Pharmacophore optimization of imidazole chalcones to modulate microtubule dynamics.

Autor: Karaj E; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA., Dlamini S; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA., Koranne R; Department of Biological Sciences, College of Natural Sciences and Mathematics, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA., Sindi SH; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA., Perera L; Laboratory of Genome Integrity and Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA., Taylor WR; Department of Biological Sciences, College of Natural Sciences and Mathematics, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA. Electronic address: william.taylor3@utoledo.edu., Viranga Tillekeratne LM; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, USA. Electronic address: ltillek@utnet.utoledo.edu.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 May; Vol. 122, pp. 105700. Date of Electronic Publication: 2022 Mar 11.
DOI: 10.1016/j.bioorg.2022.105700
Abstrakt: We recently reported a new class of imidazole-based chalcones as potential antimitotic agents. In view of their promising cytotoxic activity, a comprehensive structure-activity relationship (SAR) of these compounds was undertaken focusing on four major structural variations: the length of the molecule, the Michael acceptor character, the nature and substitution pattern of ring B, and the nature of the amide functionality tethering ring B. These second-generation analogs (IBCs) demonstrated a superior bioactivity profile than the previously reported imidazole chalcones (referred to as IPEs). The analog IBC-2 with one less methylene group (nor series) and para-fluoro substituted ring B demonstrated the best cytotoxicity profile among the library of compounds. A computational analysis of the NCI-60 data associated both IBCs and the previously reported IPEs with the privileged pharmacological pharmacophore of chalcones. Interestingly, biological studies suggest that the imidazole ring is essential for cytotoxic activity of the elongated chalcone analogues. Immunofluorescence studies revealed that IBC-2, unlike IPEs, has the ability to induce microtubule catastrophe independently of Aurora-B inhibition. The effects of IBC-2 on microtubule dynamics are similar to those of Nocodazole, but the cell cycle effects appear to be different. In-silico studies demonstrate that the members of the new series have the ability to bind to the colchicine binding site of β-tubulin with binding scores similar to those of IPEs, corresponding chalcones and Nocodazole. Although tubulin binding can partially explain the biological effects of IBC-2, on-going target identification studies are aimed at further investigation of its biological targets.
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Databáze: MEDLINE
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