Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues

TitleCorrelation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues
Publication TypeJournal Article
Year of Publication2013
AuthorsJedhe, GS, Paul, D, Gonnade, RG, Santra, MK, Hamel, E, Nguyen, TLuong, Sanjayan, GJ
JournalBioorganic & Medicinal Chemistry Letters
Volume23
Issue16
Pagination4680-4684
Date PublishedAUG
ISSN0960-894X
KeywordsColchicine, Combretastatin, Crystal, Tetrazole, Tubulin
Abstract

A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC50 value in micromolar concentrations. (C) 2013 Elsevier Ltd. All rights reserved.

DOI10.1016/j.bmcl.2013.06.004
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)

2.331

Divison category: 
Center for Material Characterization (CMC)
Organic Chemistry