钙信号传导调控酶CD38非共价结合型抑制剂的结构优化改造、合成与生物活性研究

CD38 is a well known multifunctional signaling enzyme, which is in charge of the metabolism of two Ca2 + messenger cADPR and NAADP, regulates the intracellular calcium mobilization and storage so that causing a series of physiological responses associated with calcium signaling pathways. Funded by the NSFC(20802006, finished), we synthesis 8 series of 77 compounds and found 22 non-covalent CD38 inhibitors. The compound H2 (IC50=4.7 μM) is the most active known non-covalent inhibitor, which is also better than ara-F NAD +, a very well known CD38 covalent inhibitor. The compounds achieved in this research are easy synthesis, with novel structure and high activity, which have been used as new tools for further study of multiple physiological functions of CD38 and regulation of the Ca2 + signal transduction system (HongKong University, Professor Lee). To further enhance the inhibitory activity,enrich inhibitor diversity and improve the physical and chemical properties such as water solubility and membrane permeability, this project intends to modify and optimize the indole ring in catalytic site and 3,5-substituents and all the chemicals obtained will be evaluated by NADase assay and cell-based model. The structure-activity relationship studies of those inhibitors will also be helpful for further providing lead fragments for potential therapeutic targets.

CD38是一类生物体内广泛存在的信号酶,可以催化Ca2+信使cADPR和NAADP的产生和调控细胞内钙的动员和贮存,引起一系列与钙信号通路相关的生理和病理学反应.在国家自然科学基金(20802006,已结题)的资助下,课题组设计合成了8个系列77个化合物,发现了22个CD38非共价抑制剂,其中化合物H2(IC50=4.7μM)是目前已知报道的活性最好的非共价抑制剂之一,超过了共价抑制剂ara-F NAD的生物活性;此类化合物具有结构类型新颖、合成简便等特点,在多个CD38生物学功能研究体系中得到了应用.为了进一步提高此类化合物的生物活性、丰富CD38非共价抑制剂的结构类型,改善水溶性和细胞膜通透性,本项目拟在H2结构基础上,通过电子等排、结构跃迁等技术手段,对与CD38催化部位相互作用的吲哚环和3,5位取代基的类型和长度进行衍生改造,并对设计合成得到的化合物进行酶和细胞水平的生物评价研究.

CD38是一类广泛存在的信号酶,在体内催化Ca2+信使cADPR和NAADP的产生和调控细胞内钙的动员与贮存,引起一系列与钙信号通路相关的生理性反应。在之前国家自然科学基金委面上课题资助的基础上，本课题从前期研究发现的CD38非共价抑制剂H2的结构出发,通过构效关系研究和H2与CD38的结合模式分析，将其吲哚母环改造为包括嘌呤环、苯并吡唑、吡咯并吡唑等其他杂环，同时对左右连接臂对的长度及末端取代基进行了结构优化，设计合成了超过100个新型CD38非共价抑制剂，进一步提高了此类化合物的生物活性，丰富了CD38非共价抑制剂的结构类型，同时在一定程度上改善了这类化合物的水溶性和细胞膜通透性。本研究课题得到的化合物合成简便，结构新颖，活性高，为进一步研究CD38的多重生理学功能，解析相关的Ca2+信号传导系统提供了新的工具分子。针对两类抑制剂分子的构效关系研究，为进一步的结构改造和提高生物活性、为潜在的治疗靶点提供先导结构奠定了基础。