Honokiol analogs and their use in treating cancers
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are honokiol analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. Representative honokiol analogs include diepoxide honokiol analogues. The compounds are believed to function, at least, by inhibiting angiogenesis and/or inducing apoptosis. Thus, the compounds are novel therapeutic agents for a variety of cancers.
1. A method for treating a cancer or a benign tumor in a mammal, comprising administering to the mammal a therapeutically effective amount of the formula:
W is (CHR 2 )n, O—(CHR 2 )n, S—(CHR 2 )n, or NR 2 —(CHR 2 )n, wherein the (CHR 2 )n portion of the W moiety can be fluorinated with anywhere from one fluorine atom to complete perflourination,
X is O, CR 2 , or a bond between the two carbons to which it is attached,
R 1 is H, C 1-8 alkyl phosphate, or dichloroacetate,
R 2 is H, C 1-8 alkyl, or alkylaryl, or, when bonded to carbon, can be halo,
n is an integer from 1-4,
G is selected from the group consisting of C 1-6 alkyl, C 2-8 alkenyl, halo, —OR 1 , —NR 3 R 4 , —CF 3 , —CN, —NO 2 , —C 2 R 3 , —SR 3 , —N 3 , —C(═O)NR 3 R 4 , —NR 3 C(═O)R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —OC(═O)NR 3 R 4 , —NR 3 C(═O)OR 3 , —SO 2 R 3 , —SO 2 NR 3 R 4 , and —NR 3 SO 2 R 3 , where R 3 and R 4 are individually hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl,
z is an integer of from 0-3,
wherein only 0 or 1 of the X variables can be a bond between the two carbons to which it is attached,
in an amount sufficient to induce apoptosis and/or inhibit angiogenesis, such that the growth of the tumor is at least partially inhibited,
wherein the cancer is selected from the group consisting of melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, chronic lymphocytic carcinoma, esophageal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma, and the benign tumor is a hemangioma.
2. A method of claim 1 , wherein one or two of R 1 represent an C 1-8 alkyl phosphate ester, or a dichloroacetate.
3. A method of claim 1 , wherein both of X are O.
4. A method of claim 1 , wherein one of X is O, and the other represents a bond between the two carbons to which it is attached.
5. A method of claim 1 , wherein each R 2 is H.
6. A method of claim 1 , wherein each W is CH 2 .
7. A method for treating a cancer or a benign tumor in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the formula:
wherein
W is (CHR 2 )n, O—(CHR 2 )n, S—(CHR 2 )n, or NR 2 —(CHR 2 )n, wherein the (CHR 2 )n portion of the W moiety can be fluorinated with anywhere from one fluorine atom to complete perflourination,
R 1 is H, C 1-8 alkyl phosphate, or dichloroacetate,
R 2 is H, C 1-8 alkyl, or alkylaryl,
n is an integer from 1-4,
G is selected from the group consisting of C 1-6 alkyl, C 2-8 alkenyl, halo, —OR′, —NR 3 R 4 , —CF 3 , —CN, —NO 2 , —C 2 R 3 , —SR 3 , —N 3 , —C(═O)NR 3 R 4 , —NR 3 C(═O)R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —OC(═O)NR 3 R 4 , —NR 3 C(═O)OR 3 , —SO 2 R 3 , —SO 2 NR 3 R 4 , and —NR 3 SO 2 R 3 , where R 3 and R 4 are individually hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl,
z is an integer of from 0-3,
and
in an amount sufficient to induce apoptosis and/or inhibit angiogenesis, such that the growth of the tumor is at least partially inhibited,
wherein the cancer is selected from the group consisting of melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, chronic lymphocytic carcinoma, esophageal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma, and the benign tumor is a hemangioma.
8. A method of claim 7 , wherein each R 2 is H.
9. A method of claim 7 , wherein each W is CH 2 .
10. A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
wherein the —(CH 2 )— portion of the
moiety can be fluorinated with anywhere from one fluorine atom to complete perflourination,
in an amount sufficient to induce apoptosis and/or inhibit angiogenesis, such that the growth of the tumor is at least partially inhibited,
wherein the cancer is selected from the group consisting of hemangioma, melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, chronic lymphocytic carcinoma, hairy cell leukemia, osophogeal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma.
11. The method of claim 10 , wherein the compound is honokiol diepoxide.
12. A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of valproate mono and diesters of honokiol, dichloroacetate mono and diesters of honokiol, and C 1-6 alkyl phosphate mono and di-esters of honokiol,
in an amount sufficient to induce apoptosis and/or inhibit angiogenesis, such that the growth of the tumor is at least partially inhibited,
wherein the cancer is selected from the group consisting of hemangioma, melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, chronic lymphocytic carcinoma, hairy cell leukemia, osophogeal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma.
13. The method of claim 1 wherein the mammal is a human.
14. The method of claim 1 , wherein the cancer is a metastasized cancer.
15. The method of claim 1 wherein the human is immunosuppressed by reason of having undergone anti-cancer therapy prior to administration of the composition.
16. The method of claim 15 , wherein the tumor is a tumor of epithelial tissue, lymphoid tissue, connective tissue, bone, or the central nervous system.
17. The method of claim 1 , wherein the compounds are administered parenterally, orally, or directly into the tumor.
18. The method of claim 1 , wherein the compounds are administered via an implanted device.
19. The method of claim 1 , wherein the administration is provided using a sustained release formulation.
20. The method of claim 1 , wherein the cancer is breast cancer.
21. The method of claim 7 , wherein the cancer is breast cancer.