title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, Dayalbagh Educational Institute, Dayalbagh, Agra 282110, India. Electronic address: minu.maninder@gmail.com.
authors.forename: Maninder
authors.initials: M
authors.lastname: Minu
authors.affiliation: Department of Chemistry, Dayalbagh Educational Institute, Dayalbagh, Agra 282110, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Singh
authors.affiliation: Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina, Mumbai 400098, India.
authors.forename: Tejashree
authors.initials: T
authors.lastname: Mahaddalkar
authors.affiliation: Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina, Mumbai 400098, India.
authors.forename: Manu
authors.initials: M
authors.lastname: Lopus
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Winter
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Ayoub
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Kristal
authors.initials: K
authors.lastname: Missiaen
authors.affiliation: Laboratório de Modelagem de Sistemas Biológicos, National Institute of Science and Technology for Innovation in Neglected Diseases (INCT/IDN, CNPq), Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Tatiana Martins
authors.initials: TM
authors.lastname: Tilli
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Pasdar
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D008024:Ligands; D011720:Pyrazoles; D014404:Tubulin; D050257:Tubulin Modulators
keywords: Anti-mitotic; Colchicine-binding assay; Docking; Hexahydropyrazole; Tubulin; Tubulin binding assay