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Mar. Drugs 2016, 14(3), 57; doi:10.3390/md14030057

Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds

Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
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Author to whom correspondence should be addressed.
Academic Editor: Keith B. Glaser
Received: 5 January 2016 / Revised: 27 February 2016 / Accepted: 3 March 2016 / Published: 11 March 2016
(This article belongs to the Special Issue Drug Design Based on Marine Natural Product Scaffolds)
View Full-Text   |   Download PDF [3016 KB, uploaded 11 March 2016]   |  

Abstract

Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly’s Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds. View Full-Text
Keywords: marine natural products (MNPs); angiogenesis; kinase profiling; molecular modeling marine natural products (MNPs); angiogenesis; kinase profiling; molecular modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ebrahim, H.Y.; El Sayed, K.A. Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds. Mar. Drugs 2016, 14, 57.

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