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

doi:10.1016/j.bmcl.2010.10.060

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 24, 15 December 2010, Pages 7323-7326

https://doi.org/10.1016/j.bmcl.2010.10.060 Get rights and content

Abstract

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.

Graphical abstract

A series of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ols (1a–1k), (Z)-2-benzylindol-3yl-methylene)quinuclidin-3-ones (2a–2i), (Z)-(±)-2-(1H/N-methyl-indol-3-ylmethylene)quinuclidin-3-ol (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/benzene sulfonyl moieties were evaluated for their antiangiogenic activity using Human Umbilical Vein Endothelial Cells (HUVECs). Eight analogs were identified as potent angiogenesis inhibitors at a non-toxic concentration of 10 μM. The analog, 4b was identified as the most potent antiangiogenic agent. The mechanism of inhibition is consistent with inhibition of ENOX activity.

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Acknowledgements

This research was supported in part by NIH/National Cancer Institute grants R01CA140409, P50CA095103 and T32CA093240.

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^†: Present address: Apotex Pharmachem India Pvt. Ltd, Bangalore 560 099, India.

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

Abstract

Graphical abstract

Section snippets

Acknowledgements

Semin. Oncol.

Mol. Aspects Med.

Bioorg. Med. Chem. Lett.

Exp. Cell Res.

Eur. J. Med. Chem.

Molecular Biology of the Cell