Search for New Anti-tumor Lead Compounds from Marine Organisms

作为我们旨在从海洋生物中寻找新的生物活性物质的持续计划的一部分，我们致力于通过利用极强的细胞毒性成分作为种子化合物来创造新的抗肿瘤先导。最近，我们通过生物测定引导分离从海绵中分离并鉴定了两种新的有效细胞毒性物质，Callystatin A和Arenastatin A。在本研究项目中，我们重点研究了利用这两种活性物质寻找新的抗肿瘤药物，并将研究结果总结如下。对于细胞毒性聚酮类化合物Callystatin A，我们首次以不对称Evans-Aldol缩合和E-选择性Wittig反应为关键反应实现了全合成，证实了我们提出的绝对立体结构。几种衍生物的合成和生物活性评价表明，5-R构型和8-乙基残基以及β-羟基酮功能在Callystatin A的强大细胞毒性中起着重要作用。此外，α，β-不饱和δ-内酯部分被证明是决定性的细胞毒性官能团。关于细胞毒性脱脂肽Arenastatin A，我们已经澄清，该脱肽在体内几乎没有抗肿瘤活性。因此，我们合成了三个酰胺类化合物来揭示在血清中代谢的功能基团。基于这一发现，设计了一些类似物以期在血清中保持稳定，从而产生了一种有希望的抗肿瘤先导化合物20-脱氧花生蛋白A。

As a part of our continuing programs aimed at search for new biologically active substances from marine organisms, we have engaged in creating new anti-tumor leads by utilizing extremely potent cytotoxic constituents as seed compounds. Recently, we isolated and characterized two new potent cytotoxic substances, callystatin A and arenastatin A, from marine sponges through bioassay-guided separation. In this research project, we have especially investigated on search for new anti-tumor leads by use of these two active substances and our outcome of this research is summarized as follows.1. As for the cytotoxic polyketide callystatin A, we achieved the first total synthesis using asymmetric Evans aldol condensation and E-selective Wittig reaction as key reactions to confirm the absolute stereostructure presented by us. Syntheses and biological assessment of several derivatives disclosed that 5-R configuration and 8-ethyl residue, and β-hydroxy ketone function played a significantly important role in the potent cytotoxicity of callystatin A. Furthermore, α, β-unsaturated δ-lactone portion proved to be conclusive functional group for cytotoxicity.2. With respect to cytotoxic depsipeptide arenastatin A, we had already clarified that this depsipeptide showed little anti-tumor activity in vivo. Hence, we synthesized three amide anlogues to reveal functional group metabolized in serum. Based on this finding, design for some analogues in expectation of stability in serum brought about a promising anti-tumor lead, 20-deoxoarenastatin A.