基于NQO1酶双电子还原代谢的抗肿瘤醌类类天然产物的设计、合成及构效关系研究

The toxic side-effects of quinone type antitumor drugs in clinical development are mainly ascribed to their CPR enzyme-catalyzed one-electron reductive or NADPH non-enzyme-catalyzed reductive metabolisms.Our research group has recently revealed that tanshinone IIA,an ortho-quinone natural product that can be specifically activated through NQO-1 catalyzed two-electron reduction procedure and has promising antitumor activity without the above mentioned side-effects. In the light of the ortho-quinone pharmacorphore scaffold essential for NQO1 activity and selectivity of lead compound tanshinone IIA, we will carry out the rational drug design, synthesis and structure-activity relationship(SAR) studies on the natural product-like antitumor quinones based on the NQO1 catalyzed two-electron reductive metabolitic activation. Through the evaluation of both the NQO1 activity and the NQO1 mediated antitumor activity, we ought to explore systematically the laws of the interactions between the substrates and NQO1 enzyme. Further through the evaluation of CPR activity and NADPH non-enzyme-catalyzed reductive metabolitic activity as well as redox potentials, we ought to preliminary explore the laws between the substrates and NQO1, CPR, NADPH reductive activities and the differences interaction mechanisms between them.With fully consideration of the biological activity, selectivity and druggability during the design and optimization of NQO1 substrates, we prospect to discover natural product-like quinones as novel antitumor candidates with high potency and low toxicity.

目前临床研究中的醌类抗肿瘤药物普遍存在因CPR酶单电子还原代谢或NADPH非酶催化还原代谢引起的毒副作用，本项目研究组发现邻醌天然产物--丹参酮IIA能特异性被NQO1双电子还原酶代谢活化，具有良好抗肿瘤活性且避免了上述毒副作用。本项目研究在分析提取丹参酮IIA产生NQO1酶代谢活性及选择性的关键邻醌药效骨架基础上，开展基于NQO1酶双电子还原代谢的醌类类天然产物的合理设计、合成与构效关系研究，通过NQO1酶活性及其介导的抗肿瘤活性评价，探索醌类底物与NQO1酶的相互作用规律，进一步通过CPR酶、NADPH非酶代谢活性评价、氧化还原电位表征，初步探明底物结构与NQO1酶、CPR酶和NADPH非酶代谢的内在规律及分子间相互作用机制的异同。兼顾抗肿瘤活性、选择性及成药性进行NQO1酶醌类代谢底物的设计及结构优化，以发现基于NQO1酶代谢活化的高效、低毒的醌类类天然产物作为新型抗肿瘤候选化合物。

.目前临床研究中的醌类药物（如β-拉帕醌）普遍存在因CPR酶单电子还原代谢或NADPH非酶催化还原代谢引起的毒副作用。本研究组前期发现天然产物丹参酮IIA能特异性被NQO1双电子还原代谢活化，具有良好的抗肿瘤活性且一定程度上避免了上述毒副作用。β-拉帕醌水溶性差，其注射剂需使用助溶剂羟丙环糊精，导致溶血副作用。本项目研究基于丹参酮IIA及β-拉帕醌的结构进行NQO1酶代谢活化醌类类天然产物的设计及结构优化，以期发现新型醌类抗肿瘤候选药物。在分析提取两者共有的邻萘醌药效基团基础上，结合NQO1酶还原催化口袋特征，综合考虑NQO1还原活性、NQO1/CPR选择性及水溶性，有针对性地设计并合成了邻/对醌目标化合物68个。在酶及细胞水平对化合物进行NQO1还原活性、NQO1/CPR酶选择性、NQO1/NADPH非酶选择性性评价，并考察了代表化合物的水溶性、LogD等理化性质及药代动力学参数。本研究获得了醌类底物与NQO1酶还原活性的构效关系，以及NQO1酶与CPR酶、NADPH非酶代谢选择性规律：1）发现β-拉帕醌的C环由吡喃环变为芳香环可以避免NADPH非酶代谢；2）创新性提出设计L型醌底物有利于NQO1酶还原活性；3）发现引入含氮杂环及芳香环可同时提升NQO1活性及水溶性；4）发现A环引入2,3-邻二甲基，可通过sigma-H-π作用稳定底物与NQO1结合，同时其弱推电子效应可降低氧化还原电位，从而较大提升了NQO1/CPR选择性。本研究发现了2个候选化合物具有与β-拉帕醌相当的体内抗肿瘤活性，但毒副作用更低，值得进一步研究。初步研究表明该类化合物通过NQO1介导产生大量ROS发挥抗肿瘤作用。本研究还发展了区域选择性合成邻/对醌类化合物的新方法，发现了首个基于亲和力的NQO1小分子荧光探针。这为基于NQO1靶向抗肿瘤药物开发及现有醌类药物的结构优化奠定了良好的基础。在本项目资助下，共发表第一标注本项目的SCI论文10篇，最高IF=6.364；申请国家发明专利1项，PCT专利1项；作学术会议邀请报告3次；培养博士研究生1名，硕士研究生2名；项目负责人荣获2016年第十九届中国药学会-施维雅青年药物化学奖。.

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