Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa, Japan.
Biosci Biotechnol Biochem. 2021 Jan 7;85(1):168-180. doi: 10.1093/bbb/zbaa024.
10-Methyl-aplog-1 (1), a simplified analog of debromoaplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes and potent antiproliferative activity against several cancer cells with few adverse effects. A recent study has suggested that its phenol group in the side chain is involved in hydrogen bonding and CH/π interactions with the binding cleft-forming loops in the PKCδ-C1B domain. To clarify the effects of the side chain length on these interactions, four analogs of 1 with various lengths of side chains (2-5) were prepared. The maximal PKC binding affinity and antiproliferative activity were observed in 1. Remarkably, the introduction of a bromine atom into the phenol group of 2 increased not only these activities but also proinflammatory activity. These results indicated that 1 has the optimal side chain length as an anticancer seed. This conclusion was supported by docking simulations of 1-5 to the PKCδ-C1B domain.
10-甲基-aplog-1（1）是去溴海兔毒素的简化类似物，对蛋白激酶 C（PKC）同工酶具有高结合亲和力，并对几种癌细胞具有很强的抗增殖活性，而副作用较小。最近的一项研究表明，其侧链上的酚羟基参与与 PKCδ-C1B 结构域中环形成氢键和 CH/π 相互作用。为了阐明侧链长度对这些相互作用的影响，我们合成了具有不同侧链长度的 1 的四个类似物（2-5）。在 1 中观察到最大的 PKC 结合亲和力和抗增殖活性。值得注意的是，在 2 的酚羟基中引入溴原子不仅提高了这些活性，而且还提高了促炎活性。这些结果表明，1 作为抗癌种子具有最佳的侧链长度。这一结论得到了 1-5 与 PKCδ-C1B 结构域对接模拟的支持。
