Camara Kaddy, Kamat Siddhesh S, Lasota Celina C, Cravatt Benjamin F, Howell Amy R
Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States.
Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92307, United States.
Bioorg Med Chem Lett. 2015 Jan 15;25(2):317-21. doi: 10.1016/j.bmcl.2014.11.038.
β-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.
β-内酯作为酶抑制剂和化学探针，尤其是用于抑制丝氨酸水解酶类的酶，是一种具有优势的结构基序。在此，我们证明α-亚甲基-β-内酯的交叉复分解反应（CM）能够快速获得结构多样、此前未被探索的β-内酯。将这种方法与基于竞争活性的蛋白质谱分析（ABPP）相结合，鉴定出了几种丝氨酸水解酶的先导β-内酯抑制剂/探针，包括与疾病相关的酶和功能未明确的酶。因此，α-亚甲基-β-内酯支架提供的结构多样性扩展了可被小分子抑制剂靶向的丝氨酸水解酶的范围，并应通过优化靶标选择性探针进一步推动此类酶的功能表征。
