title: Triazole tethered C5-curcuminoid-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies.
abstract: Keeping in view the confines allied with presently accessible antitumor agents and success of C5-curcuminoid based bifunctional hybrids as novel antitubulin agnets, molecular hybrids of C5-curcuminoid and coumarin tethered by triazole ring have been synthesized and investigated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and PC-3 human tumor cell lines. The results revealed that the compounds A-2 to A-9, B-2, B-3, B-7 showed significant cytotoxic potential against THP-1, COLO-205 and HCT-116 cell lines, while the PC-3 cell line among these was found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and the length of carbon-bridge (n) connecting triazole ring with coumarin moiety considerably influence the activity. Methoxy substituted phenyl ring as Ring X and two carbon-bridges were found to be the ideal structural features. The most potent compounds (A-2, A-3 and A-7) were further tested for tubulin polymerization inhibition. Compound A-2 was found to significantly inhibit the tubulin polymerization (IC50 = 0.82 μM in THP-1 tumor cells). The significant cytotoxicity and tubulin polymerization inhibition by A-2 was further rationalized by docking studies where it was docked at the curcumin binding site of tubulin.
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Harbinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.affiliation: Lloyd Institute of Management and Technology, Greater Noida, UP, India.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: ss.gq2009@gmail.com.
authors.forename: Sahil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Preet Mohinder S
authors.initials: PMS
authors.lastname: Bedi
mesh_terms: D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D003374:Coumarins; D014230:Triazoles; D014404:Tubulin; D050257:Tubulin Modulators
keywords: Antitubulin; Antitumor; C(5)-curcuminoid; Coumarin; Docking; Hybrid