山东大学娄红祥团队报道了基于生物启发骨架重建方法的Platensilin, Platensimycin, Platencin及其类似物的不对称合成和生物学评价。相关研究成果于2024年7月8日发表在国际知名学术期刊《美国化学会志》。

Platensilin、platensimycin和platncin是细菌和哺乳动物脂肪酸合成系统中β-酮酰基-酰基载体蛋白合成酶（FabF）的有效抑制剂，为抗菌和抗糖尿病治疗提供了有前景的药物线索。

该文报道了一种受生物启发的骨架重建方法，该方法能够统一合成这三种天然FabF抑制剂及其骨架多样的类似物，所有这些都源于一个共同的异海松烷核心。该合成具有非对映选择性生物催化还原和分子间Diels–Alder反应的特点，以制备常见的异海松烷核心。从该中间体中，立体选择性的Mn催化的氢原子转移氢化，和随后的Cu催化的类碳碳C–H插入提供了platensilin。

此外，通过新形成的环丙烷的区域选择性开环，分子内Diels–Alder反应成功，分别构建了platensimycin和platencin的双环[3.2.1]-辛烷和双环[2.2.2]-辛烷环体系。这种异海松烷核心的骨架重建方法有助于制备具有不同多环支架的类似物。在这些类似物中，与platensimycin相比，先前未探索的环丙基类似物47，对金黄色葡萄球菌表现出改进的抗菌活性（MIC80=0.0625μg/mL）。

附：英文原文

Title: Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach

Author: Zong-Xu Gao, Hongliang Wang, Ai-Hong Su, Qian-Ying Li, Zhen Liang, Yue-Qing Zhang, Xu-Yuan Liu, Ming-Zhu Zhu, Hai-Xia Zhang, Yue-Tong Hou, Xin Li, Long-Ru Sun, Jian Li, Ze-Jun Xu, Hong-Xiang Lou

Issue&Volume: July 8, 2024

Abstract: Platensilin, platensimycin, and platencin are potent inhibitors of β-ketoacyl–acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels–Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom–transfer hydrogenation and subsequent Cu-catalyzed carbenoid C–H insertion afford platensilin. Furthermore, the intramolecular Diels–Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 μg/mL) against S. aureus compared to platensimycin.

DOI: 10.1021/jacs.4c02256

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c02256