title: Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents.
abstract: A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, 27599-7360, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
authors.forename: Junko
authors.initials: J
authors.lastname: Ishida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagai
authors.forename: Hui-Kang
authors.initials: HK
authors.lastname: Wang
authors.forename: Hideji
authors.initials: H
authors.lastname: Itokawa
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Su
authors.forename: Charles
authors.initials: C
authors.lastname: Shih
authors.forename: Tzuying
authors.initials: T
authors.lastname: Chiang
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: YiFen
authors.initials: Y
authors.lastname: Lee
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Tsai
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011471:Prostatic Neoplasms; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D003474:Curcumin