Platensilin、Platensimycin、Platencin及其類似物的不對稱合成和生物學評價

山東大學婁紅祥團隊報道了基于生物啟發骨架重建方法的Platensilin, Platensimycin, Platencin及其類似物的不對稱合成和生物學評價。相關研究成果于2024年7月8日發表在國際知名學術期刊《美國化學會志》。

Platensilin、platensimycin和platncin是細菌和哺乳動物脂肪酸合成系統中β-酮酰基-酰基載體蛋白合成酶（FabF）的有效抑制劑，為抗菌和抗糖尿病治療提供了有前景的藥物線索。

該文報道了一種受生物啟發的骨架重建方法，該方法能夠統一合成這三種天然FabF抑制劑及其骨架多樣的類似物，所有這些都源于一個共同的異海松烷核心。該合成具有非對映選擇性生物催化還原和分子間Diels–Alder反應的特點，以制備常見的異海松烷核心。從該中間體中，立體選擇性的Mn催化的氫原子轉移氫化，和隨后的Cu催化的類碳碳C–H插入提供了platensilin。

此外，通過新形成的環丙烷的區域選擇性開環，分子內Diels–Alder反應成功，分別構建了platensimycin和platencin的雙環[3.2.1]-辛烷和雙環[2.2.2]-辛烷環體系。這種異海松烷核心的骨架重建方法有助于制備具有不同多環支架的類似物。在這些類似物中，與platensimycin相比，先前未探索的環丙基類似物47，對金黃色葡萄球菌表現出改進的抗菌活性（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

期刊信息

JACS：《美國化學會志》，創刊于1879年。隸屬于美國化學會，最新IF：16.383
官方網址：https://pubs.acs.org/journal/jacsat
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