM: MeOH 93:7 to 90:10) to yield 96 mg (quant.) of a yellowish solid. ¹ H-NMR (400 MHz, Cf ₆ -DMSO) δ 8.87 (s, 1 H), 8.73 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz, 1 H), 8.11 (dd, J ₁ = 8.0 Hz, J ₂ = 1.8 Hz, 1H), 7.58 (dd, J ₁ = 7.8 Hz, J ₂ = 5.5 Hz, 1H), 7.51 (d, J = 6.8 Hz, 2H), 7.42-7.35 (m, 3H), 6.53 (s, 2H) ₁ 6.08 (t, J = 6.9 Hz, 1 H), 5.52 (s, 2H), 5.17 (d, J = 4.4 Hz, 1 H), 5.01 (t, J = 5.5 Hz, 1 H), 4.38 (br s, 1 H), 3.82 (br s, 1 H), 3.67-3.62 (m, 1 H), 3.55- 3.49 (m, 1 H), 3.18-3.16 (m, 1 H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₂₂ H ₂₂ N ₆ O ₄ , 457.2; found 457.1.

Example 13 - Preparation of 8-(4-pyridyl)-O ⁶ -benzyl-2'-deoxyguanosine (10):

8-(4-pyridyl)-3',5'-0-bis(fert-butyldimethylsilyl)-0 ⁶ -benzyl-2 ^I -deoxyguanosine (7) (200 mg, 0.30 mmoles) was dissolved in anhydrous tetrahydrofuran (7.5 mL) and tetrabutylammonium fluoride trihydrate (234.4 mg, 0.74 mmoles) was added. The reaction was stirred at room temperature for 1 hour. The solvents and other volatiles were then evaporated in vacuo, and the crude was purified by column chromatography (DCM:MeOH 93:7 to 90:10) to yield 92 mg (quant.) of a yellowish solid. ¹ H-NMR (400 MHz, cfe-DMSO) δ 8.75 (d, J = 2.4 Hz, 2H), 7.72 (d, J = 1.5 Hz, 2H), 7.51 (d, J = 6.9 Hz, 2H), 7.40-7.34 (m, 3H), 6.59 (s, 2H), 6.14 (t, J = 6.4 Hz, 1H), 5.52 (s, 2H), 5.18 (d, J = 2.6 Hz, 1 H), 5.00 (d, J = 5.9 Hz, 1 H), 4.41 (s, 1 H), 3.84 (s, 1 H), 3.84 (br s, 1 H), 3.69- 3.66 (m, 1H), 3.55-3.49 (m, 1 H), 3.17-3.14 (m, 1 H), 2.11-2.06 (m, 1H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₂₂ H ₂₂ N ₆ O ₄ , 457.2; found 457.1.

Example 14 - Preparation of 8-bromo-3'.5'-O-bis(fe/f-butyldimethylsilyl)-O ⁶ - (trirnethylsilylethyl)-2'-deoxyquanosine (11):

Triphenylphosphine (685 mg, 2.60 mmoles) and diethyldiazocarboxylate (DEAD) 40% in toluene (1.24 ml_, 2.50 mmoles) were dissolved in anhydrous dioxane (20 ml_). The mixture was stirred at room temperature for 10 minutes and then 2-(trimethylsilyl)- ethanol (308.3 mg, 371.87 uL, 2.80 mmoles) was added. The mixture was stirred for 15 minutes at room temperature and 8-bromo-3',5 ^I -O-bis(te/t-butyldimethylsilyl)-2 ^l - deoxyguanosine (3) (1 g, 1.74 mmoles) was added. The reaction was then stirred at room temperature for 18 hours. The solvents and other volatiles were removed in vacuo. The crude was purified by column chromatography (Hex:AcOEt 93:7) to yield 588 mg (50 %) of a yellowish oil. ¹ H-NMR (400 MHz, cfe-DMSO) δ 6.32 (s, 2H), 6.17 (t, J = 6.6 Hz, 1 H), 4.69-4.65 (m, 1 H), 4.48 (t, J = 8.2 Hz, 2H), 3.77-3.73 (m, 2H), 3.65-3.61 (m, 1H) ₁ 3.52 (quint, J = 6.8 Hz, 1H), 2.22-2.17 (m, 1H), 1.16 (dd, J ₁ = 9.3 Hz, J ₂ = 7.2 Hz, 2H), 0.90 (S, 9H), 0.79 (s, 9H), 0.12 (s, 6H), 0.06 (s, 9H), -0.04 (s, 3H), -0.07 (s, 3H). ¹³ C-NMR (100 MHz, Cl ₆ -DMSO) δ 159.9, 159.8, 154.9, 124.9, 115.1 , 87.5, 85.4, 72.7, 64.3, 63.1 , 26.2, 18.4, 18.2, 17.4, -0.8, -4.2, -4.4, -5.0, -5.1. ESI MS (m/z): [M+Naf calcd for C ₂₇ H ₅₂ BrN ₅ O ₄ Si ₃ , 696.3; found 696.4.

Example 15 - Preparation of 8-(2-pyridyl)-3'.5'-O-bis(ferf-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethyl)-2'-deoxyguanosine (12):

8-bromo-3 ^I ₁ 5'-O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (119 mg, 0.17 mmoles) and 2-tributylstannyl pyridine (182.3 mg, 0.49 mmoles) were dissolved in dry toluene (8 mL) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 1.5 hours and then tetrakis(triphenyl- phosphine) palladium (23.6 mg, 0.02 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 22 hours. The solvents and other volatiles were evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 9:1) to yield 44 mg (37 %) of a yellowish oil. ¹ H-NMR (400 MHz, cfe-DMSO) δ 8.62 (dd, J ₁ = 4.0 Hz, J ₂ = 0.9 Hz, 1 H), 8.06 (d, J = 7.9 Hz ₁ 1H), 7.96 (td, J ₁ = 7.8 Hz ₁ J ₂ = 1.8 Hz ₁ 1 H) ₁ 7.50-7.47 (m, 1 H), 7.32 (t, J = 7.0 Hz ₁ 1 H) ₁ 6.32 (s, 2H) ₁ 4.62 (t, J = 2.7 Hz ₁ 1 H), 4.53 (dd, J ₁ = 9.1 Hz ₁ J ₂ = 7.4 Hz ₁ 2H) ₁ 3.80 (dd, J ₁ = 10.6 Hz, J ₂ = 6.4 Hz, 1H), 3.70-3.67 (m, 1 H), 3.63-3.59 (m, 1 H), 3.52 (quint, J = 6.4 Hz, 1 H) ₁ 2.16-2.10 (m, 1H) ₁ 1.16 (dd, J ₁ = 9.3 Hz, J ₂ = 7.2 Hz ₁ 2H) ₁ 0.89 (s, 9H) ₁ 0.81 (s, 9H) ₁ 0.11 (d, J = 3.4 Hz, 6H) ₁ 0.07 (S ₁ 9H) ₁ -0.04 (s, 6H). ESI MS (m/z): [M+H] ⁺ calcd for C ₃₂ H ₅₆ N ₆ O ₄ Si ₃ , 673.4; found 673.4.

Example 16 - Preparation of 8-(3-pyridyl)-3'.5'-O-bis(ferf-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethyl)-2'-deoxyguanosine (13):

8-bromo-3\5'-O-bis(te/f-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (200 mg, 0.29 mmoles) and 3-tributylstannyl pyridine (306.3 mg, 0.83 mmoles) were dissolved in dry toluene (13.5 mL) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 1.5 hours and then tetrakis(triphenylphosphine) palladium (39.7 mg, 0.03 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 14 hours. The solvents and other volatiles were evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 75:25) to yield 198 mg (quant.) of a yellowish oil. ¹ H-NMR (400 MHz ₁ Cf ₆ -DMSO) δ 10.81 (br s, 1 H), 8.65 (d, J = 4.8 Hz, 1H) ₁ 7.94 (dt, J ₁ = 7.7 Hz, J ₂ = 1.7 Hz, 1 H), 7.45 (t, J = 6.5 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 6.38 (s, 2H), 5.09 (t, J = 4.1 Hz, 2H), 4.42 (br s, 1H), 3.76 (t, J = 3.1 Hz, 1H), 3.68-3.63 (m, 1 H), 3.50 (quint, J = 5.4 Hz, 1 H), 3.16-3.08 (m, 2H), 2.15-2.09 (m, 1 H), 0.92 (t, J = 7.2 Hz, 2H). [M+Na] ⁺ calcd for C ₃₂ H ₅₆ N ₆ O ₄ Si ₃ , 695.4; found 695.4.

Example 17 - Preparation of 8-(4-pyridyl)-3'.5'-O-bis(fer/-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethyl)-2'-deoxyguanosine (14):

8-bromo-3',5'-O-bis(te/t-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (200 mg, 0.29 mmoles) and 4-tributylstannyl pyridine (306.3 mg, 0.83 mmoles) were dissolved in dry toluene (13.5 ml_) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 1.5 hours and then tetrakis(triphenylphosphine) palladium (39.7 mg, 0.03 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 14 hours. The solvents and other volatiles were evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 75:25) to yield 150 mg (75 %) of a yellowish oil. ¹ H-NMR (400 MHz, oVDMSO) δ 8.73 (d, J = 5.2 Hz, 2H), 7.71 (d, J = 4.5 Hz, 2H), 6.33 (s, 2H), 6.12 (t, J = 6.7 Hz, 1 H), 4.66 (d, J = 2.6 Hz, 1 H), 4.52 (t, J = 8.2 Hz, 2H), 3.79-3.77 (m, 2H), 3.70-3.64 (m, 1H), 3.48 (quint, J = 6.6 Hz, 1H), 2.18-2.12 (m, 1H), 1.16 (dd, J ₁ = 9.3 Hz, J ₂ = 7.2 Hz, 2H), 0.85 (s, 9H), 0.80 (s, 9H), 0.06 (s, 9H), -0.01 (s, 6H), -0.04 (s, 3H), -0.06 (s, 3H). [M+Na] ⁺ calcd for C ₃₂ H ₅₆ N ₆ O ₄ Si ₃ , 695.4; found 695.5.

Example 18 - Preparation of 8-(2-furyl)-3'.5'-O-bis(fert-butyldimethylsilyl)-O ⁶ - (trimethylsilyl-ethyl)-2'-deoxyguanosine (15):

8-bromo-3',5'-O-bis(fe/t-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (200 mg, 0.30 mmoles) and 2-(tributylstannyl)-furan (306.3 mg, 0.83 mmoles) were dissolved in dry toluene (13 ml_) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 30 minutes and then tetrakis(triphenyl- phosphine) palladium (39.6 mg, 0.03 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 17 hours. The solvents and other volatiles were evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 9:1) to yield 168 mg (85 %) of a yellowish oil. ¹ H-NMR (400 MHz ₁ cfe-DMSO) δ 7.57 (d, J = 1.2 Hz ₁ 1 H), 7.14 (d, J = 3.4 Hz, 1 H), 6.58 (t, J = 6.8 Hz, 1 H), 6.54 (dd, J ₁ = 3.44 Hz, J ₂ = 1.8 Hz, 1 H), 4.83 (dt, J ₁ = 5.7 Hz, J ₂ = 3.7 Hz, 1 H), 4.75 (s, 2H), 4.61- 4.56 (m, 2H), 3.98-3.89 (m, 2H), 3.73 (dd, J ₁ = 10.3 Hz, J ₂ = 4.5 Hz, 1H), 3.64 (quint., J = 6.6 Hz, 1 H), 2.19-2.13 (m, 1 H), 1.16 (dd, J ₁ = 9.3 Hz, J ₂ = 7.2 Hz, 2H), 0.94 (s, 9H) ₁ 0.87 (S, 9H), 0.16 (d, J = 2.1 Hz, 6H), 0.10 (s, 9H), 0.03 (s, 6H), -0.04 (s, 3H), -0.01 (s, 3H). [M+H] ⁺ calcd for C ₃₃ H ₆₁ N ₅ O ₅ Si ₃ , 662.4; found 662.4.

Example 19 - Preparation of 8-(2-thiophyl)-3'.5'-O-bis(fert-butyldimethylsilvn-O ⁶ - (trimethylsilyl-ethyl)-2'-deoxyquanosine (16):

8-bromo-3',5'-O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (200 mg, 0.30 mmoles) and 2-(tributylstannyl)-thiophene (310.6 mg, 0.83 mmoles) were dissolved in dry toluene (13 mL) in a dry round-bottomed flask previously purged with nitrogen. The mixture was bubbled with argon for 30 minutes and then tetrakis(tri- phenylphosphine) palladium (39.6 mg, 0.03 mmoles) was added all at once. The resulting mixture was heated at 11O ⁰ C under argon for 17 hours. The solvents and other volatiles were evaporated in vacuo and the residue was purified by column chromatography (Hex:AcOEt 8:2) to yield 178 mg (89 %) of a yellowish oil. . ¹ H-NMR (400 MHz, dβ-DMSO) δ 7.67 (d, J = 3.6 Hz, 1 H), 7.14 (d, J = 4.6 Hz, 1 H), 7.15 (dd, J ₁ = 4.9 Hz, J ₂ = 3.8 Hz, 1 H), 6.35 (t, J = 6.7 Hz, 1 H), 4.90-4.86 (m, 1 H), 4.73 (s, 2H), 4.64- 4.58 (m, 2H), 3.98-3.89 (m, 2H), 3.77-3.69 (m, 2H), 2.12 (ddd, J ₁ = 8.7 Hz ₁ J ₂ = 7.4 Hz, J ₃ = 2.9 Hz, 1 H) ₁ 1.29-1.24 (m, 2H), 0.94 (s, 9H) ₁ 0.87 (s, 9H), 0.15 (d, J = 5.0 Hz, 6H) ₁ 0.10 (s, 9H) ₁ 0.03 (s, 6H), -0.04 (s, 3H), -0.01 (s, 3H). [M+H] ⁺ calcd for C ₃₃ H _6I N ₅ O ₄ SSi ₃ , 678.3; found 678.4.

Example 20 - Preparation of 8-(2-(phenyl-2-yl)vinyl)-3'.5'-O-bis(tetf-butyldimethylsilyl )- O ⁶ -(trimethylsilylethvD-2'-deoxyguanosine (17):

8-bromo-3',5 ^I -O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilylethyl)-2'-deoxyguanosine (11) (150 mg, 0.22 mmoles) and trans-2-styreneboronic acid pinacol ester (73.3 mg, 0.33 mmoles) were suspended in DME (3.5 ml_) in a round bottomed flask purged with nitrogen. The reaction mixture was degassed with argon for 30 minutes, and then tetrakis(triphenylphosphine) palladium (30.8 mg, 0.12 mmoles) was added, followed by an aqueous Na ₂ CO ₃ 3M solution (222 uL) and toluene (2.7 ml_), both previously degassed with argon. The reaction was stirred under argon at 80 ⁰ C for 24 hours. The reaction mixture was then diluted with DCM, washed with a saturated solution of Na ₂ CO ₃ twice, dried with Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography (Hex:AcOEt 9:1) to yield 90 mg (87 %) of a yellow solid. ¹ H- NMR (400 MHz, CDCI ₃ ) δ 7.90 (d, J = 15.9 Hz ₁ 1 H), 7.57 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.6 Hz ₁ 2H), 7.35 (m, 1H), 7.15 (d, J = 15.9 Hz ₁ 1 H), 6.38 (t, J = 6.8 Hz, 1H), 4.79-4.76 (m, 1 H), 4.73 (s, 2H), 4.62 (t, J = 8.8 Hz, 2H), 3.99-3.95 (m, 1 H) ₁ 3.90-3.85 (m, 1H) ₁ 3.80-3.75 (m, 1 H), 3.45 (quint, J = 6.7 Hz, 1 H), 1.16 (dd, J ₁ = 9.3 Hz, J ₂ = 7.2 Hz, 2H), 0.96 (S ₁ 9H), 0.87 (s, 9H), 0.17 (s, 6H), 0.12 (s, 9H), 0.04 (s, 3H) ₁ 0.02 (s, 3H). ¹³ C-NMR (100 MHz ₁ CDCI ₃ ) δ 161.4, 159.0, 155.0, 148.7, 137.0, 136.8, 129.3, 127.8, 114.7, 87.7, 84.0, 72.9, 65.3, 63.5, 38.2, 30.2, 26.4, 26.3, 18.9, 18.6, 18.3, 0.5, -0.9, -4.0, -4.8. ESI MS (mlz): [M+Na] ⁺ calcd for C ₃₅ H ₅₉ N ₅ O ₄ Si ₃ , 720.4; found 720.5. Example 21 - Preparation < 3f 8-(2-pvridvl)-2 -deoxvαuanosine (18):

8-(2-pyridyl)-3' _I 5 ^I -O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethyl)-2'- deoxyguanosine (12) (43 mg, 0.06 mmoles) was dissolved in anhydrous tetrahydrofuran (4.3 mL) and tetrabutylammonium fluoride trihydrate (91.6 mg, 0.29 mmoles) was added. The reaction was stirred at room temperature for 14 hours. The solvents and other volatiles were then evaporated in vacuo and the crude was purified by column chromatography (DCM: MeOH 85:15). The solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with hexane (ca. 1 mL) and twice with methanol (ca. 400 uL). The residue was then dried to yield 6 mg (27 %) of a white solid. ¹ H-NMR (400 MHz ₁ Cf ₆ -DMSO) δ 10.80 (s, 1 H) ₁ 8.66 (dd, J ₁ = 2.5 Hz ₁ J ₂ = 0.8 Hz, 1 H) ₁ 8.05 (dd, J ₁ = 8.0 Hz ₁ J ₂ = 0.9 Hz ₁ 1 H) ₁ 7.95 (td, J ₁ = 7.8 Hz ₁ J ₂ = 1.6 Hz ₁ 1 H) ₁ 7.46 (t, J = 6.2 Hz, 1 H), 7.26 (t, J = 6.9 Hz, 1 H), 6.38 (s, 2H), 5.11 (d, J = 4.2 Hz, 1 H), 5.04 (t, J = 4.9 Hz, 1 H), 4.44 (d, J = 2.7 Hz, 1 H), 3.77 (d, J = 3.4 Hz, 1 H), 3.69- 3.64 (m, 1 H), 3.54-3.48 (m, 1H), 3.13 (quint, J = 6.7 Hz, 1H), 2.16-2.11 (m, 1 H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₁₅ H ₁₆ N ₆ O ₄ , 367.1 ; found 367.1

Example 22 - Preparation of 8-(3-pyridyl)-2'-deoxyguanosine (19):

8-(3-pyridyl)-3',5 ^> -O-bis(fert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethyl)-2'- deoxyguanosine (13) (200 mg, 0.32 mmoles) was dissolved in anhydrous tetrahydrofuran (21.5 mL) and tetrabutylammonium fluoride trihydrate (457.9 mg, 1.45 mmoles) was added. The reaction was stirred at room temperature for 14 hours. The solvents and other volatiles were then evaporated in vacuo and the crude was purified by column chromatography (DCM: MeOH 85:15). The solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with water (ca. 500 uL) and four times with methanol (ca. 500 uL). The residue was then dried to yield 16 mg (14 %) of a yellowish solid. ¹ H-NMR (400 MHz, cfe-DMSO) δ 10.77 (br s, 1 H), 8.83 (d, J = 3.8 Hz, 1 H), 8.68 (d, J = 6.5 Hz, 1 H), 8.05 (t, J = 6.2 Hz, 1 H), 7.57 (s, 1 H), 6.45 (s, 2H), 6.03 (d, J = 6.0 Hz, 1 H), 5.14 (s, 1 H), 4.90 (d, J = 5.3 Hz, 1 H), 4.30 (br s, 1H), 3.78 (br s, 1H) ₁ 3.60 (d, J = 3.4 Hz, 1H), 3.53-3.49 (m, 1H), 3.16-3.12 (m, 1H), 2.08-2.04 (m, 1 H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₁₅ H ₁₆ N ₆ O ₄ , 367.1 ; found 367.1.

Example 23 - Preparation of 8-(4-pyridyl)-2'-deoxyguanosine (20):

8-(4-pyridyl)-3',5 ^I -O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethyl)-2'- deoxyguanosine (14) (145 mg, 0.21 mmoles) was dissolved in anhydrous tetrahydrofuran (14.2 mL) and tetrabutylammonium fluoride trihydrate (301.8 mg, 0.95 mmoles) was added. The reaction was stirred at room temperature for 14 hours. The solvents and other volatiles were then evaporated in vacuo and the crude was purified by column chromatography (DCM:MeOH 85:15). The solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with hexane (ca. 500 uL) and four times with water (ca. 500 uL). The residue was then lyophilized to yield 33 mg (44 %) of a yellowish solid. ¹ H-NMR (400 MHz, cfe-DMSO) δ 10.83 (br s, 1 H) ₁ 8.73 (d, J = 4.4 Hz, 2H), 7.68 (d, J = 4.4 Hz, 2H), 6.51 (s, 2H), 6.11 (t, J = 7.6 Hz, 1H), 5.15 (d, J = 3.5 Hz, 1 H), 4.93-4.89 (m, 1H), 4.36 (br s, 1H), 3.81 (br s, 1H), 3.67- 3.63 (m, 1H), 3.57-3.51 (m, 1 H), 3.16 (quint, J = 6.3 Hz, 1 H), 2.09-2-04 (m, 1 H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₁₅ H ₁₆ N ₆ O ₄ , 367.1 ; found 367.1.

Example 24 - Preparation of 8-(2-furvh-2'-deoχyquanosine (21):

8-(2-furyl)-3',5'-0-bis(tert-butyldimethylsilyl)-0 ⁶ -(trimethylsilyl-ethyl)-2'-deoxyguanosine (15) (157 mg, 0.23 mmoles) was dissolved in anhydrous tetrahydrofuran (15.6 ml_) and tetrabutylammonium fluoride trihydrate (332.1 mg, 1.05 mmoles) was added. The reaction was stirred at room temperature for 17 hours. The solvents and other volatiles were then evaporated in vacuo and the crude was purified by column chromatography (DCM: MeOH 91 :9). The solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed twice with hexane (ca. 400 μl_), twice with acidic water (acetic acid, pH 4) (ca. 400 μl_) and twice with water (ca. 400 μL). The residue was then lyophilized to yield 45 mg (57 %) of a yellow solid. ¹ H-NMR (400 MHz, Cf ₆ -DMSO) δ 10.67 (br s, 1 H), 7.80 (dd, J ₁ = 1.7 Hz, J ₂ = 0.8 Hz, 1 H), 6.85 (dd, J ₁ = 3.4 Hz, J ₂ = 0.76 Hz, 1 H), 6.59 (dd, J ₁ = 3.4 Hz, J ₂ = 1.8 Hz, 1 H), 6.33 (br s, 2H), 6.26 (t, J = 7.8 Hz, 1 H), 5.08 (br s, 1 H), 4.83 (br s, 1 H) ₁ 4.28 (br s, 1 H), 3.73-3.68 (m, 1 H), 3.53-3.49 (m, 1 H), 3.39 (dd, J ₁ = 11.5 Hz, J ₂ = 5.3 Hz, 1 H), 3.06 (quint., J = 6.9 Hz, 1 H), 2.00-1.96 (m, 1 H). ESI MS {m/z): [M+Na] ⁺ calcd for C ₁₄ H ₁₅ N ₅ O ₅ , 333.1 ; found 333.1.

Example 25 - Preparation of 8-(2-thiophyl)-2'-deoxyguanosine (22):

8-(2-thiophyl)-3',5'-O-bis(tert-butyldimethylsilyl)-O ⁶ -(trimethylsilyl-ethyl)-2'- deoxyguanosine (16) (162 mg, 0.24 mmoles) was dissolved in anhydrous tetrahydrofuran (15.7 ml.) and tetrabutylammonium fluoride trihydrate (334.9 mg, 1.06 mmoles) was added. The reaction was stirred at room temperature for 17 hours. The solvents and other volatiles were then evaporated in vacuo and the crude was purified by column chromatography (DCM:MeOH 85:15). The solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed twice with hexane (ca. 400 u L), twice with acidic water (acetic acid, pH 4) (ca. 500 μ L) and twice with water (ca. 500 uL). After drying, the whole washing process was repeated a second time. The residue was then lyophilized to yield 47 mg (56 %) of a white solid. ¹ H-NMR (400 MHz, oVDMSO) δ 10.65 (br s, 1 H), 7.64 (dd, J ₁ = 5.1 Hz, J ₂ = 1.0 Hz, 1 H), 7.38 (dd, J ₁ = 3.7 Hz, J ₂ = 1.1 Hz, 1 H), 7.11 (dd, J ₁ = 5.1 Hz, J ₂ = 3.7 Hz, 1 H), 6.34 (br s, 2H), 6.16 (t, J = 7.0 Hz, 1 H), 5.08 (d, J = 4.5 Hz, 1 H), 4.83 (t, J = 6.2 Hz, 1 H), 4.30-4.26 (m, 1 H), 3.73- 3.68 (m, 1H), 3.53-3.49 (m, 1H), 3.45-3.39 (m, 1H), 3.25-3.16 (m, 1H), 2.00-1.96 (m, 1 H). ESI MS (m/z): [M+Na] ⁺ calcd for C ₁₄ H ₁₅ N ₅ O ₄ S, 372.1 ; found 372.1.