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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Jedhe, Ganesh S.¹  Paul, Debasish²  Gonnade, Rajesh G.³  Santra, Manas K.²  Hamel, Ernest⁴  Tam Luong Nguyen⁵  Sanjayan, Gangadhar J.¹ 

[1] Natl Chem Lab, Div Organ Chem, Pune 411008, Maharashtra, India

[2] Univ Pune Campus, Natl Ctr Cell Sci, Pune 411007, Maharashtra, India

[3] Natl Chem Lab, Ctr Mat Characterizat, Pune 411008, Maharashtra, India

[4] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[5] Frederick Natl Lab Canc Res, Target Struct Based Drug Discovery Grp, SAIC Frederick, Frederick, MD 21702 USA

关键词: Combretastatin;    Tetrazole;    Crystal;    Colchicine;    Tubulin;   

DOI  :  10.1016/j.bmcl.2013.06.004

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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