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https://www.arca.fiocruz.br/handle/icict/59644
Tipo
PreprintDerechos de autor
Acceso restringido
Fecha del embargo
2030-12-31
Colecciones
- CDTS - Preprint [22]
Metadatos
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CHEMICAL SYNTHESIS, PHARMACOLOGICAL EVALUATION AND IN SILICO ANALYSIS OF NEW 2,3,3A,4,5,6-HEXAHYDROCYCLOPENTA[C]PYRAZOLE DERIVATIVES AS POTENTIAL ANTI-MITOTIC AGENTS
Colchicine-binding assay
Hexahydropyrazole
Structure-activity relationship
Antineoplastic agents
Drug screening assays
Molecular docking simulation
Antitumor
Anticancer drugs
Tubulin modulators
Autor
Afiliación
Department of Chemistry. Dayalbagh Educational Institute. Agra, India / Chemistry and Biochemistry Department, Old Dominion University. Norfolk, USA.
Department of Chemistry. Dayalbagh Educational Institute. Agra, India.
Experimental Cancer Therapeutics and Chemical Biology. UM-DAE Centre for Excellence in Basic Sciences. University of Mumbai. Mumbai, India.
Experimental Cancer Therapeutics and Chemical Biology. UM-DAE Centre for Excellence in Basic Sciences. University of Mumbai. Mumbai, India.
Division of Experimental Oncology. Cross Cancer Institute, University of Alberta. Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta, Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. National Institute of Science and Technology for Innovation in Neglected Diseases. Laboratório de Modelagem de Sistemas Biológicos. Rio de Janeiro, RJ, Brazil.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Department of Chemistry. Dayalbagh Educational Institute. Agra, India.
Experimental Cancer Therapeutics and Chemical Biology. UM-DAE Centre for Excellence in Basic Sciences. University of Mumbai. Mumbai, India.
Experimental Cancer Therapeutics and Chemical Biology. UM-DAE Centre for Excellence in Basic Sciences. University of Mumbai. Mumbai, India.
Division of Experimental Oncology. Cross Cancer Institute, University of Alberta. Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta, Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. National Institute of Science and Technology for Innovation in Neglected Diseases. Laboratório de Modelagem de Sistemas Biológicos. Rio de Janeiro, RJ, Brazil.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Division of Experimental Oncology. Cross Cancer Institute. University of Alberta. Edmonton, Canada.
Resumen en ingles
We have synthesized new, biologically active mono- and di-substituted 2,3,3a,4,5,6-hexahydrocyclopenta[c]pyrazole derivatives bearing electron withdrawing groups and electron donating groups. These derivative structures were characterized by their spectral and analytical data. The newly synthesized hexahydropyrazole analogues were evaluated for their in vitro anticancer activity against breast and lung cancer cell lines using a cytotoxicity bioassay. To understand their mechanism of action, tubulin binding assays were performed which pointed to their binding to microtubules in a mode similar to but not identical to colchicine, as evidenced by their KD value evaluation. Computational docking studies also suggested binding near the colchicine binding site on tubulin. These results were further confirmed by colchicine-binding assays on the most active compounds, which indicated that they bound to tubulin near but not at the colchicine site. The moderate cytotoxic effects of these compounds may be due to the presence of electron donating groups on the para-position of the phenyl ring, along with the hexahydropyrazole core nucleus. The observed anti-cancer activity based on inhibition of microtubule formation may be helpful in designing more potent compounds with a hexahydropyrazole moiety.
Palabras clave en ingles
Anti-mitoticColchicine-binding assay
Hexahydropyrazole
Structure-activity relationship
Antineoplastic agents
Drug screening assays
Molecular docking simulation
Antitumor
Anticancer drugs
Tubulin modulators
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