构象锁定小分子直链肽Dolastatin 10, Grassystatin A, Tubulysins和Symplocin A 多样性研究

This project will be focused on locking small molecular straight-chain polypeptides into constrained conformations through macrocycle strategy. The structural design of our target molecules is mainly based on the known polypeptide natural products, Dolastatin 10, Grassystatin A, Tubulysins and Symplocin A, with the sizes of macrocycles and actual cyclization points determined by the reported structure-activity relationship (SAR) and computational models. The key synthetic intermediates, chiral -substituted tertiary amino acids, will be prepared via the following approaches: 1) Expand our highly selective keto-imine addition via radical 1,3-migration process, 2) Expand our one-pot tandem cyclization protocols from keto-imines and various organometallics, 3) Explore transitional metal-catalyzed intra or intermolecular cross-coupling through C-H bond activation strategy. Further transformations toward macrocyclic analogs will be based on olefin metathesis and [4+2] cycloadditions. All the synthetic constrained analogues of Dolastatin 10, Grassystatin A, Tubulysins, Symplocin A will be subjected to different bioassays to evaluate the pharmacological effects after these small molecular straight-chain polypeptides are chemically locked into certain conformations. We believe, our synthetic accomplishment and the subsequent biological research will not only contribute to fundamental understanding in this hot field, but also provide a very valuable tool to investigate their drug properties in terms of in vitro and in vivo stability and permeability.

本项目以构象锁定小分子直链杂聚肽为研究目标，开展构象锁定小分子直链杂聚肽Dolastatin 10，Grassystatin A，Tubulysins及Symplocin A类似物的合成及活性评价研究。具体基于自由基与酮亚胺的高选择性1,3-迁移反应、邻位诱导金属试剂与酮亚胺串联环合反应、过渡金属催化邻位诱导的分子内N-ɑ位“C-H活化”反应、过渡金属催化邻位羧基参与的N-ɑ位甲基C-H活化烷化及三催化活化反应建立高选择性合成ɑ-取代氨基酸的方法。基于烯烃复分解及[4+2]环加成反应，开展构象锁定小分子直链杂聚肽Dolastatin 10，Grassystatin A，Tubulysins及Symplocin A类似物的合成和活性评价研究。本项目的开展不仅能对构象锁定小分子直链杂聚肽研究做出基础性贡献，也能为进一步开展上述小分子直链肽类似物在稳定性、透膜性等方面的药理学研究奠定基础。

本项目主要取得如下结果：基于Lewis Acid催化邻位诱导炔酰胺、炔烃、酮与N,O-缩醛的加成-环合串联反应及Mannich反应，建立了顺、反式2位或者5（6）位取代吡咯/哌啶特殊氨基醇的合成新方法，首次发现Lewis acid可调控产物的立体化学；基于Lewis acid 催化炔烃、炔酰胺与酮、仲胺、环内、外N,O-缩醛、吲哚及芳环Ar-H（sp2）的加成反应，建立了一系列特殊骨架片段的合成新方法；基于过渡金属盐催化的三组分脱羧串联反应，建立了N-烯丙基-N-α位炔基哌啶/吡咯烷、多取代吡咯里西啶骨架、双环[2.2.2]辛烷骨架、双环[3.3.1]壬烷骨架的快速构筑方法；基于烷基镁试剂、砜试剂、酮负离子、官能化烷基锌与亚胺、亚胺鎓的加成反应，建立了一系列特殊手性片段合成新方法；基于以上的合成方法学，完成了项目所申报的Dolastatin 10，Grassystatin A，Tubulysins 及Symplocin A四类天然产物总共120多个类似物结构分子的合成，并初步进行了细胞活性评价。本项目资助下已公开在Chem. Commun. Org. Lett. Adv. Synth. Catal. J. Org. Chem. Org. Chem. Front.等二区发表SCI刊物论文30篇，其中在J. Org. Chem.及以上刊物发表论文18篇，2篇被Org. Chem. Highlights 进行Highlights评述。项目执行期间获授权专利7项，新申请国家发明专利16项。值得一提的是，基于项目所建立的新方法，成功实现了常山酮、海兔毒素、苦马豆素公斤级的合成工艺。常山酮和苦马豆素的工艺被企业采用为I类新药研究，目前进入临床前研究阶段。