Nakagawa Yu, Kikumori Masayuki, Yanagita Ryo C, Murakami Akira, Tokuda Harukuni, Nagai Hiroshi, Irie Kazuhiro
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Biosci Biotechnol Biochem. 2011;75(6):1167-73. doi: 10.1271/bbb.110130. Epub 2011 Jun 13.
Aplog-1 is a unique analog of tumor-promoting aplysiatoxin that inhibits tumor-promotion by phorbol diesters and proliferation of tumor cells. While the structural features relevant to the biological activities of Aplog-1 remain to be identified, recent studies by us have suggested that local hydrophobicity around the spiroketal moiety of Aplog-1 is a crucial determinant of its anti-proliferative activity. This hypothesis led us to design 12,12-dimethyl-Aplog-1 (3), in which a hydrophobic geminal dimethyl group is installed proximal to the spiroketal moiety to improve biological potency. As expected, 3 was more effective than Aplog-1 in inhibiting cancer cell growth and binding to protein kinase Cδ, a putative receptor responsible for the biological response of Aplog-1. Moreover, an induction test on Epstein-Barr virus early antigen demonstrated 3 to be a better anti-tumor promoter than Aplog-1. These results indicate that 3 is a superior derivative of Aplog-1, and thus a more promising lead for anti-cancer drugs.
Aplog-1是一种独特的促肿瘤海兔毒素类似物，可抑制佛波酯的促肿瘤作用以及肿瘤细胞的增殖。虽然与Aplog-1生物活性相关的结构特征尚待确定，但我们最近的研究表明，Aplog-1螺环缩酮部分周围的局部疏水性是其抗增殖活性的关键决定因素。这一假设促使我们设计了12,12-二甲基-Aplog-1（3），其中在螺环缩酮部分附近引入了一个疏水偕二甲基基团以提高生物活性。正如预期的那样，3在抑制癌细胞生长和与蛋白激酶Cδ结合方面比Aplog-1更有效，蛋白激酶Cδ是一种假定的负责Aplog-1生物反应的受体。此外，对爱泼斯坦-巴尔病毒早期抗原的诱导试验表明，3比Aplog-1是更好的抗肿瘤促进剂。这些结果表明，3是Aplog-1的一种更优衍生物，因此是一种更有前景的抗癌药物先导物。
