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

Author:

Bejcek, Lauren P

Eli, Orugbani S

Kapkayeva, Diana M

Nafie, Jordan

Beutler,John [ORCID]

Gallicchio, Emilio [ORCID]

Sackett, Dan L

Murelli, Ryan P [ORCID]
Author Address

PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States., Department of Chemistry and Biochemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States., Biotools, Inc., 17546 Bee Line Highway, Jupiter, Florida 33478, United States., Molecular Targets Program, National Cancer Institute, National Institutes of Health. 1050 Boyles Street, Frederick, Maryland 21702, United States., The Graduate Center of the City University of New York, PhD Program in Biochemistry, New York, New York 10016, United States., Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 1 Center Dr, Bethesda, Maryland 20892, United States.,

Abstract:

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 39;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.

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