We describe an attempt to apply the concept of covalent binding towards the highly active allocolchicinoids selected on the basis of SAR analysis of previously synthesized molecules. To achieve the irreversible binding of the agent to the cysteine residues of the colchicine site of tubulin protein, we synthesized a number of new allocolchicinoids bearing the acceptor moiety. Some of the new derivatives possess cytotoxic activity against COLO-357, BxPC-3, HaCaT, and HEK293 cell lines in a low nanomolar range of concentrations. A substoichiometric mode of microtubule assembly inhibition was demonstrated. The most active compounds possess close to colchicine general toxicity on mice.
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| http://dx.doi.org/10.1039/d0md00060d | DOI Listing |
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Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin.
RSC Med Chem
June 2020
Department of Chemistry , N. I. Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Avenue , 603950 Nizhny Novgorod , Russian Federation.
We describe an attempt to apply the concept of covalent binding towards the highly active allocolchicinoids selected on the basis of SAR analysis of previously synthesized molecules. To achieve the irreversible binding of the agent to the cysteine residues of the colchicine site of tubulin protein, we synthesized a number of new allocolchicinoids bearing the acceptor moiety. Some of the new derivatives possess cytotoxic activity against COLO-357, BxPC-3, HaCaT, and HEK293 cell lines in a low nanomolar range of concentrations.
View Article and Find Full Text PDFSynthesis of Colchicinoids and Allocolchicinoids through Rh(I)-Catalyzed [2+2+2+1] and [2+2+2] Cycloadditions of o-Phenylenetriynes with and without CO.
J Org Chem
October 2018
Department of Chemistry , Stony Brook University, Stony Brook , New York 11794-3400 , United States.
The nonbenzenoid aromatics, tropones and tropolones, are found in various natural products such as colchicine and hinokitol, which possess significant biological activities. The traditional methods to construct the tropone skeletons include oxidation of cycloheptatriene and [4+3] cycloadditions. In addition, the total synthesis of colchicine and its analogues requires laborious organic transformations in the formations of 6-7-7 fused-ring systems.
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J Med Chem
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
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