无环核苷与氧化吲哚的不对称杂合衍生化及其抗肿瘤、抗HIV、抗感染活性与构效关系研究

In view that both oxindole and nucleotide scaffolds exhibit anti-HIV, anti-tumor and anti-infective activities etc., according to the thoughts of drug discovery, the functional groups with different mechanisms of action, however, with same activities, can be hybridized to form multi-functional derivatives using grafting principle, to further improve the activity and applications (such as anti-HIV, anti-tumor and anti-infective activities etc.), the inherent problem of drug resistance of the separated ingredient may be solved to some extent. This project aimed at the study on the asymmetric construction of new hybridized derivatives of acyclic nucleotides with onxindoles using ten types of new methodologies, and investigation of the rules of interaction between bioactive molecules and targets from molecular level. From the research cycle of hybridized derivativatization based on new methodologies-bioactivity evaluation-structure-activities relationship investigation-pharmacore establishment-design and synthesis of more active compounds, more than 160 new hybridized derivatives containing acyclic nucleotides and onxindoles will be synthesized and screened, over 15 compounds with good bioactivity will be found. This research will lay a solid foundation for the further new chemical drugs research and development.

鉴于氧化吲哚母核与核苷母核普遍具有抗HIV活性、抗肿瘤活性以及抗感染活性等，依据新药创制思路，利用相同活性官能团拼接原理将不同作用机制的基团杂合成多基团衍生物，以进一步提高其原有活性和应用范围（抗HIV活性、抗肿瘤活性以及抗感染活性等），并且有可能在一定程度上解决原有药物的抗药性问题。 本项目主要是想利用10种类型的新方法学研究不对称催化构建无环核苷与氧化吲哚的杂合新衍生物, 并且从分子水平上探讨生物活性小分子与作用标靶之间的相互作用规律来开展药物分子设计与构效关系研究。通过"新方法学杂合衍生化-活性研究-构效关系研究-组建药效基团-设计合成更高活性化合物"的研究循环，力争合成160余种含母核无环核苷与氧化吲哚的杂合新衍生物，筛选出15余种高活性的杂合衍生物。为以后更深入创制化学新药打下基础。

针对中药、民族药分离的吲哚生物碱化合物其本身存在一些缺陷（如：抗肿瘤活性不强、特异性不高、毒副作用较大、药代动力学性质不合理）而不能直接药用, 本研究合成了11类200余个含吲哚骨架化合物（其中合成了核苷嘧啶碱基拼接氧化吲哚类化合物40余个）。构效关系表明氧化吲哚骨架对抗肿瘤活性起关键作用，开环产物活性消失；抑菌活性构效关系表明，异恶唑基团明显增强2-吡咯酮的。体外活性筛选表明抗HIV活性不明显。本研究获得新型抗肿瘤、抑菌活性先导化合物40余个，为创新药物研究奠定物质基础.