Antitumor Agents 288: Design, Synthesis, SAR, and Biological Studies of Novel Heteroatom-Incorporated Antofine and Cryptopleurine Analogues as Potent and Selective Antitumor Agents

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• 作者：Xiaoming Yang ; Qian Shi ; Shuenn-Chen Yang ; Chi-Yuan Chen ; Sung-Liang Yu ; Kenneth F. Bastow ; Susan L. Morris-Natschke ; Pei-Chi Wu ; Chin-Yu Lai ; Tian-Shung Wu ; Shiow-Lin Pan ; Che-Ming Teng ; Jau-Chen Lin ; Pan-Chyr Yang ; Kuo-Hsiung Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5097-5107
• 全文大小：1116K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI₅₀: 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.