Improved Total Synthesis and Biological Evaluation of Coibamide A Analogues

To
enable the large-scale synthesis of coibamide A, we developed
an improved synthetic strategy for this class of cyclodepsipeptide.
The versatility of the synthetic procedure was demonstrated by the
preparation of a series of designed coibamide A analogues, which enabled
the preliminary structure–activity relationship (SAR) studies
for this compound. Although most modifications of coibamide A resulted
in decrease or loss of the antiproliferativity, we found that versatile
substitution at position 3 was well tolerated. Remarkably, a simplified
analogue, [MeAla3-MeAla6]-coibamide (1f), not only showed
nearly the same inhibition as coibamide A against the tested cancer
cells but also significantly inhibited tumor growth in vivo. The improved
synthetic strategy and the relevant trends of SAR disclosed in this
study will be valuable for further optimization of the overall profile
of coibamide A.

为实现共衣酰胺A（coibamide A）的大规模合成，我们针对该类环酯肽（cyclodepsipeptide）开发了一种优化的合成策略。我们通过制备一系列设计得到的共衣酰胺A类似物，验证了该合成方法的通用性，由此可开展该化合物的初步构效关系（structure–activity relationship, SAR）研究。尽管共衣酰胺A的多数修饰会导致其抗增殖活性下降或丧失，但我们发现3号位的多样化取代具有良好的耐受性。值得注意的是，简化类似物[MeAla3-MeAla6]-coibamide（1f）不仅在受试癌细胞中展现出与共衣酰胺A几乎一致的抑制活性，还可在体内显著抑制肿瘤生长。本研究中提出的优化合成策略以及所揭示的构效关系相关规律，将为共衣酰胺A整体活性谱的进一步优化提供宝贵参考价值。