天然产物griseofamines及其衍生物的合成以及抗菌活性研究

Antibiotic resistance has become one of the biggest threats to public health in the 21st century. The development of new antibacterial agents, especially those with novel mechanisms of action, are in extreme urgency. It is well known that the metabolites derived from microorganisms are important sources of antibacterial agents. As such, we will conduct the total synthesis of griseofamine A and B, isolated from Penicillium griseofulvum by Zhang in 2018, as well as the systematically structural modification about them with the hope of developing antibacterial agents with novel mechanism of action. In previous work, we have accomplished the total synthesis of griseofamine A in 23% yield over 7 steps and obtained its diastereomer 16-epi-griseofamine A in 7% yield simultaneously. In vitro, griseofamine A exhibited efficiency against a panel of drug-resistant Gram-positive bacteria with MIC values of 8-16 μg/mL. The diastereomer 16-epi-griseofamine A showed 2-3 fold more potent than griseofamine A with MIC values of 2-8 μg/mL. Inspired by these results, we will continue to carry out studies on griseofamines with the hope of developing new antibacterial agents with high efficiency, low toxicity, novel mechanism of action and low drug resistance.

细菌耐药性是21世纪威胁人类健康的重大问题之一，开发具有全新作用机制的抗菌药物迫在眉睫。微生物的代谢产物是获得新型抗菌药物的重要途径，本项目从灰黄青霉菌的次级代谢产物griseofamines出发，开展griseofamine A和B的全合成及系统性的结构改造。在前期工作中，本课题组已经完成了griseofamine A的全合成，通过7步反应，总收率23%，并制备了其差向异构体16-epi-griseofamine A。体外抗菌试验结果显示，griseofamine A对革兰氏阳性耐药菌表现出了较好的抑制作用(MIC=8-16μg/mL)，16-epi-griseofamine A的活性比它高2-3倍，对革兰氏阳性耐药菌的MIC值在2-8μg/mL范围内。本项目拟继续开展抗菌药物的研究工作，希望通过对grisofamines的结构优化最终优选出高效、低毒、机制新、耐药性低的新型抗菌先导物。

新型抗菌药物，尤其是对耐药菌有效的新型抗菌药物的研发是医药生物领域的重大课题。本项目首先完成了天然产物griseofamines及立体异构体的全合成，路线简洁、高效，并以griseofamines为先导，设计合成了一类新型的对耐药菌有效的抗菌化合物，优选化合物对耐药菌的活性最高达到了0.3μg/mL，我们将对优选化合物开展系统的耐药菌株试验以及深入的作用机制研究，希望在抗菌药物研发上取得突破。