Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC.

Generation and Application of Homoallylic α,α-Diboryl Radicals via Diboron-Promoted Ring-Opening of Vinyl Cyclopropanes: cis-Diastereoselective Borylative Cycloaddition.

Carbon-centered radicals stabilized by adjacent boron atoms are underexplored reaction intermediates in organic synthesis. This study reports the development of vinyl cyclopropyl diborons (VCPDBs) as a versatile source of previously unknown homoallylic α,α-diboryl radicals via thiyl radical catalyzed diboron-directed ring opening. These diboryl stabilized radicals underwent smooth [3+2] cycloaddition with a variety of olefins to provide diboryl cyclopentanes in good to excellent diastereoselectivity. In contrast to the trans-diastereoselectivity observed with most of the dicarbonyl activated VCPs, the cycloaddition of VCPDBs showed a remarkable preference for formation of cis-cyclopentane diastereomer which was confirmed by quantitative NOE and 2D NOESY studies. The cis-stereochemistry of cyclopentane products enabled a concise intramolecular Heck reaction approach to rare tricyclic cyclopentanoid framework containing the diboron group. The mild reaction conditions also allowed a one-pot VCP ring-opening, cycloaddition-oxidation sequence to afford disubstituted cyclopentanones. Control experiments and DFT analysis of reaction mechanism support a radical mediated pathway and provide a rationale for the observed diastereoselectivity. To the authors' knowledge, these are the first examples of the use of geminal diboryl group as an activator of VCP ring opening and cycloaddition reaction of α-boryl radicals.