3,5-二芳基-噁二唑类HIF-1α-ARNT异源二聚抑制剂的结构优化和抗肿瘤活性研究

HIF-1 is the key nuclear transcription factor which regulate the tumor cells adaptation to hypoxia.The HIF-1 targeted antitumor agents have the potential to overcome tumor resistance to chemotherapy and prevent tumor invasion and metastasis. HIF-1α-ARNT heterodimerization inhibitors exhibited advantages with single target and specificity, while there is few structure of this series inhibitors been reported. Our previous work reveals compound LS-50 as novel structure HIF-1α-ARNT inhibitor, and its HIF-1 inhibitory activity and physico-chemical properties need to be improved. This project will combine the classic drug design and molecular docking together to carry out the targeted optimization of LS-50. Meanwhile, the molecular docking and virtual screening of compound libraries were performed to obtain novel skeletons of HIF-1α-ARNT heterodimerization inhibitors. On the basis of structure-activity relationship of all the compounds,highly potent compounds were chosen for the evaluations of acute toxicity, pharmacokinetics and pharmacodynamic to obtain 1-2 candidate compounds for anti-tumor metastasis research. In addition, the study is expected to get compounds as dual or single HIF-1α-ARNT and HIF-2α-ARNT heterodimerization inhibitor, which will be employed as specific molecular probes to explore the biological function of HIF-1α and HIF-2α in tumor hypoxia.

HIF-1是肿瘤细胞适应缺氧环境的关键核转录调控因子，以HIF-1靶点的抗肿瘤药物有望克服肿瘤对放化疗的耐受，抑制肿瘤侵袭、转移。HIF-1α-ARNT异源二聚抑制剂具有靶点单一、特异性强的优点，但是目前结构稀缺。课题组前期发现LS-50为全新结构的HIF-1α-ARNT抑制剂，其活性和理化性质有待提升。本课题以LS-50为先导物，将经典药物设计与分子对接相结合，开展LS-50的针对性结构优化；同时采用分子对接方法，对化合物库进行虚拟筛选，获得全新骨架的HIF-1α-ARNT异源二聚抑制剂；在总结构效关系的基础上，优选高活性分子开展急性毒性、药动学和药效学评价，获得1-2个候选化合物用于抗肿瘤转移研究。另外，本研究有望获得HIF-1α-ARNT和HIF-2α-ARNT异源二聚的双重抑制剂及单一抑制剂，以其为特异性分子探针，探索HIF-1α和HIF-2α在缺氧肿瘤细胞中的生物学功能。

HIF-1/HIF-2是肿瘤细胞适应缺氧环境的关键核转录调控因子，在肿瘤侵袭、转移过程中起着关键作用。HIF-2α-ARNT异源二聚抑制剂机制明确、特异性强，但目前结构稀缺。本课题主要开展以下工作：1）采用分子对接与经典药物设计相融合的策略，以前期发现的LS-50为先导物，对其开展系统的结构优化，共设计合成3,5-二芳基-恶二唑、2,4-二芳基咪唑、2,5-二芳基咪唑、3,5-二芳基异噁唑、2,5-二芳基-恶二唑、N-芳基2-吡啶-酰胺等8类新骨架的目标分子67个；2）构建基于结构的虚拟筛选模型，获得全新3-苯基-4-异噁唑酰胺骨架，并对其结构进行系统优化，共设计、合成108个目标分子； 3）以PT-2385其作为先导化合物，采用经典的生物电子等排、骨架跃迁原理与分子对接研究相融合，设计、合成全新骨架的邻苯甲酰磺酰亚胺类和2,3-二氢苯并[d]异噻唑类衍生物共63个。4）以硅罗丹明近红外荧光团SiR720为先导，设计出溶解性良好、光稳定的新型近红外荧光团w-11，并以FRET机理与具有光动力作用（PDT）的卟啉衍生物Pyro用偶氮基团连接，开发出新型的近红外探针azo-PDT，实现实时细胞低氧成像以及选择性杀伤低氧肿瘤细胞，体现探针的诊疗一体化功能，有望成为检测肿瘤低氧和治疗的双重功能工具分子。5）对上述目标分子开展体外HIF-1/HIF-2抑制活性评价，并总结其构效关系，分别优选出5个高活性分子开展药动学和药理学研究，发现1个邻苯甲酰磺酰亚胺类有作为HIF-2α/ARNT二聚抑制剂的潜力,有望今后用于肾透明细胞癌的治疗。

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