FIELD OF INVENTION

The present invention relates to compounds produced by or derived from aMalasseziayeast, as well as chemical analogs thereof. Compounds of the present invention, and compositions containing said compounds, have, among other beneficial properties, photoprotective properties. Methods of using the compounds and compositions of the present invention are also contemplated.

BACKGROUND OF THE INVENTION

Individuals around the world use skin brightening agents to achieve a number of cosmetic goals, including producing an anti-aging effect, correcting sun damage, and meeting certain cultural standards of beauty. Many commercially available skin brightening products, while effective to varying degrees, contain harmful ingredients, some of which have been linked to cancer. Thus, there exists a need for novel skin brightening agents and formulations that exhibit higher levels of safety and/or efficacy than agents currently on the market.

Malasseziais a genus of lipophilic yeast commonly found in the normal flora of human skin.Malasseziais responsible for a number of skin diseases, including tinea versicolor (pityriasis versicolor), seborrheic dermatitis, and atopic dermatitis.

The natural habitat forM. furfuris the upper epidermis. However, exposure to ultraviolet light destroys the organism in its natural habitat. Therefore, UV filtering agents may be necessary for the survival of the organism. Two such UV-filtering indoles produced by the organism have been identified: pityriacitrin and pityrialactone. Pityriacitrin, first described in Mayser et al., 2002, is synthesized byM. furfur. It is a stable yellow lipophilic compound showing broad absorption in the UVA, UVB, and UVC spectrum. A similar compound from the genusParacoccushas been isolated and patented as a UV protective agent. (Zhang et al., 2018).

Gambichler et al., 2007 investigated the UV protective effect of pityriacitrin in humans using in vitro and in vivo test methods. Spectrophotometry of pityriacitrin cream and vehicle was performed in the 290-400 nm wavelength range. UV transmission and the sun protection factor (“SPF”) were assessed for different cream formulations. Using colorimetry, the authors evaluated erythema and pigmentation following irradiation of cream-protected and non-protected skin of healthy subjects. UVB as well as UVA transmission decreased with increasing pityriacitrin concentrations. An increase of pityriacitrin concentration of 1.25, 2.5, and 5% was associated with slightly increasing SPFs of 1.4, 1.5, and 1.7, respectively. The in vivo tests confirmed the validity of the SPF of pityriacitrin 5% cream determined in vitro. Overall, the UV protective effect of pityriacitrin was very weak, suggesting that pityriacitrin likely is only an inferior cofactor in the development of hypopigmentation in pityriasis versicolor alba lesions following sun exposure.

Further studies of the UV filtering effects of pityriacitrin were performed on human skin microflora. (Machowinski et al., 2006). The authors determined pityriacitrin has a UV-protective effect onCandida albicansand staphylococci with no toxicity in the ranges tested. The UV protective properties of pityrialactone have also been confirmed in a yeast model. (Mayser et al., 2003). Pityrialactone appears to be responsible for the yellow fluorescence of Tinea Versicolor under Wood's Light examination.

Tinea versicolor is a non-contagious skin disease caused byMalasseziaovergrowth that locally alters pigmentation levels.Malasseziayeasts have two metabolic pathways for synthesizing melanin and tryptophan-derived indole pigments. Malassezin and Indirubin are tryptophan metabolites ofMalasseziathat may contribute to the depigmentation characteristic ofMalasseziaovergrowth.

The invention disclosed herein utilizes compounds produced by or derived fromMalasseziayeast, including Malassezin. Indirubin, and chemical analogs thereof, as the basis for safe and efficacious skin brightening and skin darkening compositions. Photoprotective compositions comprising Malassezin, Indirubin, and chemical analogs thereof are also disclosed herein.

SUMMARY OF THE INVENTION

One embodiment of the present invention is a compound for brightening skin. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating melanocyte activity. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a compound for agonizing the arylhydrocarbon receptor (AhR). The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for improving hyperpigmentation caused by a hyperpigmentation disorder. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating melanin production. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a compound for modulating melanosome biogenesis. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for modulating melanosome transfer. The compound is a chemical analog of a compound produced by aMalasseziayeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a composition. The composition comprises aMalasseziayeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier. An additional embodiment of the present invention is a composition. The composition comprises a compound isolated or isolatable from aMalasseziayeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

Another embodiment of the present invention is a composition. The composition comprises any of the compounds, including analogs, disclosed herein and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

A further embodiment of the present invention is a method of brightening skin in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

An additional embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

Another embodiment of the present invention is a method for modulating melanocyte activity in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

A further embodiment of the present invention is a method for agonizing an arylhydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

An additional embodiment of the present invention is a method for improving hyperpigmentation caused by a hyperpigmentation disorder in a subject in need thereof. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

Another embodiment of the present invention is a method for modulating melanin production in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

A further embodiment of the present invention is a method for modulating melanosome biogenesis in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

An additional embodiment of the present invention is a method for modulating melanosome transfer in a subject. The method comprises contacting the subject with any of the compounds or compositions disclosed herein.

Another embodiment of the present invention is a compound. The compound has the structure of formula (II):


wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 is methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound. The compound has the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a compound for brightening skin. The compound has the structure of formula (II)


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for brightening skin. The compound has the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for agonizing the arylhydrocarbon receptor (AhR). The compound has the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for agonizing the arylhydrocarbon receptor (AhR). The compound has the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a composition. The composition comprises a compound having the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

Another embodiment of the present invention is a composition. The composition comprises a compound having the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises: contacting the subject with a compound having the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a method for brightening skin in a subject. The method comprises: contacting the subject with a compound having the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises: contacting the subject with a compound having the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises: contacting the subject with a compound having the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for agonizing an arylhydrocarbon receptor (AhR) in a subject. The method comprises: contacting the subject with a compound having the structure of formula (II):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for agonizing an arylhydrocarbon receptor (AhR) in a subject. The method comprises: contacting the subject with a compound having the structure of formula (III):


wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

One embodiment of the present invention is a compound. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; wherein: if Rais hydrogen, Y is CR5R6, and R13and R14are both hydrogen, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11is R16; or, R5is selected from the group consisting of hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10is not hydrogen; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

An additional embodiment of the present invention is a compound for brightening skin. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond. CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for brightening skin. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for brightening skin. The compound is selected from the group consisting of:



An additional embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound is selected from the group consisting of:



An additional embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound is selected from the group consisting of:



An additional embodiment of the present invention is a compound for modulating melanogenesis. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond. CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating melanogenesis. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for modulating melanogenesis. The compound is selected from the group consisting of:



An additional embodiment of the present invention is a compound for modulating melanin concentration. The compound has the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating melanin concentration. The compound has the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound for modulating melanin concentration. The compound is selected from the group consisting of:



An additional embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a composition. The composition comprises a compound selected from the group consisting of:



An additional embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R11is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:



An additional embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond. CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:



An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:



An additional embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond. CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R6, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:



An additional embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: X is selected from the group consisting of NR14and O; Y is a covalent bond. CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the structure of the following formula:


wherein: R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:



One embodiment of the present invention is a compound for brightening skin. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a compound for modulating melanogenesis. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a compound for modulating melanin concentration. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a composition comprising a compound. The compound has a structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula:


or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a composition for brightening skin. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a composition for inducing melanocyte apoptosis. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a composition for modulating arylhydrocarbon receptor (AhR) activity. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a composition for modulating melanogenesis. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a composition for modulating melanin concentration. The composition comprises one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

A further embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

An additional embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. A further embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof.

Another embodiment of the present invention is a composition. The composition comprises aMalasseziayeast and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

An additional embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula:


wherein:
X is selected from the group consisting of NR14and O; Y is a covalent bond, CR5R6, O, or NR15; R1, R2, R3, R4, R7, R8, R9, R10, and R11are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R16, or OR16; R13, R14, and R15are independently hydrogen or R16; R5and R6are independently selected from the group consisting of hydrogen, hydroxyl, OR16, R16, and C3-6cycloalkyl, or R5and R6combine to form an oxo (═O) group or a C3-6cycloalkyl; R12is selected from the group consisting of hydrogen, —CORa, and R16; each R16is independently formyl, C1-9alkyl, C2-9alkenyl, or C2-9alkynyl; and, Rais selected from the group consisting of hydrogen, hydroxyl, and OR16:
or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof,
and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

A further embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula:


wherein:
R1, R4, R5, R6, R9, and R10are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO; R2and R3are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R2and R3combine to form a 5- or 6-membered heterocyclyl; R7and R8are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R13, OR13, OCOR13and —CHO, or R7and R8combine to form a 5- or 6-membered heterocyclyl; R11and R12are independently hydrogen or R13; and, each R13is independently C1-9alkyl, C2-9alkenyl, or C2-9alkynyl:
or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof,
and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

Another embodiment of the present invention is a composition. The composition comprises a compound listed in Table 5 orFIG. 130, or a chemical analog, crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

An additional embodiment of the present invention is a method of treating or preventing UV-induced skin damage in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

A further embodiment of the present invention is a method of treating or preventing UV-induced erythema in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

Another embodiment of the present invention is a method of treating or preventing UV-induced aging of the skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

An additional embodiment of the present invention is a method of treating or preventing sunburn in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

A further embodiment of the present invention is a method of treating or preventing UV-induced hyperpigmentation in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

Another embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

An additional embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

A further embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

Another embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

An additional embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with any of the compositions disclosed herein.

