丹参酮I衍生物的设计、合成及抗肿瘤活性研究

Tanshinone I has been attracting a rising attention in recent years due to its unique anticancer pharmacological profiles. However, the clinical development of Tanshinone I for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor oral bioavailability. Therefore, it is highly necessary to develop novel Tanshinone I analogues to overcome these drawbacks. In our previous studies, an efficient synthetic approach was established allowing for a convenient construction of tricyclic hydroxyphenanthraquinones, the key precursor for total synthesis of tanshinone I. In this proposal, we will take advantage of this established synthetic approach to rationally modify A-, B- and C- rings of the core scaffold based on the strategies for drug structural optimization including bioisosteric replacement, embedding privileged scaffold and derivatization of the druggable functional groups. Meanwhile, we will also optimize the o-quinone structural unit in the C-ring through expanding or opening ring system and fusing the druggable heterocycles. New Tanshinone I derivatives with improved potency and better drug-like properties will be achieved based on the overall structure-activity and -druggability relationships we established, and the in vitro anti-MDR activities of these compounds will be especially evaluated. Based on the above data, the preliminary evaluations on the safety and pharmacodynamics in animal model will be further performed. The research results from the proposed studies are anticipated to obtain novel drug leads with good drug-like properties, which opens new avenues for developing the novel patentable drugs for cancer therapy.

丹参酮I独特的抗肿瘤活性正在受到广泛关注，然而其活性强度相对较弱, 水溶性及口服生物利用度极差; 这些不足极大地制约着该类化合物进一步的临床开发。本项目拟针对目前丹参酮I作为潜在的抗肿瘤药物所存在的问题及其研究发展瓶颈，利用前期已建立的高效、便捷的丹参酮I全合成方法，结合等排置换、优势片段嵌入和类药性官能团衍生等药物结构优化策略，对其核心骨架A、B和D三环进行合理结构改造与优化；同时通过环系打开和扩增、类药杂环骈合等技术手段，优化C环的“问题”邻醌结构片段；通过建立全面的构效关系，在改善药物成药性的同时寻找活性更好的化合物，同时特别考察其抗肿瘤多药耐药活性；进而进行初步的安全性和动物药效模型评价，以期获得一些结构新颖、成药性良好的药物先导物，为进一步发展具有自主知识产权的抗肿瘤创新药物奠定基础。

本项目主要针对丹参酮I作为潜在的抗肿瘤药物所存在的问题及其研究发展瓶颈，如其活性强度相对较弱, 水溶性及口服生物利用度极差等缺陷，利用前期已建立的高效、便捷的丹参酮I全合成方法，结合等排置换、优势片段嵌入和类药性官能团衍生等药物结构优化策略，对其核心骨架的多个位点进行合理结构改造与优化，主要通过环系打开和扩增、类药杂环骈合等技术手段，构建多样性天然产物衍生物库；通过系统的细胞水平抗肿瘤活性评价，建立全面的结构-活性关系，同时获得15个IC50小于1μM的天然产物衍生物，相比于丹参酮I，抗肿瘤活性显著提高。其中，部分高活性化合物的水溶性和不同种属的肝微粒体代谢稳定性大大提高。特别是，化合物SOMCL-15-222（22h）相对于天然产物(T1/2 = 0.17 h; F = ~0%) 具有显著改善的PK性质（T1/2 = 2.58 h; F = 21%）。此外，该化合物还具有较广抗肿瘤谱，特别对直肠癌细胞，其IC50达0.14 μM。初步的作用机制研究显示，SOMCL-15-222（22h）主要通过激活caspase3/7和PARP活性来剂量依赖性诱导肿瘤细胞凋亡。最后，该化合物10mg/kg静脉注射时能够显著抑制裸鼠HCT-116移植瘤的生长，而没有明显的体重下降。本项目通过三年的实施，最终获得了一个全新结构的活性增强成药性显著改善的抗肿瘤候选化合物，为进一步发展具有自主知识产权的抗肿瘤创新药物奠定基础。