Antiangiogenic properties of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives.

Venkateswaran A, Reddy YT, Sonar VN, Muthusamy V, Crooks PA, Freeman ML, Sekhar KR
Bioorg Med Chem Lett. 2010 20 (24): 7323-6

PMID: 21055930 · PMCID: PMC3001633 · DOI:10.1016/j.bmcl.2010.10.060

In the past half century research efforts have defined a critical role for angiogenesis in tumor growth and metastasis. We previously reported that inhibition of a novel target, ENOX1, by a (Z)-2-benzylindol-3-ylmethylene) quinuclidin-3-ol, suppressed tumor angiogenesis. The present study was undertaken in order to establish structure-activity relationships for quinuclidine analogs. The angiogenesis inhibiting activity of a series of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ols (1a-1k), (Z)-2-benzylindol-3-ylmethylene)quinuclidin-3-ones (2a-2h), (Z)-(±)-2-(1H/N-methyl-indol-3-ylmethylene)quinuclidin-3-ols (3a-3b), and substituted (Z)-(±)-2-(N-benzenesulfonylindol-3-yl-methylene)quinuclidin-3-ols and their derivatives (4a-4d) that incorporate a variety of substituents in both the indole and N-benzyl moieties was evaluated using Human Umbilical Vein Endothelial Cells (HUVECs) subjected to in vitro cell migration scratch assays, tubule formation in Matrigel, cell viability and proliferation assays. In total, 25 different analogs were evaluated. Based on in vitro cell migration scratch assays, eight analogs were identified as potent angiogenesis inhibitors at 10 μM, a concentration that was determined to be nontoxic by colony formation assay. In addition, this approach identified a potent antiangiogenic ENOX1 inhibitor, analog 4b.

Copyright © 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Angiogenesis Inhibitors Cell Movement Endothelial Cells Endothelium, Vascular Humans NADH, NADPH Oxidoreductases Quinuclidines Structure-Activity Relationship Umbilical Veins

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