海洋天然产物Psymberin的全合成及其类似物的生物活性研究

The therapeutic area of oncology has benefited from numerous drug classes derived from natural product sources. Oceans provide us with many complex natural products that have interesting medicinal properties. Unfortunately, the amount of these compounds that is isolated is usually quite low, making their development into useful medicinal agents very difficult. The total chemical synthesis of these compounds is therefore important and has been a key tool in drug discovery and development. The synthesis can be employed to study and address some of shortcomings of natural products through manipulation of pharmacological properties, structure activity relationship studies, and the preparation of drug candidates for mechanistic studies..Our present studies focus on a marine-sponge-derived anticancer natural product called psymberin. Biological studies of this marine natural product indicated that it possesses potent cytotoxicity activity to four cancer cells in the low nanomolar range (< 2.5 nM). The important biological properties of psymberin and its natural scarcity, coupled with its intriguing molecular architecture, render it an attractive synthetic target for further development. We are directing our efforts to prepare psymberin by total synthesis, employing strategies and methods that can be modified for the preparation of analogues. We are also going to carry out analogue synthesis that aims at improving the pharmacokinetics of psymberin, which would pave the way toward the future development of anticancer lead compound.

大量抗癌药物都是基于天然产物发展而来。海洋为我们提供了大量复杂的天然产物，它们均具有有趣的医药特性。令人遗憾的是，这些化合物极低的分离产率导致对它们在医药方向的实用化开发非常艰难。因此，这些化合物的全合成是后续药物发现发展过程中的关键。通过对其药理学特性的处理、构效关系的研究及备选药物的制备，化学合成研究能为研究和克服天然产物在成药方面的缺陷提供巨大帮助。.本项目研究的目标分子是一种从海绵中分离到，被称为psymberin的抗癌症海洋天然产物。这种海洋天然产物的生物活性检测显示它们具有很强的细胞毒性，对四种癌细胞的毒性可达小于2.5纳摩尔。Psymberin在生物性质上的重要性、在自然界的罕见性及独特的的分子结构，让它成为一个引人注目的研究对象。本项目将针对psymberin开发最佳的合成策略及方法，完成为其全合成。并以全合成工作为基础，将对其衍生物进行制备和研究，以探寻具有良好药代动力学

项目组对具有抗肿瘤活性天然产物psymberin展开研究，在实施过程中攻克了一系列难关并取得了重要的科学意义：1.调整了之前的反式四氢吡喃环的制备策略，创新性的探索并实现了利用跨环Michael加成/内酯还原的策略完成psymberin中关键反式四氢吡喃环的制备。2.针对天然产物psymberin中另一个关键结构——二氢异香豆素的合成，本项目组结合模型分析以及大量的条件摸索，利用联苯类配体Sphos完成了大位阻芳基片段与四氢吡喃片段的拼接。3.在全合成路线中，在完成了C-17位的手性中心构建后，实现了用Diels-Alder反应构建psymberin中的芳环。总体来说，本项目结合条件优化以及官能团调控的方式，以最长线性步骤27步，完成了psymberin的第一代全合成。此后，项目组顺利的完成了psymberin的第二代合成策略的探索，将吡喃片段到关键的De Brabander中间体的步骤由原来的15步缩短到了8步，区间产率由原来的5.7%提高到了9.3%，提升psymberin的合成效率。在此基础之上，项目组合成了一系列psymberin的结构类似物，为进一步开发其抗肿瘤药用价值奠定了基础。