Structure鈥揂ctivity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity

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• 作者：Masayuki Kikumori ; Ryo C. Yanagita ; Harukuni Tokuda ; Nobutaka Suzuki ; Hiroshi Nagai ; Kiyotake Suenaga ; Kazuhiro Irie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5614-5626
• 全文大小：448K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (未, 畏, and 胃) with subnanomolar K_i values, approximately 10鈥?0 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.