TY - JOUR T1 - Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues JF - Bioorganic & Medicinal Chemistry Letters Y1 - 2013 A1 - Jedhe, Ganesh S. A1 - Paul, Debasish A1 - Gonnade, Rajesh G. A1 - Santra, Manas K. A1 - Hamel, Ernest A1 - Tam Luong Nguyen A1 - Sanjayan, Gangadhar J. KW - Colchicine KW - Combretastatin KW - Crystal KW - Tetrazole KW - Tubulin AB -

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.

PB - PERGAMON-ELSEVIER SCIENCE LTD CY - THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND VL - 23 IS - 16 U3 - Foreign U4 - 2.331 ER -