title: Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies.
abstract: Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB-3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO-205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50=1.2 μM against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling 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: Sahil
authors.initials: S
authors.lastname: Sharma
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.
authors.forename: Preet Mohinder S
authors.initials: PM
authors.lastname: Bedi
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007510:Isatin / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014230:Triazoles; D014404:Tubulin; D050257:Tubulin Modulators; D007510:Isatin; D003474:Curcumin
keywords: Anticancer; Hybrids; Isatin; Molecular modeling; Mono carbonyl curcumin; Tubulin