非平面小分子氮杂螺烯季铵盐的合成及其在肿瘤精准治疗中的应用和机理研究

肿瘤是当前全球面临的重大公共卫生事件，目前仍然缺乏有效的治疗方法。以抑制DNA合成为基础的化学治疗是多数肿瘤病人的主要选择，然而这些化疗药物因其自身的低选择性、严重的副作用以及多重耐药问题，在临床上的应用受到不同程度的限制。因此，开发高选择性和低毒副作用的化疗药物仍是肿瘤治疗的前沿研究方向。本课题组最新发表的一项研究显示一种非平面多环芳烃——小分子氮杂螺烯季胺盐[4]helicenium具备很好的水溶性，且与DNA分子具有强烈的结合能力，在体内外能够选择性杀伤肝癌细胞，而对正常肝细胞无明显毒性作用。这一研究表明以[4]helicenium为代表的非平面氮杂螺烯季胺盐可以作为一种新的肿瘤治疗药物研发方向。在本项目中，我们将通过合成多个具有不同稠环数量的非平面氮杂螺烯季胺盐，探索其在肿瘤精准治疗中的作用，为临床开发新型肿瘤治疗药物提供理论基础。

Cancer is a major public health event currently facing the world, and effective treatments are still lacking. Chemotherapy based on inhibition of DNA synthesis is the main choice for most tumor patients. However, these chemotherapeutic drugs are limited in their clinical application due to their low selectivity, severe side effects, and multiple drug resistance. Therefore, the development of chemotherapeutics with high selectivity and low toxicity and side effects is still the frontier research direction of cancer therapy. Our latest study found that a nonplanar polycyclic aromatic hydrocarbon, a small molecule azahelicenium named [4]helicenium, has good water solubility and strong binding ability with DNA molecules. It can selectively kill liver cancer cells in vitro and in vivo, but has no obvious toxic effect on normal hepatocyte, which indicated that nonplanar azahelicenia represented by [4]helicenium can be used as a new direction for the development of cancer therapeutic drugs. Herein, we will explore the role of nonplanar azahelicenia with different aromatic ring numbers in precise cancer therapy, and provide a theoretical basis for clinical development of new cancer therapeutic drugs.