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Deconstruction of Desacetamidocolchicine’s B Ring Reveals a Class 3 Atropisomeric AC Ring with Tubulin Binding Properties

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Colchicine is one of the oldest known microtubule-targeting agents and also represents a classic example of axial chirality and atropisomerism in medicine. This is because colchicine’s axially chiral methoxytropone-trimethoxybenzene (called the AC ring) is directly responsible for tubulin binding and is thermodynamically set into the requisite aR form by a point chiral acetamido group on its B ring. Indeed, desacetamidocolchicine (DAAC), a colchicine analogue without the acetamido group, racemizes within minutes. Herein, we describe the synthesis as well as physical and biological characterization of a series of AC ring-containing molecules that represent B-ring further deconstructed variants of DAAC. These studies revealed a novel analogue with an AC ring that is highly stable to epimerization based not on thermodynamic stabilization but rather a high rotational barrier energy. Profiling and characterization of the dihedral angles were carried out computationally and experimentally using vibrational circular dichroism, demonstrating that the ground state dihedral angles of the new molecules differ significantly from those of colchicine. However, despite this difference, the molecule retained antiproliferative, tubulin-binding, and tubulin polymerization inhibitory activity.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.5c00284