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Novel curcumin analogues and uses thereof

This application is a continuation-in-part of PCT International Application No. PCT/US2003/009350, filed Mar. 27, 2003, titled Novel Curcumin Analogues and Uses Thereof, published in English on Oct. 30, 2003, which claims priority from U.S. patent application Ser. No. 10/124,642, filed Apr. 17, 2002, titled Novel Curcumin Analogues and Uses Thereof, now issued as U.S. Pat. No. 6,790,979, the disclosures of which are incorporated by reference herein in their entirety.

This invention was made with Government support under Grant No. CA-17625 and Grant No. CA-55639. The government has certain rights in this invention.

The present invention relates to compounds capable of acting as androgen receptor antagonists, pharmaceutical formulations containing the same, and methods of use thereof.

The androgen receptor (AR) is a member of a large family of ligand-dependent transcriptional factors known as the steroid receptor superfamily. Chang et al., Proc. Natl. Acad. Sci. USA, 85, 7211-7215 (1988). Beato, M., Cell, 56, 335-344 (1989). Androgens and the AR play an important role in the growth of the normal prostate and prostate cancer. Prostate cancer represents the most common male malignancy in the United States. Landis et al., Cancer J. Clin., 48, 6-29 (1998). Recently, antiandrogens such as hydroxyflutamide (HF) in combination with surgical or medical castration have been widely used for the treatment of prostate cancer. Crawford et al., New Engl. J. Med., 321, 419-424 (1989). Several compounds, including cyprosterone, HF, and bicalutamide (shown below), have been used clinically in the treatment of prostate cancer.

The synthetic steroidal antiandrogen cyprosterone is one of the first antiandrogens used clinically in Europe, McLeod, D., G., Cancer, 71, 1046-1049 (1993) but it has many side effects. Neumann et al., J. Clin. Oncol., 1, 41-65 (1982). HF and bicalutamide are both nonsteroidal antiandrogens. Bicalutamide is a newer nonsteroidal antiandrogen originally thought to have a pure antiandrogen activity without agonist activity. It has a longer half-life (6 days) and a higher binding affinity to the AR than H F. Verhelst et al., Clin. Endocrinol., 41, 525-530 (1994). (a) Kelly et al., J. Urol. (1993), 149, 607-609; (b) Scher et al., Prostate Cancer. J. Clin. Oncol., 11, 1566-1572 (1993).

Although antiandrogen hormone therapy has been widely used for the treatment for prostate cancer, some antiandrogens may act as AR agonists which may result in “antiandrogen withdrawal syndrome.” Miyamoto et al., Proc. Natl. Acad. Sci. USA, 95, 7379-7384 (1998). A currently accepted hypothesis postulates that mutations in androgen receptors may account for why HF, the active metabolite of flutamide, can activate androgen receptor target genes and stimulate prostate cancer growth. Miyamoto et al., Proc. Natl. Acad. Sci. USA, 95, 7379-7384 (1998). The same mechanism is used to explain the “flutamide withdrawal syndrome,” in which patients who experience an increase in prostate-specific antigen (PSA) while taking flutamide, have a decrease in PSA after withdrawal of treatment. Indeed, HF can activate androgen receptor target genes, such as PSA and MMTV-LTR (a reporter gene which expressed androgen-response element), in the presence of ARA70, the first identified androgen receptor co-activator. Yeh et al., The Lancet, 349, 852-853 (1997). Because this syndrome often leads to the failure of androgen-ablative therapy, it is desirable to develop better antiandrogens without agonist activity.

The phenolic diarylheptanoid curcumin (1) is the major pigment in turmeric. Curcumin and its analogs show potent anti-oxidant activity, anti-inflammatory activity, Nurfina et al., Eur. J. Med. Chem., 32, 321-328 (1997) cytotoxicity against tumor cells, Syu et al., J. Nat. Prod., 61, 1531-1534 (1998), antitumor-promoting activities, Sugiyama et al., Biochem. Pharmacol., 52, 519-525 (1996). Ruby et al., Cancer Lett., 94, 79-83 (1995) and antiangiogenesis activity (J. L. Arbiser et al. Mol. Med. 4: 376 (1998)).

Two cyclic diarylheptanoids, 13-oxomyricanol and myricanone, exhibiting potent antitumor promoting effects on DMBA-initiated and TPA-induced mouse skin carcinogenesis have been reported. Ishida et al., Cancer Lett., 159. 135-140 (2000). In the present study, a number of novel curcumin analogues have been prepared and evaluated for antagonistic activity against the AR in the presence of androgen receptor coactivator, ARA70, using two human prostate cancer cell lines, PC-3 and DU-145. PC-3 cells are androgen-independent tumor cells that do not express functional AR. DU-145 cells are androgen-independent tumor cells that also do not express functional AR.

According to embodiments of the present invention, the present invention relates to a compound according to formula I:

A first aspect of the present invention is a compound according to formula I or Ia: