基于优势骨架的片螺素类似物的设计、优化及抗肿瘤活性研究

Multidrug resistance is one of the main challenge for clinical chemotherapy treatment on tumors. Therefore, continuing efforts in discovering novel antitumor drugs that could overcome multidrug resistance is urgent. Lamellarins possess promising bioactivities of both cytotoxicity against multidrug resistant tumor cell lines and reversing multidrug resistant phenotype, and thus were selected as lead compounds for further antitumor drug development. We embark on designing novel analogues of Lamellarins through scaffold hopping with pyrrolo[2, 1-f][1,2,4]triazine on the basis of their core unit. This strategy is involved with cutting the original polycyclic nucleus and introducing new modified sites to balance their antitumor activities and pharmacokinetic profiles, which is of great scientific research value.

肿瘤耐药是当今化疗中最常见和棘手的问题，找寻相应的抗多药耐药肿瘤的有效药物具有十分重要的意义。本项目以兼具细胞毒活性（对耐药肿瘤有效）和逆转肿瘤多药耐药活性的片螺素为先导，提取其核心活性单元，与吡咯并三嗪优势骨架相结合，分别从这两个方向开发新型抗多药耐药肿瘤药物。该结构改造简化了复杂的多环结构，引入了新的可修饰位点，以平衡化合物的生物活性和药代动力学性质，有望从根本上解决片螺素成药性差的难题，具有较高的研究意义与应用价值。

本项目以片螺素为先导，提取其核心活性单元，与吡咯并三嗪优势骨架相结合，通过结构改造简化复杂的多环结构，引入了新的可修饰位点，设计并合成了3个系列的吡咯并三嗪化合物。从这些结构新型的吡咯并三嗪类化合物中分别发现了PI3K、FGFR抑制剂，其中化合物37可以高选择性的抑制PI3Kα，并显示了良好的体内抗肿瘤活性，具有较高的研究意义及应用前景。与此同时，基于可见光催化和有机催化合成策略，开发了系列条件温和、操作简单的高效合成方法，快速构建了结构多样的杂环小分子化合物库；从而为后续药物发现提供了结构基础。