靶向秋水仙碱结合位点的新型抗紫杉醇耐药微管蛋白抑制剂的设计与合成

茚并吡唑衍生物LL-01和LL-02是我们最近发现的、靶向秋水仙碱结合位点的强力微管蛋白抑制剂。它们通过抑制微管蛋白的聚合，发挥抗有丝分裂和破坏肿瘤血管的双重作用，对包括多药耐药、紫杉醇耐药在内的多种肿瘤细胞具有强抑制作用（nM）。“增强与活性中心蛋白骨架的结合”是克服因靶点蛋白变异而造成耐药的有效方法。基于这一药物设计策略，我们以LL-01的结构为基础，针对它与秋水仙碱结合位点的三个结合区域，综合考虑电性、疏水性、立体性、氢键结合等因素，拟在A、B和D环进行合理的结构修饰和优化，构建结构多样性茚并吡唑，苯并呋喃并吡唑和吡唑并吲哚三个系列化合物库。通过氢键受体、供体和极性基团的引入，增强它们与微管蛋白的多位点结合，提高其活性、水溶性和成药性。通过系统抗肿瘤药理学研究、初步毒性学、药代动力学评价等，阐明该类化合物的作用机制和构效关系，发现高效低毒、抗紫杉醇耐药、成药性好的新型微管蛋白抑制剂。

The indenopyrazol derivatives LL-01 and LL-02 are the newly discovered potent tubulin inhibitors targeting the colchicine binding site. Through the inhibiton of tubulin polymerization, they act as both antimitotic and vascular disrupting agents (VDAs), inhibit the proliferation of a variety of tumor cells, including those multi-drug resistant (MDR), Pgp-over-expressing and taxol–resistant, with IC50 values in the nM level. “Enhancing protein backbone binding” is a fruitful concept for combating drug-resistance caused by the target protein mutation. Following this drug design strategy and based on the structure of LL01 and its interactions with the three zones in the tubulin colchicine site, and by the full consideration of electronic parameters, hydrophobic properties, steric effects and hydrogen-bondings, etc., in this research, we will make rational modifications and optimizations at the A-, B-, and C-rings, to design and construct the structurally diverse indenopyrazole, benzofuropyrazole and pyrazoloindole series of compound libraries. By introducing hydrogen bond donors and acceptors, as well as the polar functional groups, these molecules are expected to make multiple interactions with the backbones in the active site and thus increase their binding potency to the tubulin. As a result, the antitumor and anti-drug resistance activities, water solubility and drug-like properties will be improved accordingly. Through the systematic pharmacological studies and the preliminary toxicological and pharmacodynamic evaluations, we will make a full understanding of their action mechanisms and structure-activity-relationships (SARs). We hope to find novel high efficient, low toxic tubulin inhibitors that can overcome paclitaxel resistance and have good water solubity and drugability.