Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Bioorg Med Chem Lett. 2013 Aug 1;23(15):4319-23. doi: 10.1016/j.bmcl.2013.05.096. Epub 2013 Jun 7.
Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.
去溴海兔毒素（DAT）是从海兔中分离出的一种肿瘤促进剂，对多种癌细胞系具有抗增殖活性。为了阐明负责其肿瘤促进活性的关键残基，我们专注于侧链中的手性甲氧基，其作用以前尚未讨论或检查过。去甲氧基-DAT（8）是从 DAT 衍生而来的，我们评估了其肿瘤促进活性、抗增殖活性以及与蛋白激酶 C（PKC）同工酶的结合能力。化合物 8 在体外和体内均表现出比 DAT 稍弱的肿瘤促进活性，但对几种癌细胞系显示出更高的抗增殖活性。尽管 8 与新型 PKC 同工酶的亲和力与 DAT 相当，但与传统 PKC 同工酶的亲和力略有下降。这些结果表明，DAT 的甲氧基是关键残基之一，对于肿瘤促进活性至关重要，但对于抗增殖活性则不重要。由于甲氧基对分子疏水性的影响很小，这是第一个表明 DAT 侧链中非疏水性结构因素影响其生物学活性的报告。
