SION BONDING PROCESS

STATEMENT OF RELATED APPLICATIONS The present application claims priority to U.S. Provisional Patent Applications Serial Nos. 60/668,338, filed on April 5, 2005, and 60/713,979, filed on September 2, 2005, both of which are incorporated herein by reference in their entirety.

BACKGROUND

Many compounds are currently used to modify a surface property of skin. For example, sunscreen agents and insect repellants enjoy widespread consumer acceptance. Typically, a consumer topically applies a lotion, cream, or spray containing these compounds to the skin before or during exposure. However, this method has several disadvantages. The consumer may forget to apply these materials, or may apply the materials after significant exposure. Once applied, these materials may be easily removed by environmental factors (e.g., washing, sweating, swimming, physical contact, etc.) and may inhibit sweating and heat regulation. Consequently, the need remains for methods to modify the skin of a mammal.

SUMMARY

The present invention is directed to methods of providing a desired effect to the skin of a mammal (i.e., to modify one or more surface properties of the skin). In particular, the methods involve the use of a Maillard initiating reagent(s) (in particular, dihydroxyacetone (DHA) or similar compounds) with a skin-modifying compound (i.e., secondary compound) that will associate (e.g., covalently bond) with the Maillard initiating reagent(s) (e.g., DHA) once the Maillard initiating reagent has reacted with the skin.

More specifically, the present invention provides a method of bonding agents for a desired effect to the skin. Such desired effects include, insect repellency, sun screen protection, antimicrobial effect, antifungal effect,

antiparasitic effect, anti-inflammatory effect, anti-aging effect, anti-itch effect, skin lightening effect, skin conditioning effect, fragrance, exfoliation, antiblister effect, antioxidant effect, lipid barrier effects, barriers to and neutralizers of acute contact allergens, cosmetic soothing effect, other cosmetic effects, and the like.

In one embodiment, the present invention provides a method of modifying the skin of a mammal to provide a desired effect that includes: providing a Maillard initiating reagent; providing a skin-modifying compound; contacting the skin with the Maillard initiating reagent under conditions effective to initiate a Maillard reaction with one or more proteins of the skin of the mammal; and contacting the skin with the skin-modifying compound under conditions effective to associate with the Maillard initiating reagent and modify the skin to provide a desired effect; with the proviso that the skin-modifying compound is not juglone (5-hydroxy-l,4-napthoquinone); menadione (2- methyl-l,4-napthoquinone); lawsone (2-hydroxy-l,4-napthoquinone); 2,6- dimethoxybenzoquinone; 2,5-dimethylquinone; 2,5-dihydroxy-3-undecyl-l ,4- benzoquinone; 2-hydroxy-3 -methyl- 1 ,4-napthoquinone; 3,5,8-trihydroxy-2- methyl-l,4-napthoquinone; and 2-hydroxy-3-isobutyl-l,4-napthoquinone.

In another embodiment, the present invention provides a method of modifying the skin of a mammal to provide a desired effect that includes: providing a Maillard initiating reagent; providing a skin-modifying compound; contacting the skin with the Maillard initiating reagent under conditions effective to initiate a Maillard reaction with one or more proteins of the skin of the mammal; and contacting the skin with the skin-modifying compound under conditions effective to associate with the Maillard initiating reagent and modify the skin to provide a desired effect; with the proviso that if only one skin- modifying compound is used it is not a quinone.

In another embodiment, the present invention provides a method of modifying the skin of a mammal to provide a desired effect that includes: providing a Maillard initiating reagent; providing a skin-modifying compound; contacting the skin with the Maillard initiating reagent under conditions effective to initiate a Maillard reaction with one or more proteins of the skin of the mammal; and contacting the skin with the skin-modifying compound under conditions effective to associate with the Maillard initiating reagent and modify

the skin to provide a desired effect; with the proviso that the skin-modifying compound is not a quinone when the Maillard initiating reagent is dihydroxyacetone, 5-(hydroxymethyl)-2-furaldehyde, pyruvic aldehyde, glyceraldehyde, alloxan, or monohydroxyacetone.

In another embodiment, the present invention provides a method of modifying the skin of a mammal to provide a desired effect, the method that includes: providing a Maillard initiating reagent; providing a skin-modifying compound; contacting the skin with the Maillard initiating reagent under conditions effective to initiate a Maillard reaction with one or more proteins of the skin of the mammal; and contacting the skin with the skin-modifying compound under conditions effective to associate with the Maillard initiating reagent and modify the skin to provide a desired effect; with the proviso that the skin-modifying compound and the Maillard initiating reagent are substantially simultaneously applied to the skin.

Typically, the method consists essentially of contacting the skin with the Maillard initiating reagent and the skin-modifying compound.

In one embodiment, the method includes contacting the skin with a skin- modifying compound before contacting the skin with a Maillard initiating reagent.

In another embodiment, the method includes contacting the skin with a skin-modifying compound after contacting the skin with a Maillard initiating reagent.

In yet another embodiment, the method includes mixing the Maillard initiating reagent and the skin-modifying compound together prior to contacting the skin.

The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition that comprises "a" skin-modifying compound can be interpreted to mean that the composition includes "one or more" skin-modifying compounds. Similarly, a composition comprising "a" Maillard initiating reagent can be interpreted to mean that the composition includes "one or more" Maillard initiating reagents. Furthermore, a "composition" as used herein, can consist of just one skin-modifying

compound and/or one Maillard initiating reagent without any other components (e.g., pharmaceutically acceptable carrier).

As used herein, the term "organic group" refers to a hydrocarbyl group (aliphatic and/or aromatic) optionally including other atoms (e.g., heteroatoms) or groups (e.g., functional groups) replacing the carbon and/or hydrogen atoms. The term "aliphatic group" means a saturated or unsaturated linear (i.e., straight chain), cyclic, or branched hydrocarbon group. This term is used to encompass alkyl (e.g., --CH ₃ ) (or alkylene if within a chain such as -CH ₂ --), alkenyl (or alkenylene if within a chain), and alkynyl (or alkynylene if within a chain) groups, for example. The term "alkyl group" means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t- butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like. The term "alkenyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group. The term "alkynyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds. The term "aromatic group" or "aryl group" means a mono- or polynuclear aromatic hydrocarbon group. These hydrocarbon groups may be substituted with heteroatoms, which can be in the form of functional groups. The term "heteroatom" means an element other than carbon (e.g., nitrogen, oxygen, sulfur, chlorine, etc.).

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

As used herein, the term "Maillard initiating reagent" refers to any compound, preferably a carbonyl-containing compound that reacts with the skin to produce melanoids.

As used herein, the term "skin-modifying compound" refers to any compound, preferably a napthoquinone-containing compound that reacts with the melanoids to produce a desired effect.

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various

combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention is directed to the use of a Maillard initiating reagent with a skin-modifying compound to modify one or more properties of the skin of a mammal. This typically will involve application of a Maillard initiating reagent (e.g., DHA or similar compound) followed by a skin- modifying compound. Alternatively, a skin-modifying compound is applied followed by a Maillard initiating reagent. In yet another alternative, they can be in a mixture and then immediately applied to the skin. Alternatively, and preferably, they are applied substantially simultaneously to the skin without forming a mixture before contacting the skin.

More specifically, the present invention provides a method of bonding agents for a desired effect to the skin. Such desired effects include, insect repellency, sun screen protection, antimicrobial effect, antifungal effect, antiparasitic effect, anti-inflammatory effect, anti-aging effect, anti-itch effect, skin lightening effect, skin conditioning effect, fragrance, exfoliation, antiblister effect, antioxidant effect, lipid barrier effects, barriers to and neutralizers of acute contact allergens, cosmetic soothing effect, and other cosmetic effects.

The Maillard reaction is the reaction between the amino groups of amino acids, peptides, and proteins with the hydroxyl group of reducing sugars to afford brown pigments. This reaction is generally responsible for the browning of food; hence the name non-enzymatic browning. The Maillard reaction has also been used to produce brown pigments in the skin for a sunless tan.

Although not necessarily limiting to the invention, the Maillard reaction typically involves a series of complex reactions with numerous intermediates, but can be generally described as involving three steps. The first step of the Maillard reaction typically involves the combination of a free amino group (from amino acids and/or proteins) with a reducing sugar (such as glucose) to form Amadori or Heyns rearrangement products. The second step typically involves degradation of the Amadori or Heyns rearrangement products via different alternative routes involving deoxyosones, fission, or Strecker degradation. A complex series of reactions including dehydration, elimination,

cyclization, fission, and fragmentation results in the formation of intermediates and other compounds. The third step of the Maillard reaction is typically characterized by the formation of brown nitrogenous polymers and copolymers.

The Maillard initiating reagents (e.g., DHA) are believed to react with the soluble amines in the skin's stratum cornenm, followed by the incorporation of the intermediates into the skin proteins. The reaction typically proceeds over an interval of three to five hours, at skin temperature, a pH of about 5, and in a moist environment. The reaction is generally inhibited by overly moist conditions and pretreatment of skin with formaldehyde.

For example, dihydroxyacetone reacts mainly with the upper portion of the skin keratin layer. When dihydroxyacetone reaches the lower part of the keratin layer, the water present in that layer is believed to stop the reaction according to the law of mass action.

The Maillard initiating reagent and the skin-modifying compound may be used in one or in separate compositions. Preferably, the Maillard initiating reagent and the skin-modifying compound are in separate compositions.

The compositions, as disclosed herein, may include one or more Maillard initiating reagents at a suitable level to produce the desired result. The amount of the Maillard initiating reagent typically depends upon its solubility in the desired solvents. Such compositions preferably include a total amount of at least 0.01 weight percent (wt-%), and preferably up to the saturation limit of the solvent(s) used, based on the total weight of a "ready to use" or "as used" composition.

The Maillard initiating reagent, preferably dihydroxyacetone, for example, may be present in a total amount of at least 0.01 weight percent (wt- %), preferably at least 0.1 wt-%, more preferably at least 1 wt-%, even more preferably at least 2 wt-%, and most preferably at least 3 wt-%, based on the total weight of the "ready to use" or "as used" composition. The Maillard initiating reagent, preferably dihydroxyacetone, is present in an amount of no greater than 40 wt-%, more preferably no greater than 10 wt-%, even more preferably no greater than 4 wt-%, and most preferably no greater than 3 wt-%, based on the total weight of the "ready to use" or "as used" composition. The

Maillard initiating reagent, preferably dihydroxyacetone, may be present in even higher amounts if the compositions are intended to be diluted prior to use.

Suitable solvents useful for the Maillard initiating reagent composition may include, for example, Ci to Cjo alcohols, glycerin, water, C ₂ -C ₄ alkoxydiglycols, fractionated coconut oil, Cs-C] ₅ alkyl palmitate, C ₈ -Ci ₅ alkyl benzoate, dimethicone, trisodium EDTA, Ci-C ₃ alkylparaben, propylene, and combinations thereof. Typically, the solvents include alcohols and/or water, or preferably, a mixture of alcohols and water.

Preferably, the Maillard initiating reagent is present in a composition comprising water, two- or three-carbon alcohols, and a nonreactive cosmetologically acceptable carrier.

The compositions, as disclosed herein, that include one or more Maillard initiating reagents may have a pH sufficient to produce the desired effect. Such compositions preferably include a pH of at least 3, preferably at least 4, and more preferably at least 5 in the "ready to use" or "as used" composition. In a preferred embodiment, the pH of the compositions is no greater than 7, more preferably no greater than 6, and even more preferably no greater than 5.

Preferably, the conditions effective to initiate a Maillard reaction with one or more proteins of the skin of the mammal comprise at least one hour at room temperature.

The compositions, as disclosed herein, may include one or more skin- modifying compounds at a suitable level to produce the desired result. The amount of the skin-modifying compound typically depends upon its' solubility in the desired solvents. Such compositions preferably include a total amount of such material of at least 0.001 weight percent (wt-%), and preferably up to the saturation limit of the solvent(s) used, based on the total weight of the "ready to use" or "as used" composition.

Suitable solvents useful for the skin-modifying compound compositions may include, for example, Cj to Qo alcohols, glycerin, water, C ₂ -C ₄ alkoxydiglycols, fractionated coconut oil, C ₈ -C] ₅ alkyl palmitate, C ₈ -C] ₅ alkyl benzoate, dimethicone, trisodium EDTA, Ci-C ₃ alkylparaben, propylene glycol, and combinations thereof. Typically, the solvents include alcohols and/or water, or preferably, a mixture of alcohols and water.

Preferably, the skin-modifying compound is present in a composition comprising water, two- or three-carbon alcohols, and a nonreactive cosmetologically acceptable carrier.

The compositions, as disclosed herein, that include one or more skin- modifying compounds may have a pH sufficient to produce the desired effect. Such compositions preferably include a pH of at least 3, preferably at least 4, and more preferably at least 5 in the "ready to use" or "as used" composition. In a preferred embodiment, the pH of the compositions is no greater than 7, more preferably no greater than 6, and even more preferably no greater than 5.

Preferably, the conditions effective to associate the skin-modifying compound with the Maillard initiating reagent comprise at least four hours at room temperature.

One or more Maillard initiating reagents may be used separately or in combinations. Likewise, one or more different skin-modifying compounds may be used separately or in combinations. Further, one or more Maillard initiating reagents may be used with one or more skin-modifying compounds.

In some embodiments, the skin-modifying compound covalently bonds with the Maillard initiating reagent.

Preferably, the skin-modifying compounds (e.g., fragrances, stabilizers, etc.) should not act as inhibitors of the Maillard reaction. Typically, the skin affords the amino groups and the carbonyl groups are present on the Maillard initiating reagent.

If the Maillard initiating reagent(s) and the skin-modifying compound(s) are combined in a single composition, the composition may contain at least one physiologically acceptable inhibitor of the Maillard reaction in an amount effective to substantially prevent condensation of amino groups and reactive carbonyl groups in the composition.

The inhibitor of the Maillard initiating reagent may be any known in the art. The inhibitor is present in an amount sufficient to prevent, or substantially prevent, condensation of amino groups and reactive carbonyl groups. Various classes of compounds are known to exhibit an inhibiting effect on the Maillard initiating reagent and may be useful in the compositions described herein. These compounds are generally either competitive or noncompetitive inhibitors. Competitive inhibitors include, but are not limited to, amino acid residues (both

D and L), combinations of amino acid residues, and peptides. Particularly preferred are lysine, arginine, histidine, and tryptophan. Lysine and arginine are the most effective. There are many known noncompetitive inhibitors. These include, for example, aminoguanidine and derivatives, amphotericin B, 4- hydroxy-5,8-dioxoquinoline derivatives, thiosemicarbazides, and benzoylhydrazine.

The Maillard initiating reagent(s) and the skin-modifying compound(s) may each be applied directly to the skin in various forms, for example, as a lotion, or when admixed with a hydrophilic cream base they may be applied as a cream or an ointment. Depending upon the physical form of the compositions, they may be painted, sprayed, or rubbed on the areas of the skin.

Compositions intended for application as sprays or mists, for example, may be formulated as aerosols by inclusion therein of aerosol propellants; the compositions may also be applied as sprays and mists without aerosols, generally using mechanical dispersion. Compositions may also be applied as milks, creams, gels or lotions, and rubbed into the skin. The amount of water contained within the compositions varies according to the desired consistency of the final product (i.e., free- or thick-flowing liquids, lotions, creams, gels or sticks). When the compositions are prepared as creams, any compatible readily available proprietary toilet or cosmetic or medicinal cream base including synthetic base may be used.

Typically, the Maillard initiating reagent(s) and the skin-modifying compound(s) may be prepared as separate compositions. Preferably, the Maillard initiating reagent(s) and the skin-modifying compound(s) are contained in separate portions of the same container and are allowed to mix substantially simultaneously upon application to the skin. This method avoids the instability of formulations containing both the Maillard initiating reagent and the skin-modifying compound.

Alternatively, the Maillard initiating reagent composition and the skin- modifying compound composition may be applied alternately with a waiting period between applications. In one embodiment, the Maillard initiating composition is applied first to the skin. After this composition has remained on the skin for a period of time, preferably less than fifteen minutes in some embodiments, preferably more than fifteen minutes in other embodiments, and

presumably during that period of time has commenced reaction with the skin, the skin-modifying compound composition is applied to the skin.

In one embodiment, the skin-modifying compound composition is applied first to the skin. After this composition has remained on the skin for a period of time, preferably less than fifteen minutes in some embodiments, preferably more than fifteen minutes in other embodiments, and presumably during that period of time has commenced reaction with the skin, the Maillard initiating reagent composition is applied to the skin.

Preferably, in the embodiments as disclosed herein, the Maillard initiating reagent(s) and the skin-modifying compound(s), whether applied separately or together, are applied at bedtime. Typically, the Maillard initiating reagent(s) and the skin-modifying compound(s) may be applied to the skin at least one time, preferably at least 4 times, and more preferably at least 7 times. Typically, increasing the number of applications increases the level of protection. The concept here is that application once a day at bedtime over the span of a week or more should produce a maximum effect by establishing a steady-state concentration gradient of DHA/napthoquionone-derived photoprotective melanoidins in the stratum corneum.

Typically, temperature of the skin upon application is at least 3O ⁰ C, preferably at least 36 ⁰ C, and more preferably at least 37 ⁰ C. Typically, the temperature of the skin upon application is no greater than 44 ⁰ C, preferably no greater than 39 ⁰ C, and more preferably no greater than 38 ⁰ C.

In one embodiment, the Maillard initiating reagent(s) and the skin- modifying compound(s) may be combined in one composition at the time of application and the resulting combined composition is applied in one-step. In one embodiment, this mixing may occur on the skin when the two compounds are applied substantially simultaneously.

Typically, Maillard initiating reagent(s) and the skin-modifying compound(s) may be present in the combined composition in the relative proportion of at least 1:1, preferably at least 2:1, and more preferably at least 5:1. Typically, Maillard initiating reagent(s) and the skin-modifying compound(s) may be present in the combined composition in the relative proportion of no greater than 50: 1, preferably no greater than 20:1, and more preferably no greater than 10:1.

The compositions of the present invention react with the skin to produce the desired effect. This reaction creates a modified epidermal layer of the skin, which cannot be removed easily by water, washing with soap, perspiration, or mild mechanical abrasion.

After a sufficient amount of the skin-modifying compound(s) is built up in the skin to produce the desired effect, there will be a slow loss of the desired effect due to desquamation over a period of two weeks. However, the desired effect may be maintained by a periodic treatment of the Maillard initiating reagent(s) and the skin-modifying compound(s), preferably, each night at bedtime.

Typically, the Maillard initiating reagent is a carbonyl-containing compound. Many compounds analogous to DHA can initialize Maillard reactions with proteins in the stratum corneum necessary for the skin bonding process. Generally, aldoses, ketoses, aldosamines, ketosamines and their fragmentation products, and combinations thereof, can be used as Maillard initiating reagents. Simple 2-6 carbon-containing carbonyl compounds with or without α- and vinylogously α-oxygen bonds or groups functionally equivalent to them, and hydrates, dimers, acetals, aminals, and imines of these compounds, and combinations thereof, may also be used as Maillard initiating reagents.

Suitable Maillard initiating reagents include, for example, dihydroxyacetone, monohydroxyacetone, 2-oxopropanal, 3-hydroxy-2- oxopropanal, glyceraldehyde, hydroxymalonaldehyde, malonaldehyde, glycoaldehyde, ribulose, diacetyl, hydroxydi acetyl, dihydroxydiacetyl, 2- hydroxy-3-oxobutanol, 2,4-dihydroxy-3-oxobutanal, 2-hydroxy-l ,4-butanedial, 2,3-dihydroxy-l,4-butanedial, alloxan, α-hydroxy-γ-butyrolactone, 2- furaldehyde, 5-(hydroxymethyl)-2-furaldehyde, glyoxal, and pyruvaldehyde (methylglyoxal), and combinations thereof.

Preferred Maillard initiating reagents include, for example, dihydroxyacetone, monohydroxyacetone, 2-oxopropanal, glyceraldehyde, glycoaldehyde, ribulose, diacetyl, 2,3-dihydroxy-l,4-butanedial, alloxan, α- hydroxy-γ-butyrolactone, 2-furaldehyde, 5-hydroxymethyl-2-furaldehyde, glyoxal, and combinations thereof.

More preferred Maillard initiating reagents include, for example, dihydroxyacetone, monohydroxyacetone, glyceraldehyde, glycoaldehyde,

ribulose, diacetyl, 2,3-dihydroxy-l,4-butanedial, alloxan, α-hydroxy-γ- butyrolactone, 2-furaldehyde, glyoxal, and combinations thereof.

The Maillard initiating reagents may be used singly or in admixture with one another.

These compounds are reactive with amino derivatives of proteins, as present in the skin of a mammal, to form melanoids. They are readily polymerizable. They are tolerable to the skin in that upon application, they do not normally cause undue discomfort arising from erythema, itching, burning, etc.

SKIN-MODIFYING COMPOUNDS

Suitable skin-modifying compounds (i.e., secondary compounds) have the following Formula (I):

wherein Y and X is independently selected from the group consisting of O, S, and NR, wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are organic groups (Preferably containing up to 20 carbon atoms).

In certain embodiments, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from the group consisting of hydrogen; methyl; primary, secondary, or tertiary (preferably C ₂ - C ₂₀ , more preferably C ₂ - C _J2 , and even more preferably, C ₂ -C ₆ ) branched and unbranched alkyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Cj - C ₇ , more preferably C]-C ₄ , and even

more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; vinyl;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -C] ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched alkenyl, alkadienyl, and alkatrienyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably Ci-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -C] ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched alkynyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, Cj-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -C] ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched cycloalkyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; phenyl; benzyl;

(preferably C] - C ₂₀ , more preferably C]-C] ₂ , and even more preferably, C]-C ₆ ) branched and unbranched mono-, di-, tri-, terra-, and penta-alkylphenyl, mono-, di-, tri-, terra-, and penta-cycloalkylphenyl, mono-, di-, tri-, tetra-, and penta-alkenylphenyl, and mono-, di-, tri-, tetra-, and penta-cycloalkenylphenyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Cj - C ₇ , more preferably Cj-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably Ci - C ₂₀ , more preferably Ci-Ci ₂ , and even more preferably, Ci-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta-alkylbenzyl, mono-, di-, tri-, tetra-, and penta-cycloalkylbenzyl, mono-, di-, tri-, tetra-, and penta-alkenybenzyl, and mono-, di-, tri-, tetra-, and penta-cycloalkenylbenzyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenyl amino; amino;

(preferably Cj - C ₂ o, more preferably C]-C] ₂ , and even more preferably, Ci-C ₆ ) branched and unbranched alkylamino, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; phenylamino; benzylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -Cj ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched alkenyl, alkadienyl, and alkatrienyl amino, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₁ - C ₂₀ , more preferably C]-C] ₂ , and even more preferably, C]-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylphenylamino, mono-, di-, tri-, tetra-, and penta-cycloalkylphenylamino, mono-, di-, tri-, tetra-, and penta-alkenylphenylamino, and mono-, di-, tri-, tetra-, and penta-cycloalkenylphenylamino, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, Cj-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably Ci - C20, more preferably C ₁ -Ci ₂ , and even more preferably, C]-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylbenzylamino, mono-, di-, tri-, tetra-, and penta-cycloalkylbenzylamino, mono-, di-, tri-, tetra-, and penta-alkenylbenzylamino, and mono-, di-, tri-, tetra-, and penta-cycloalkenylbenzylamino, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C ₁ - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; hydroxy; methoxy;

(preferably C ₂ - C ₂₀ , more preferably C ₂ -Cj ₂ , and even more preferably, C ₂ -C ₆ ) branched and unbranched alkoxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C ₁ - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₂ - C ₂₀ , more preferably C ₂ -C ₁₂ , and even more preferably, C ₂ -C ₆ ) branched and unbranched alkenyl, alkadienyl, and alkatrienyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -C] ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched cycloalkoxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; phenyloxy; benzyloxy;

(preferably C ₁ - C ₂₀ , more preferably C ₁ -Cj ₂ , and even more preferably, C ₁ -C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta-

alkylphenyloxy, mono-, di-, tri-, tetra-, and penta-cycloalkylphenyloxy, mono-, di-, tri-, tetra-, and penta-alkenylphenyloxy, and mono-, di-, tri-, tetra-, and penta-cycloalkenylphenyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably Cj-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably Ci - C ₂ o, more preferably C]-Ci ₂ , ^an d even more preferably, Ci -C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylbenzyloxy, mono-, di-, tri-, tetra-, and penta-cycloalkylbenzyloxy, mono-, di-, tri-, tetra-, and penta-alkenylbenzyloxy, and mono-, di-, tri-, tetra-, and penta-cycloalkenylbenzyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Ci - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; acetoxy;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -Ci ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched alkylcarbonyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Cj - C ₇ , more preferably C]-C ₄ , and even more preferably, Cj-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₂ - C ₂ o, more preferably C ₂ -C] ₂ , and even more preferably, C ₂ -C ₆ ) branched and unbranched alkenyl, alkadienyl, and alkatrienylcarbonyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably Cj-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -Cj ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched cycloalkylcarbonyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably Cj-C ₄ , and even more preferably, C]-C ₂ )

branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; benzoyloxy; phenylacetoxy;

(preferably Ci - C ₂₀ , more preferably C ₁ -Ci ₂ , and even more preferably, Cj-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylbenzoyloxy, mono-, di-, tri-, tetra-, and penta-cycloalkylbenzoyloxy, mono-, di-, tri-, tetra-, and penta-alkenylbenzoyloxy, and mono-, di-, tri-, tetra-, and penta-cycloalkenylbenzoyloxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Ci - C ₇ , more preferably CpC ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably Cj - C ₂₀ , more preferably C]-C] ₂ , and even more preferably, CpC ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylphenylacetoxy, mono-, di-, tri-, tetra-, and penta-cycloalkylphenylacetoxy, mono-, di-, tri-, tetra-, and penta-alkenylphenylacetoxy, and mono-, di-, tri-, tetra-, and penta-cycloalkenylphenylacetoxy, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Ci - C ₇ , more preferably Cj-C ₄ , and even more preferably, C)-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; formyl; acetyl;

(preferably C ₃ - C2 ₀ , more preferably C ₃ -C] ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched alkylcarbonyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably Cj - C ₇ , more preferably CpC ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₂ - C ₂ o, more preferably C ₂ -C] ₂ , and even more preferably, C ₂ -C ₆ ) branched and unbranched alkenyl, alkadienyl, and alkatrienylcarbonyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably Cj-C ₄ , and even

more preferably, C)-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino;

(preferably C ₃ - C ₂₀ , more preferably C ₃ -Cj ₂ , and even more preferably, C ₃ -C ₆ ) branched and unbranched cycloalkylcarbonyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C ₁ - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, Ci-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; benzoyl; phenylacetyl;

(preferably C ₁ - C ₂₀ , more preferably Ci-C] ₂ , and even more preferably, C]-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta-alkylbenzoyl, mono-, di-, tri-, tetra-, and penta-cycloalkylbenzoyl, mono-, di-, tri-, tetra-, and penta-alkenylbenzoyl, and mono-, di-, tri-, tetra-, and penta- cycloalkenylbenzoyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino; or

(preferably Cj - C ₂ o, more preferably Cj-C] ₂ , and even more preferably, Ci-C ₆ ) branched and unbranched mono-, di-, tri-, tetra-, and penta- alkylphenylacetyl, mono-, di-, tri-, tetra-, and penta-cycloalkylphenylacetyl, mono-, di-, tri-, tetra-, and penta-alkenylphenylacetyl, and mono-, di-, tri-, tetra- , and penta-cycloalkenylphenylacetyl, which can be further substituted with hydroxy, benzyloxy, aryloxy, amino, benzylamino, arylamino, (preferably C] - C ₇ , more preferably C]-C ₄ , and even more preferably, C]-C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino.

In the above discussion of compounds of Formula (I), in a phrase such as "(preferably Cj - C ₇ , more preferably Cj-C ₄ , and even more preferably, Q- C ₂ ) branched and unbranched alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, or dialkenylamino," the clause "(preferably C] - C ₇ , more preferably C ₁ -C ₄ , and even more preferably, Ci-C ₂ ) branched and

unbranched" modifies each of the following terms: alkoxy, alkenyloxy, alkylamino, alkenylamino, dialkylamino, alkenylalkylamino, and dialkenylamino.

Suitable skin-modifying compounds may include, for example, juglone, menadione, lawsone, vitamin K ₁ (phylloquinone), vitamin K ₂ (menaquinone), vitamin K ₃ (menadione), 2,6-dimethoxybenzoquinone, 2,5-dimethylquinone, 2,5-dihydroxy-3-undecyl-l,4-benzoquinone, 2-hydroxy-3-methyl-l,4- naphthoquinone, 3,5,8-trihydroxy-2-methyl- 1 ,4-naphthoquinone, 2-hydroxy-3- isobutyl-l,4-naphthoquinone, 1 ,2-naphthoquinone, 1,4-naphthoquinone, 2,2'- bi(3-hydroxy-l ,4-naphthoquinone), 2,3-dimethoxy-l ,4-naphthoquinone, 2- methoxy-1 ,4-naphthoquinone, 5, 8-dihydroxy-l ,4-naphthoquinone, phylloquinone, plumbagin, lapachol, 2,2 -ethylenebis(3-ethoxy)- 1,4- naphthoquinone, 2,2'-ethylenebis(3-hydroxy)-l ,4-naphthoquinone, 2,2'- ethylenebis(3-isopropyl)- 1,4-naphthoquinone, 2,2'-ethylenebis(3-methoxy)- 1,4- naphthoquinone, 2,2'-ethylenebis(3-methyl)-l ,4-naphthoquinone, 2,2 - ethylenedi- 1,4-naphthoquinone, 2,2'-methylenebis(3-hydroxy)- 1,4- naphthoquinone, 2,2'-methylenebis(3-hydroxy)- 1,4-naphthoquinone diacetate, 2,2'-methylenebis(3-methyl)- 1,4-naphthoquinone, 2,3, 5, 7-tetrahydroxy- 1,4- naphthoquinone, 2,3,5,7-tetrahydroxy-l,4-naphthoquinone, tetraacetate 2,3,5,7- tetramethoxy-1 ,4-naphthoquinone, 2,3,5, 8-tetrahydroxy-l ,4-naphthoquinone, 2,3,5,8-tetrahydroxy-l,4-naphthoquinone, 2,3-diacetate-2,3,5,8-tetrahydroxy-6- methyl-1 ,4-naphthoquinone, tetraacetate, 2,3,5-trihydroxy-l ,4-naphthoquinone, 2,3,5-trihydroxy-l ,4-naphthoquinone, triacetate 2,3,5-trihydroxy-7-methoxy- 1 ,4-naphthoquinone, 2,3,5-trimethoxy-l,4-naphthoquinone, 2,3,5-trimethyl- 1,4- naphthoquinone, 2, 3,6,7-tetramethyl- 1,4-naphthoquinone, 2,3, 6-trihydroxy- 1,4- naphthoquinone, 2,3,6-trimethyl- 1,4-naphthoquinone, 2,3-diacetamido- 1,4- naphthoquinone, 2,3-diethyl-l ,4-naphthoquinone, 2,3-dihydroxy-l ,4- naphthoquinone, 2,3-dihydroxy- 1 ,4-naphthoquinone, diacetate-2,3-dihydroxy- 5,6,7, 8-tetramethoxy-l ,4-naphthoquinone, 2,3-dihydroxy-5,7-dimethoxy-l ,4- naphthoquinone, 2,3-dihydroxy-5,7-dimethoxy-l ,4-naphthoquinone, diacetate- 2,3-dihydroxy-5,8-dimethoxy-l,4-naphthoquinone, 2,3-dihydroxy-5,8- dimethoxy-1 ,4-naphthoquinone, diacetate-2,3-dihydroxy-5,8-dimethyl-l ,4- naphthoquinone, 2,3-dihydroxy-5-methoxy-l ,4-naphthoquinone, 2,3-dihydroxy- 5-methoxy-l ,4-naphthoquinone, diacetate 2,3-dihydroxy-5-methyl-l ,4-

naphthoquinone, 2,3-dihydroxy-6,7-dimethoxy- 1 ,4-naphthoquinone, 2,3- dihydroxy-6-acetyl-l,4-naphthoquinone, 2,3-dihydroxy-6-ethyl-l,4- naphthoquinone, 2,3-dihydroxy-6-methoxy- 1 ,4-naphthoquinone, 2,3-dihydroxy- 6-methoxy-l,4-naphthoquinone, diacetate 2,3-dimethoxy-5,8-dimethyl-l,4- naphthoquinone, 2,3-dimethoxy-6,7-dimethyl- 1 ,4-naphthoquinone, 2,3- dimethyl-l,4-naphthoquinone, 2,5,6,7,8-pentahydroxy-3-methoxy-l,4- naphthoquinone, 2,5,6,7,8-pentamethoxy-l,4-naphthoquinone, 2,5,6,7- tetrahydroxy-1 ,4-naphthoquinone, 2,5,6,7-tetramethoxy- 1 ,4-naphthoquinone, 2,5,6,8-tetrahydroxy-l,4-naphthoquinone, 2,6-diacetoxy-5,8-dihydroxy-l,4- naphthoquinone, 2,5,6,8-tetrahydroxy-3,7-dimethoxy-l ,4-naphthoquinone, 2,6- diacetoxy-5,8-dihydroxy-3,7-dimethoxy-l,4-naphthoquinone, 2,5,6,8- tetrahydroxy-3,7-dimethyl-l,4-naphthoquinone, 2,5,6,8-tetrahydroxy-3- methoxy-l,4-naphthoquinone, 2,5,6,8-tetrahydroxy-3-methyl-l,4- naphthoquinone, 2,5,7, 8-tetrahydroxy-l ,4-naphthoquinone, 2,7-diacetoxy-5,8- dihydroxy-l,4-naphthoquinone, 2,5,7,8-tetrahydroxy-3,6-dimethoxy-l,4- naphthoquinone, 2,7-diacetoxy-5,8-dihydroxy-3,6-dimethoxy- 1 ,4- naphthoquinone, 2,5,7 -tri(te/-f-butyl)- 1 ,4-naphthoquinone, 2,5,7-trihydroxy- 1 ,4- naphthoquinone, 2,5,7-trimethoxy-l ,4-naphthoquinone, 2,5,8-trihydroxy-l ,4- naphthoquinone, 2,5, 8-trimethoxy-l ,4-naphthoquinone, 2-acetoxy-5,8- dihydroxy-l,4-naphthoquinone, 2,5,8-trihydroxy-3,6,7-trimethoxy-l,4- naphthoquinone, 2,5,8-trihydroxy-3,6-dimethoxy-l,4-naphthoquinone, 2,5,8- trihydroxy-3-methoxy-l,4-naphthoquinone, 2-acetoxy-5,8-dihydroxy-3- methoxy-1 ,4-naphthoquinone, 2,5, 8-triacetoxy-3-methoxy-6-methyl-l ,4- naphthoquinone, 2,5,8-trihydroxy-3-methyl-l ,4-naphthoquinone, 2,5,8- triacetoxy-3-methyl-l,4-naphthoquinone, 2,5,8-trihydroxy-6,7-dimethoxy-l,4- naphthoquinone, 2,5, 8-trihydroxy-6-methoxy-l ,4-naphthoquinone, 2,5,8- trihydroxy-7-methoxy-l,4-naphthoquinone, 2,5,8-trimethoxy-6-methyl-l,4- naphthoquinone, 2,5, 8-trimethoxy-7-methyl-l ,4-naphthoquinone, 2,5- dihydroxy-l,4-naphthoquinone, 2,5-dihydroxy-l,4-naphthoquinone 4-oxime, 2,5-diacetoxy-l ,4-naphthoquinone, 2,5-dihydroxy-3-methyl-l ,4- naphthoquinone, 2,5-diacetoxy-3-methyl-l ,4-naphthoquinone, 2,5-dihydroxy- 6,7-dimethoxy-l,4-naphthoquinone, 2,5-dihydroxy-7-methoxy-3-(5-oxohexyl)- 1 ,4-naphthoquinone, 2,5-dihydroxy-7 -methyl- 1 ,4-naphthoquinone, 2,5- dimethyl-1 ,4-naphthoquinone, 2,6,7, 8-tetramethoxy-l ,4-naphthoquinone, 2,6,7-

trimethyl-l,4-naphthoquinone, 2,6,7-trimethyl-3-phytyl-l,4-naphthoquinone, 2,6,8-trihydroxy-l ,4-naphthoquinone, 2,6,8-trimethoxy- 1 ,4-naphthoquinone, 2,6,8-trimethyl-l,4-naphthoquinone, 2,6-di(te?t-butyl)-l,4-naphthoquinone, 2,6- diacetyl-3,5,8-trihydroxy-l,4-naphthoquinone, 2,6-diacetyl-5,8-dihydroxy-l,4- naphthoquinone, 2,6-diacetyl-5,8-dihydroxy-3,7-dimethoxy-l ,4- naphthoquinone, 2,6-dihydroxy- 1 ,4-naphthoquinone, 2,6-diacetoxy- 1 ,4- naphthoquinone, 2,6-dimethoxy-l,4-naphthoquinone, 2,6-dimethoxy-3-methyl- 1 ,4-naphthoquinone, 2,6-dimethyl-l,4-naphthoquinone, 2,7,8-triacetoxy-l,4- naphthoquinone, 2,7-di(tert-butyl)-l,4-naphthoquinone, 2,7-diacetyl-3,5,6,8- tetrahydroxy-l,4-naphthoquinone, 2,7-diacetyl-5,8-dihydroxy-3,6-dimethoxy- 1 ,4-naphthoquinone, 2,7-dihydroxy-l ,4-naphthoquinone, 2,7-dihydroxy-3- methyl-6-octyl- 1 ,4-naphthoquinone, 2,7-diacetoxy-3-methyl-6-octyl- 1 ,4- naphthoquinone, 2,7-dimethoxy- 1 ,4-naphthoquinone, 2,7-dimethyl- 1 ,4- naphthoquinone, 2,8-dihydroxy-l,4-naphthoquinone, 2,8-diacetoxy-l,4- naphthoquinone, 2,8-dihydroxy-3-(4-hydroxy-3,7,l l-trimethyldodecyl)-5- isopentyl-6,7-dimethyl-l,4-naphthoquinone, 2,8-dihydroxy-6-methoxy-l,4- naphthoquinone, 2,8-dimethyl- 1 ,4-naphthoquinone, 2-( 1 ,2-dimethylallyl)-3- hydroxy-l,4-naphthoquinone, 2-(l,2-dimethylpropenyl)-3-hydroxy-l,4- naphthoquinone, 2-( l-hydroxyethyl)-l ,4-naphthoquinone, 2-(l-acetoxyethyl)-l,4-naphthoquinone, 2-(l-hydroxyethyl)-3-methyl-l,4- naphthoquinone, 2-(l-acetoxyethyl)-3-methyl-l,4-naphthoquinone, 2-(l 1- cyclopropylundecyl)-3-hydroxy-l,4-naphthoquinone, 2-(12- cyclopropylundecyl)-3-hydroxy-l ,4-naphthoquinone, 2-( 12-hydroxy-3,7, 11 - trimethyl-2-dodecenyl)-3-methyl- 1 ,4-naphthoquinone, 2-(2,3-dihydroxy-3- methylbutyl)-3-hydroxy- 1 ,4-naphthoquinone, 2-(2-cyclohexylethyl)-3-hydroxy- 1,4-naphthoquinone, 2-cyclohexyl-3-hydroxy-l ,4-naphthoquinone, 2-(2- eicosenyl)-3-methyl-l ,4-naphthoquinone, and 2-(2-hexadecenyl)-3-methyl-l ,4- naphthoquinone.

In one embodiment, preferred skin-modifying compounds may include, for example, lawsone, juglone, vitamin K ₁ (phylloquinone), vitamin K ₂ (menaquinone), vitamin K ₃ (menadione), 5-hydroxy-2-methylnaphthoquinone, 5-hydroxy-2,3-dimethylnaphthoquinone, 2-hydroxy-5-methylnaphthoquinone, 2-hydroxy-8-methylnaphthoquinone, 2-hydroxy-6-methylnaphthoquinone, 5- acetoxynaphthoquinone, 2,2-bis-(5-naphthoqinonyloxy)propane, 3-[bis(2-

hydroxy- l,4-naphthoquinonyl)]methane, 2-hydroxy-3-[(/V-octylamino)methyl]- 1,4-naphthoquinone, 3-[2-(4-ethoxycarbonylphenylamino)ethyl]methyl-2- hydroxy- 1 ,4-naphthoquinone, 3-[2-(4-t-butylbenzoyl)-2-(4- methoxybenzoyl)ethyl]-2-hydroxy-l ,4-naphthoquinone, 3-[(4-f- butylbenzoyl)(4-methoxybenzoyl)methyl]-2-hydroxy- 1 ,4-naphthoquinone, 5-(4- aminophenylcarbonyloxy)-l,4-naphthoquinone, l-(4-f-butylphenyl)-3-[4-(l,4- naphthoquinoyl-5-oxy)phenyl]- 1 ,3-propanedione, 2-[(4-t-butylbenzoyl)(4- methoxybenzoyl)methyl]-5-hydroxy-l,4-naphthoquinone, l-(4- aminobenzoyloxy)-3-hydroxy-2-propanone, l-(4-t-butylphenyl)-3-[4-(3- hydroxy-2-oxoprop-5-oxy)phenyl]-l,3-propanedione, alpha-(3-hydroxy-2- oxopropoxy)avobenzone, 2-hydroxy-3-(3-hydroxy-2-oxopropyl)-l,4- naphthoquinone, 5-(3-hydroxy-2-oxopropoxy)-l ,4-naphthoquinone, 2-hydroxy- 3-[2-(4-[3-hydiOxy-2-oxopropoxycarbonyl]phenylaminoethyl)met hyl]-l,4- naphthoquinone, 2-hydroxy-3-(2-[4-r-butylbenzoyl]-2-[4-(3-hydroxy-2- oxopropoxy)benzoyl]ethyl)-l ,4-naphthoquinone, 3-(4- ethoxycarbonylphenylamino)-5-(3-hydroxy-2-oxopropoxy)- 1 ,4- naphthoquinone, and 5-hydroxy-3-[2-(4-f-butylbenzoyl)-2-(4- methoxybenzoyl)methyl]-l,4-naphthoquinone, and combinations thereof.

In one embodiment, more preferred skin-modifying compounds may include, for example, lawsone, juglone, vitamin Ki (phylloquinone), vitamin K ₂ (menaquinone), vitamin K ₃ (menadione), 5-hydroxy-2-methylnaphthoquinone, 5-hydroxy-2,3-dimethylnaphthoquinone, 2-hydroxy-5-methylnaphthoquinone, 2-hydroxy-8-methylnaphthoquinone, 2-hydroxy-6-methylnaphthoquinone, and combinations thereof.

In one embodiment, more preferred skin-modifying compounds may include, for example, 3-[bis(2-hydroxy-l,4-naphthoquinonyl)]methane, 2- hydroxy-3-[(7V-octylamino)methyl]-l ,4-naphthoquinone, 3-[2-(4- ethoxycarbonylphenylamino)ethyl]methyl-2-hydroxy- 1 ,4-naphthoquinone, 3- [2-(4-t-butylbenzoyl)-2-(4-methoxybenzoyl)ethyl]-2-hydroxy-l ,4- naphthoquinone, 3-[(4-r-butylbenzoyl)(4-methoxybenzoyl)methyl]-2-hydroxy- 1,4-naphthoquinone, 5-(4-aminophenylcarbonyloxy)-l,4-naphthoquinone, l-(4- t-butylphenyl)-3-[4-( 1 ,4-naphthoquinoyl-5-oxy)phenyl]-l ,3-propanedione, 2- [(4-/-butylbenzoyl)(4-methoxybenzoyl)methyl]-5-hydroxy-l,4-n aphthoquinone, l-(4-aminobenzoyloxy)-3-hydroxy-2-propanone, l-(4-t-butyIphenyl)-3-[4-(3-

hydroxy-2-oxoprop-5-oxy)phenyl]-l,3-propanedione, alpha-(3-hydroxy-2- oxopropoxy)avobenzone, 2-hydroxy-3-(3-hydroxy-2-oxopropyl)- 1 ,4- naphthoquinone, 5-(3-hydroxy-2-oxopropoxy)-l ,4-naphthoquinone, 2-hydroxy- 3-[2-(4-[3-hydroxy-2-oxopropoxycarbonyl]phenylaminoethyl)met hyl]-l,4- naphthoquinone, 2-hydroxy-3-(2-[4-f-butylbenzoyl]-2-[4-(3-hydroxy-2- oxopropoxy)benzoyl]ethyl)-l ,4-naphthoquinone, 3-(4- ethoxycarbonylphenylamino)-5-(3-hydroxy-2-oxopropoxy)- 1 ,4- naphthoquinone, 5-hydroxy-3-[2-(4-t-butylbenzoyl)-2-(4- methoxybenzoyl)methyl]-l,4-naphthoquinone, and combinations thereof.

In one embodiment, the present invention provides that the skin- modifying compound(s) is not juglone (5-hydroxy-l,4-napthoquinone); menadione (2-methyl-l,4-napthoquinone); lawsone (2-hydroxy-l ,4- napthoquinone); 2,6-dimethoxybenzoquinone; 2,5-dimethylquinone; 2,5- dihydroxy-3-undecyl- 1 ,4-benzoquinone; 2-hydroxy-3-methyl- 1 ,4- napthoquinone; 3,5,8-trihydroxy-2-methyl-l,4-napthoquinone; or 2-hydroxy-3- isobutyl- 1 ,4-napthoquinone.

In another embodiment, the present invention provides that if only one skin-modifying compound(s) is used, it is not a quinone.

In yet another embodiment, the present invention provides that the skin- modifying compound(s) is not a quinone when the Maillard initiating reagent(s) is dihydroxyacetone, 5-(hydroxymethyl)-2-furaldehyde, pyruvic aldehyde, glyceraldehyde, alloxan, or monohydroxyacetone.

The skin-modifying compounds may be used singly or in admixture with one another.

The compositions of the present invention may also include, for example, a nonreactive cosmetologically acceptable carrier. The nonreactive cosmetologically acceptable carrier includes acidifying and alkalizing agents; aerosol propellants; antimicrobial agents including antibacterial, antifungal and antiprotozoal agents; antimicrobial preservatives; antioxidants; buffering agents; chelating agents; coloring additives including dyes and pigments; dermatologically active agents; dispersing agents; emollients; emulsifying agents including emulsifying and stiffening agents and emulsion adjuncts; excipients; humectants; ointment bases; penetration enhancers; perfumes and fragrances; preservatives; sequestering agents; solvents; stabilizers; stiffening

agents; sugars; sunscreen agents; surfactants; suspending agents; thickening agents; vehicles; viscosity-increasing agents; wetting agents; and wetting and/or solubilizing agents.

EXAMPLES

Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

ABBREVIATIONS, DESCRIPTIONS, AND SOURCES OF MATERIALS

Example 1

Reaction of 1,4-Naphthoquinones (NQ) with dihydroxyacetone (DHA) to form covalent adducts with nucleophilic side chains of amino acid residues common to soft α-keratins.

Add 10 milliliters (mL) of a 0.1 Molar (M) DCM solution of amino acid amide N-Boc-Cys-N-πBu, (N-Boc-Cys-N-7zBu) ₂ , N-Boc-Lys-N-nBu, N-Boc- Tyr-N-/zBu, or N-Boc-Ser-N-nBu at room temperature to 5 mL of a 0.1 M (molar) DCM solution of DHA. Stir for 60 minutes (min); add 5 ml of a 0.1 M DCM solution of a NQ; and stir for 16 hours (h). Monitor adduct formation with thin layer chromatography (TLC) and isolate adducts with column chromatography. Identify adducts with Infrared Spectroscopy (IR), Ultraviolet- Visible Spectroscopy (UV-Vis), ¹ H Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR), ¹³ C Nuclear Magnetic Resonance Spectroscopy ( ¹³ C NMR), and Mass Spectrometry (MS).

Example 2

Reaction of 1 ,4-Naphthoquinones (NQ) with dihydroxyacetone (DHA) to form covalent adducts with nucleophilic side chains of amino acid residues common to soft α-keratins and have λ _max values in the UV-Vis range of 405-415 nanometers (nm).

Take up the crude and purified adducts of Example 1 in ethanol and dilute to a working concentration of 100 milligram/liter (mg/1). Determine the λ _max values by serial dilution using Ultraviolet- Visible Spectroscopy (UV-Vis). Augment the molar absorptivity in the 405-415 nm range by assaying using equivalent concentration solutions of NQ and amino acid amide, DHA and amino acid amide, NQ and DHA, NQ alone, DHA alone, and amino acid amide alone.

Example 3 Reaction of 1,4-Naphthoquinones (NQ) with dihydroxyacetone (DHA) to form covalent adducts with nucleophilic side chains of soft α-keratins.

A. Add 1.8 mL of a 1.0 milligram/milliliter (mg/mL) aqueous solution of DHA to 2 mL of a 20 mg/mL, 8 M urea, 50 millimolar (mM) TRIS, 0.1 M.β- mercaptoethanol and a 0.1 % sodium azide room temperature solution of α-

keratin from human callus. Stir for 60 minutes, add a 3.0 micromolar (μmol) of a 1.0 rng/mL aqueous solution of NQ, and stir for 16 hours. Lyophilize the reaction and purify the lyophilate on a G75 column with a pH 7.6 buffer containing 0.5% Sodium Dodecyl Sulfate (SDS), 10 mM Tris(hydroxymethyl)aminomethane hydrochloride (TRIS-HCl) and 10 mM Dithiothreitol (DTT). Pool the appropriate fractions and dialyze against water to provide purified keratinaceous material. Generate a peptide sequencing map by Mass Spectrometry-Mass Spectrometry (MS-MS). Identify the modified residues and provide the stoichiometry of adduct formation by normalized differential MS-MS versus unmodified α-keratin.

B. Add 1.8 mL of a 1.0 mg/mL aqueous solution of 1,2,3- ¹³ C-DHA to 2 mL of a 20 mg/mL, 8 M urea, 50 mM TRIS, 0.1 M. β-mercaptoethanol and 0.1% sodium azide room temperature solution of α-keratin from human callus. Stir for 60 minutes, add 3.0 μmol of a 1.0 mg/mL aqueous solution of all- ¹³ C- NQ, and stir for 16 hours. Lyophilize the reaction and purify the lyophilate on a G75 column with a pH 7.6 buffer containing 0.5% SDS, 10 mM TRISΗC1 and 10 mM DTT. Pool the appropriate fractions and dialyze against water to provide purified keratinaceous material. Analyze the purified keratinaceous material by ¹³ C Nuclear Magnetic Resonance Spectroscopy to determine adduct structure.

Example 4

Reaction of 1 ,4-Naphthoquinones (NQ) with dihydroxyacetone (DHA) to form covalent adducts with nucleophilic side chains of soft α-keratins and have λ _max values in the UV-Vis range of 405-415 nm.

Take up the crude and purified keratinaceous material of Example 3 A in ethanol and dilute to a working concentration of 100 mg/1. Determine λ _max values by serial dilution using Ultraviolet- Visible Spectroscopy (UV-Vis). Augment the molar absorptivity in the 405-415 nm range by assaying using equivalent concentration solutions of keratinaceous materials derived from NQ and α-keratin, DHA and α-keratin, NQ and DHA, NQ alone, DHA alone, and α- keratin alone.

Example 5

Preparation of 3-[Bis(2-hydroxy-l,4-naphthoquinonyl)]methane.

A 50 mL round bottom flask was equipped with a magnetic stirring bar, heating mantle, and reflux condenser. In a separate 50 mL Erlenmeyer flask, 0.87 g ( 5.0 mmol) of lawsone was dissolved in 25 mL of glacial acetic acid by warming. 0.5 mL (6.4 mmol) of formalin was added, followed by 0.5 mL of boron trifluoride etherate. The warm solution immediately clarified by vacuum filtration, then transferred to the 50 mL round bottom flask. The solution was heated with stirring at 100 ⁰ C for 1.5 h. Cooling to room temperature was followed by vacuum filtration and air drying to afford 0.54 g (60%) of 3-[bis(2- hydroxy-l,4-naphthoquinonyl)]methane: m.p. 248-250°C (dec); Literature m.p. 249-251 ⁰ C (dec) (L.F. Fieser, et al., J. Am. Chem. Soc. 1948, 70, 3174-3215).

The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.