title: Synthesis and anti-cancer screening of novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer agents.
abstract: trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a-i,9and11a-e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50values in the low nanomolar range. The most potent compound,8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound8aexhibited GI50values of <10 nM against 80% of the cancer cell lines in the panel. Three triazole analogues,8a,8band8g, showed particularly potent growth inhibition against the triple negative Hs578T breast cancer cell line with GI50values of 10.3 nM, 66.5 nM and 20.3 nM, respectively. Molecular docking studies suggest that these compounds bind to the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine andcis-CA-4, and are stabilized by Van der Waals' interactions with surrounding amino acid residues. Compound8awas found to inhibit tubulin polymerizationin vitrowith an IC50value of 1.7 µM. The potent cytotoxicity of these novel compounds and their inhibition of tubulin dynamics make these triazole analogues promising candidates for development as anti-cancer drugs.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Narsimha Reddy
authors.initials: NR
authors.lastname: Penthala
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, U.S.A.
authors.forename: Leena
authors.initials: L
authors.lastname: Madhukuri
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Thakkar
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Nikhil Reddy
authors.initials: NR
authors.lastname: Madadi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Gauri
authors.initials: G
authors.lastname: Lamture
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, U.S.A.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eoff
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks