Design, synthesis, and biological evaluation of 1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of anti-prostate cancer agents

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• 作者：Xiaojie Zhang^a ; Rubing Wang^a ; German Ruiz Perez^a ; Guanglin Chen^a ; Qiang Zhang^b ; Shilong Zheng^b ; Guangdi Wang^b ; ^c ; Qiao-Hong Chen^a ; ^{qchen@csufresno.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Curcumin ; Prostate cancer ; Heteroaromatic ring ; Cell proliferation ; Cell apoptosis ; Cell cycle regulation
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：24
• 期：19
• 页码：4692-4700
• 全文大小：2945 K

文摘

In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G₀/G₁ phase.