Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.

Debromoaplysiatoxin（DAT）是一种有效的蛋白激酶C（PKC）激活剂，具有促肿瘤和促炎作用。Irie和同事发现10-methyl-aplog-1（1）是DAT的简化类似物，对几种癌细胞系具有很强的抗增殖活性，几乎没有不良反应。因此，1是用于癌症治疗的潜在先导化合物。我们合成了一种新的衍生物2，该衍生物在侧链末端位置具有一个萘环而不是苯环，以增加CH /π与PKCδ-C1B结构域的Pro-241的相互作用。基于的合成路线上1，2由6-羟基-1-萘甲酸以26个线性步骤聚合合成总收率为0.18％。虽然抗增殖活性2比的更有效1，结合效力2到PKCδ-C1B域没有超过的1。分子动力学模拟表明2具有同时形成氢键和与PKCδ-C1B结构域的CH /π相互作用的能力。着眼于氢键，它们在涉及CH /π相互作用的结合模式中的几何形状似乎不是最理想的，这可以解释2的亲和力比1略低。这项研究可能有助于优化此类相互作用并合成有希望的铅癌化合物。