13-Oxyodendron diterpene alcohol derivatives and uses thereof
阅读说明：本技术 13-氧化巨大戟二萜醇衍生物及其用途 (13-Oxyodendron diterpene alcohol derivatives and uses thereof ) 是由 吴潇 潘勤 李彦赟 杨昱 管玉真 吴晓磊 孙传腾 王原 于 2018-06-07 设计创作，主要内容包括：涉及13-氧化巨大戟二萜醇的衍生物,其用于预防和/或治疗与受试者的增生或肿瘤相关的疾病或美容适应症的用途,以及其用于预防和/或治疗对嗜中性粒细胞的氧化爆发有响应的疾病,对角质形成细胞的IL-8释放有响应的疾病,或对诱导坏死有响应的疾病的用途。(Relates to derivatives of 13-oxoingenol, to the use thereof for the prevention and/or treatment of diseases or cosmetic indications associated with hyperplasia or tumors in a subject, and to the use thereof for the prevention and/or treatment of diseases responsive to the oxidative burst of neutrophils, to the release of IL-8 from keratinocytes, or to the induction of necrosis.)
A compound shown as a formula (I), and pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystal form thereof,
wherein the content of the first and second substances,
R1selected from hydrogen and M-C (O) -, wherein M is selected from hydrogen and C1-C11Straight or branched alkyl, C2-C11Straight or branched chain alkenyl, 6-10 membered aryl and 5-8 membered heteroaryl;
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from hydrogen and C1-C11Straight or branched alkyl, C2-C11Linear or branched alkenyl, 5-8 membered cycloalkyl, 6-10 membered aryl, 5-8 membered lipoheterocyclyl, 5-8 membered heteroaryl, 8-10 membered saturated or semi-saturated fused heterocyclyl, NR 'R ", wherein R' is C1-C4Straight or branched chain alkyl, R "is phenyl optionally substituted with halogen;
R3selected from hydrogen, hydroxyl and X-C (O) -O-, wherein X is selected from hydrogen, C1-C11Straight or branched alkyl, C2-C11Linear or branched alkenyl, 5-8 membered cycloalkyl, 6-10 membered aryl, 5-8 membered lipoheterocyclyl, 5-8 membered heteroaryl, 8-10 membered saturated or semi-saturated fused heterocyclyl, NR 'R ", wherein R' is C1-C4Straight or branched chain alkyl, R "is phenyl optionally substituted with halogen;
optionally, said C1-C11Straight or branched alkyl or C2-C11Linear or branched alkenyl groups are independently substituted with one or more phenyl groups, optionally substituted with methyl;
optionally, the 5-8 membered cycloalkyl, 6-10 membered aryl, 5-8 membered lipoheterocyclyl, 5-8 membered heteroaryl, or 8-10 membered saturated or semi-saturated fused heterocyclyl is independently substituted with one or more substituents selected from the group consisting of: halogen, C1-C4Straight chainOr branched alkyl, C1-C4Straight-chain or branched alkoxy, phenyl, -NH2、-NHCH3and-NH-CH2-Ph；
Preferably, when R is2When Q-C (O) -is present, R3Is hydrogen or hydroxy, more preferably hydroxy;
preferably, when R is3When X-C (O) -O-, R2Is hydrogen.
The compound of claim 1, a pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof, wherein R1Selected from hydrogen and M-C (O) -, wherein M is selected from C1-C11Straight chain alkyl (e.g., methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl) and C2-C11Straight chain alkenyl groups (e.g., nonadienyl, nonatrienyl);
preferably, R1Selected from hydrogen and M-C (O) -, wherein M is selected from methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl, 1, 3-nonadienyl and 1, 3, 5-nonatrienyl.
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of claim 1 or 2, wherein R2Selected from hydrogen and Q-C (O) -, wherein Q is selected from C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing aliphatic heterocyclic group, 5-6 membered heteroaryl, 8-10 membered semi-saturated nitrogen containing fused heterocyclic group, NR 'R ", wherein R' is methyl and R" is phenyl optionally substituted by halogen; in the 5-6 membered heteroaryl, the heteroatom is selected from nitrogen and oxygen;
optionally, said C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight-chain alkenyl or C3-C5The branched alkenyl groups are independently substituted with one or more phenyl groups, optionally substituted with methyl groups;
optionally, aThe 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing alicyclic heterocyclic group, 5-6 membered heteroaryl or 8-10 membered semi-saturated nitrogen containing fused heterocyclic group is independently substituted with one or more substituents selected from the group consisting of: halogen, methyl, ethyl, methoxy, phenyl, -NH2、-NHCH3and-NH-CH2-Ph；
Preferably, R2Selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-pentyl, tert-butyl,
Preferably, R2Selected from hydrogen and Q-C (O) -, wherein Q is selected from C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight chain alkenyl, C3-C5A branched alkenyl group, a 5-membered heteroaryl group substituted with an ethyl group, wherein in the 5-membered heteroaryl group, the heteroatoms are selected from nitrogen and oxygen;
preferably, R2Selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-pentyl, tert-butyl,
Preferably, R2Selected from hydrogen and Q-C (O) -,wherein Q is selected from methyl, n-propyl,
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-3, wherein R3Selected from hydrogen, hydroxyl and X-C (O) -O-, wherein X is selected from hydrogen, C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing aliphatic heterocyclic group, 5-6 membered heteroaryl, 8-10 membered semi-saturated nitrogen containing fused heterocyclic group, NR 'R ", wherein R' is methyl and R" is phenyl optionally substituted by halogen; in the 5-6 membered heteroaryl, the heteroatom is selected from nitrogen and oxygen;
optionally, said C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight-chain alkenyl or C3-C5The branched alkenyl groups are independently substituted with one or more phenyl groups, optionally substituted with methyl groups;
optionally, the 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing lipidic heterocyclyl, 5-6 membered heteroaryl or 8-10 membered semi-saturated nitrogen containing fused heterocyclyl is independently substituted with one or more substituents selected from the group consisting of: halogen, methyl, ethyl, methoxy, phenyl, -NH2、-NHCH3and-NH-CH2-Ph；
Preferably, R3Selected from the group consisting of hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from the group consisting of methyl, n-propyl, tert-butyl, n-pentyl,
Preferably, R3Selected from hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from C1-C3Straight chain alkyl, C3-C5Straight chain alkenyl, C3-C5A branched alkenyl group and a 5-membered heteroaryl group substituted with an ethyl group, wherein in the 5-membered heteroaryl group, the heteroatoms are selected from nitrogen and oxygen;
preferably, R3Selected from the group consisting of hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from the group consisting of methyl, n-propyl, n-pentyl, tert-butyl, n-pentyl,
Preferably, R3Selected from the group consisting of hydroxyl and X-C (O) -O-, wherein X is selected from the group consisting of n-propyl, n,
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-4, wherein,
R1selected from hydrogen and M-C (O) -, wherein M is selected from C1-C11Straight chain alkyl (e.g., methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl) and C2-C11Straight chain alkenyl groups (e.g., nonadienyl, nonatrienyl);
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, phenyl, 5-membered heteroaryl substituted with ethyl, wherein in the 5-membered heteroaryl the heteroatoms are selected from nitrogen and oxygen;
R3selected from hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from C1-C5Straight chain alkyl, C4-C5Branched alkyl radical, C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, phenyl and 5-membered heteroaryl substituted with ethyl, wherein in the 5-membered heteroaryl the heteroatoms are selected from nitrogen and oxygen;
preferably, R1Selected from hydrogen and M-C (O) -, wherein M is selected from methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl, 1, 3-nonadienyl, and 1, 3, 5-nonatrienyl;
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-pentyl, tert-butyl,
R3selected from the group consisting of hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from the group consisting of methyl, n-propyl, tert-butyl, n-pentyl,
the compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein,
R1selected from hydrogen and M-C (O) -, wherein M is selected from methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, 1, 3-nonadienyl and 1, 3, 5-nonatrienyl;
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-pentyl, tert-butyl,
R3Selected from hydrogen and X-C (O) -O-, wherein X is selected from methyl, n-propyl, tert-butyl, n-pentyl,
And the number of the first and second electrodes,
when R is1Is M-C (O) -, M is methyl or 1, 3, 5-nonatrienyl, R3Is X-C (O) -O-, and X is
when R is1Is M-C (O) -, M is n-nonyl, and R3Is CH3when-C (O) -O-, R2Is not that
When R is1Is hydrogen, and R3Is (CH)3)3When C-C (O) -O-, R2Is not hydrogen or (CH)3)3C-C(O)-。
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein,
R1selected from hydrogen and M-C (O) -, wherein M is selected from methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, 1, 3-nonadienyl and 1, 3, 5-nonatrienyl;
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-pentyl, tert-butyl,
R3Is a hydroxyl group;
and the number of the first and second electrodes,
when R is2Is Q-C (O) -, and Q is
when R is2When it is hydrogen, R1Is not hydrogen or 1, 3, 5-nonanetrienyl.
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein R1Is M-C (O) -, M is n-undecyl;
R2is Q-C (O) -, wherein Q is selected from methyl, n-propyl, n-butyl, n-,
R3Selected from the group consisting of hydrogen, hydroxy and X-C (O) -O-, wherein X is selected from the group consisting of methyl, n-propyl, t-butyl, n-butyl,
preferably, R3Selected from hydrogen, hydroxy;
preferably, R3Is X-C (O) -O-, wherein X is selected from methyl, n-propyl, n-butyl, n-,
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein R1Is M-C (O) -, M is n-undecyl; r2Is hydrogen; r3Is X-C (O) -O-, wherein X is selected from methyl, n-propyl, n-butyl, n-,
The compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein R1Is M-C (O) -, M is n-undecyl; r2Is composed of
the compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-4, wherein,
R1selected from hydrogen and M-C (O) -, wherein M is selected from C1-C11Straight chain alkyl (e.g., methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl) and C2-C11Straight chain alkenyl groups (e.g., nonadienyl, nonatrienyl);
R2selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl and C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing aliphatic heterocyclic group, 5-6 membered heteroaryl, 8-10 membered semi-saturated nitrogen containing fused heterocyclic group, NR 'R ", wherein R' is methyl and R" is phenyl optionally substituted by halogen; in the 5-6 membered heteroaryl, the heteroatom is selected from nitrogen and oxygen;
wherein, the methyl group and C3-C5Straight-chain alkenyl or C3-C5The branched alkenyl groups are independently substituted with one or more phenyl groups, optionally substituted with methyl groups;
optionally, the 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing lipidic heterocyclyl, 5-6 membered heteroaryl or 8-10 membered semi-saturated nitrogen containing fused heterocyclyl is independently substituted with one or more substituents selected from the group consisting of: halogen, methyl, ethyl, methoxy, phenyl, -NH2、-NHCH3and-NH-CH2-Ph；
R3Selected from hydroxyl and X-C (O) -O-, wherein X is selected from hydrogen, methyl, C3-C5Straight chain alkenyl, C3-C5Branched alkenyl, 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen-containing aliphatic heterocyclic group,5-6 membered heteroaryl, 8-10 membered semi-saturated nitrogen containing fused heterocyclyl, NR 'R ", wherein R' is methyl and R" is phenyl optionally substituted with halogen; in the 5-6 membered heteroaryl, the heteroatom is selected from nitrogen and oxygen;
wherein, the methyl group and C3-C5Straight-chain alkenyl or C3-C5The branched alkenyl groups are independently substituted with one or more phenyl groups, optionally substituted with methyl groups;
optionally, the 5-6 membered cycloalkyl, phenyl, 5-6 membered nitrogen containing lipidic heterocyclyl, 5-6 membered heteroaryl or 8-10 membered semi-saturated nitrogen containing fused heterocyclyl is independently substituted with one or more substituents selected from the group consisting of: halogen, methyl, ethyl, methoxy, phenyl, -NH2、-NHCH3and-NH-CH2-Ph；
Preferably, Q and X are independently selected from the following groups:
the compound of any one of claims 1-11, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or crystalline form thereof, selected from the group consisting of:
the compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-5, wherein,
R1is M-C (O) -, M is n-nonyl, n-heptyl or n-undecyl;
R2selected from hydrogen and Q-C (O) -, wherein Q is selected fromTert-butyl, n-pentyl,
R3selected from hydroxyl and X-C (O) -O-, wherein X is selected fromMethyl, tert-butyl, n-pentyl, phenyl; preferably, the compound is selected from:
a compound shown as a formula (II), and a pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystal form thereof
Wherein R is1、R3As defined in any one of claims 1 to 5;
preferably, R1Selected from hydrogen and M-C (O) -, wherein M is selected from C1-C11Straight chain alkyl groups (e.g., methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl);
preferably, R3Is a hydroxyl group;
preferably, the compound is selected from:
13-hydroxy-ingenol 3, 4-acetonide
13-O-acetyl-ingenol 3, 4-acetonide
13-O-butyryl-ingenol 3, 4-acetonide
13-O-Hexanoylingenol 3, 4-acetonide
13-O-n-octanoyl-ingenol 3, 4-acetonide
13-O-decanoyl-ingenol 3, 4-acetonide
13-O-lauroyl-ingenol 3, 4-acetonide (2 c).
A compound as shown in formula (III), and pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystal form thereof
Wherein R is1、R2As defined in any one of claims 1 to 5;
preferably, R1Selected from hydrogen and M-C (O) -, wherein M is selected from C1-C11Straight chain alkyl groups (e.g., methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl);
preferably, R2Selected from hydrogen and Q-C (O) -, wherein Q is selected from methyl, n-propyl, tert-butyl, n-pentyl,
Preferably, R1R is M-C (O) -, and M is n-undecyl2Is not hydrogen;
preferably, R1Is M-C (O) -, M is n-undecyl, and R2When Q-C (O) -is not
preferably, the compound is selected from:
13-hydroxy-ingenol 5, 20-acetonide (33)
13-O-acetyl-ingenol 5, 20-acetonide (81)
13-O-butyryl-ingenol 5, 20-acetonide
13-O-Hexantanyl-ingenol 5, 20-acetonide
13-O-n-octanoyl-ingenol 5, 20-acetonide
13-O-decanoyl-ingenol 5, 20-acetonide
3-O-angeloyl-13-hydroxy-ingenol 5, 20-acetonide (34)
3-O-angeloyl-13-O-acetyl-ingenol 5, 20-acetonide (82)
3-O-angeloyl-13-O-butyryl-ingenol 5, 20-acetonide
3-O-angeloyl-13-O-hexanoyl-ingenol 5, 20-acetonide
3-O-angeloyl-13-O-n-octanoyl-ingenol 5, 20-acetonide
3-O-angeloyl-13-O-decanoyl-ingenol 5, 20-acetonide
3-O-acetyl-13-O-lauroyl-ingenol 5, 20-acetonide
3-O-n-butyryl-13-O-lauroyl-ingenol 5, 20-acetonide
3-O-tiglyl-13-O-dodecanoyl-ingenol 5, 20-acetonide
3-O- (2, 3-dimethylbutenoyl) -13-O-dodecanoyl-ingenol 5, 20-acetonide
3-O- (3, 5-diethylisoxazole-4-carbonyl) -13-O-lauroyl-ingenol 5, 20-acetonide.
A compound as shown in formula (IV), and pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystal form thereof
Wherein R is1As defined in any one of claims 1 to 5;
preferably, R1Is M-C (O) -, wherein M is selected from C1-C10A linear alkyl group;
preferably, the compound is selected from:
13-O-acetyl-ingenol 3, 4, 5, 20-diacetone compound (41)
13-O-butyryl-ingenol 3, 4, 5, 20-diacetone (51)
13-O-Hexanoylingenol 3, 4, 5, 20-diacetone compound (61)
13-O-n-octanoyl-ingenol 3, 4, 5, 20-diacetone compound (71)
13-O-decanoyl-ingenol 3, 4, 5, 20-diacetone compound.
A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or crystalline form thereof of any one of claims 1-16, and a pharmaceutically acceptable carrier (e.g., excipient, disintegrant, binder, absorption enhancer, flavoring agent, or surfactant).
Use of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof according to any one of claims 1 to 16 for the manufacture of a medicament for the prevention and/or treatment of a cosmetic indication or a hyperplasia or tumor-associated disease in a subject;
preferably, the cosmetic indication is selected from the group consisting of photodamage to the skin, seborrheic keratosis, keloids;
preferably, the disease associated with hyperplasia or tumor in a subject is selected from cutaneous warts, genital warts, porokeratosis, lung cancer, stomach cancer, breast cancer, colon cancer, bladder cancer, leukemia, liver cancer, cervical cancer, lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer, and precancerous lesions including solar keratosis, malignant freckles, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia.
Use of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof according to any one of claims 1 to 16 for the manufacture of a medicament for promoting healing of a skin wound in a subject, or for preventing and/or treating the following diseases in a subject: a disorder responsive to oxidative burst of neutrophils, a disorder responsive to IL-8 release from keratinocytes, or a disorder responsive to induction of necrosis;
preferably, the wound is a wound associated with diabetes or a wound caused by a pathogenic infection;
preferably, the disease is selected from: viral infectious skin diseases including verruca vulgaris, verruca plana, molluscum contagiosum, and genital warts; skin cancer, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer; and skin precancerous lesions including solar keratosis, malignant freckle, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia.
Use of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof according to any one of claims 1 to 16 for the manufacture of a formulation for inhibiting proliferation of cells associated with hyperplasia or tumors, for stimulating oxidative burst of neutrophils, or for stimulating release of IL-8 by keratinocytes;
preferably, the hyperplasia or tumor is selected from cutaneous warts, genital warts, porokeratosis, lung cancer, stomach cancer, breast cancer, colon cancer, bladder cancer, leukemia, liver cancer, cervical cancer, lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer, and precancerous lesions including solar keratosis, malignant freckles, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia.
A method of preventing and/or treating a cosmetic indication or a disease associated with hyperplasia or tumor in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof of any one of claims 1-16;
preferably, the cosmetic indication is selected from the group consisting of photodamage to the skin, seborrheic keratosis, keloids;
preferably, the disease associated with hyperplasia or tumor is selected from cutaneous warts, genital warts, porokeratosis, lung cancer, stomach cancer, breast cancer, colon cancer, bladder cancer, leukemia, liver cancer, cervical cancer, lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer, and precancerous lesions including solar keratosis, malignant freckles, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia.
A method of promoting healing of a skin wound in a subject, or preventing and/or treating: a disorder responsive to an oxidative burst of neutrophils, a disorder responsive to IL-8 release from keratinocytes, or a disorder responsive to induction of necrosis, comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite or crystalline form thereof according to any one of claims 1-16;
preferably, the wound is a wound associated with diabetes or a wound caused by a pathogenic infection;
preferably, the disease is selected from: viral infectious skin diseases including verruca vulgaris, verruca plana, molluscum contagiosum, and genital warts; skin cancer, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer; and skin precancerous lesions including solar keratosis, malignant freckle, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia.
A method of inhibiting proliferation of cells associated with hyperplasia or tumors, stimulating oxidative burst of neutrophils, and/or stimulating IL-8 release from keratinocytes, comprising administering to a cell in need thereof an effective amount of a compound, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or crystalline form thereof of any one of claims 1-16;
preferably, the hyperplasia or tumor is selected from cutaneous warts, genital warts, porokeratosis, lung cancer, stomach cancer, breast cancer, colon cancer, bladder cancer, leukemia, liver cancer, cervical cancer, lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, vaginal cancer, vulvar cancer, and precancerous lesions including solar keratosis, malignant freckles, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia;
preferably, the proliferation or tumor associated cells, neutrophils or keratinocytes are primary cells or cultures thereof from the subject, or established cell lines.