Design, synthesis, and biological evaluation of dihydronaphthalene and chalcone-based anticancer agents inspired by the natural product combretastatin A-4.
type: CreativeWork
description: Hallmarks of tumor progression include, abnormal tumor-associated vasculature, regions of hypoxia, and overexpressed proteins. These abnormalities provide opportunities for therapeutic intervention though various targeting modalities. One such strategy takes advantage of the dependence that many solid tumors have for the rapid establishment of a vasculature network capable of supplying oxygen and nutrients to rapidly proliferating cancer cells. A class of small-molecules, referred to as vascular disrupting agents (VDAs), affect the tubulin dynamics of endothelial cells lining tumor-associated blood vessels. Tubulin depolymerization causes the endothelial cells to change shape and detach from the vessel wall leading to vessel collapse, which ultimately results in tumor necrosis. The natural product combretastatin A-4 (CA4) is widely accepted as the gold standard of VDAs and the clinical success of its corresponding water-soluble phosphate prodrug salt CA4P has inspired the development of a myriad of analogues and derivatives. Two dihydronaphthalene-based agents (KGP03 and KGP413) and their corresponding phosphate prodrug salts (KGP04 and KGP152), previously discovered by the Pinney Research Group (Baylor University), function as promising VDAs. These molecules provided impetus for our effort to devise improved synthetic routes to facilitate the preparation of sufficient material for progressive biological evaluation. The parent agents (KGP03 and KGP413) demonstrated profound inhibition of tubulin polymerization and potent cytotoxicity against human cancer cell lines (NCI-H460, SK-OV-3, and DU-145). The phosphate prodrug salts (KGP04 and KGP152), functioned as VDAs, evidenced (in collaborative studies) by disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor (KGP04), and in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc (KGP152). Tangential synthetic strategies provided access to a focused library of α…
abstract: Hallmarks of tumor progression include, abnormal tumor-associated vasculature, regions of hypoxia, and overexpressed proteins. These abnormalities provide opportunities for therapeutic intervention though various targeting modalities. One such strategy takes advantage of the dependence that many solid tumors have for the rapid establishment of a vasculature network capable of supplying oxygen and nutrients to rapidly proliferating cancer cells. A class of small-molecules, referred to as vascular disrupting agents (VDAs), affect the tubulin dynamics of endothelial cells lining tumor-associated blood vessels. Tubulin depolymerization causes the endothelial cells to change shape and detach from the vessel wall leading to vessel collapse, which ultimately results in tumor necrosis. The natural product combretastatin A-4 (CA4) is widely accepted as the gold standard of VDAs and the clinical success of its corresponding water-soluble phosphate prodrug salt CA4P has inspired the development of a myriad of analogues and derivatives. Two dihydronaphthalene-based agents (KGP03 and KGP413) and their corresponding phosphate prodrug salts (KGP04 and KGP152), previously discovered by the Pinney Research Group (Baylor University), function as promising VDAs. These molecules provided impetus for our effort to devise improved synthetic routes to facilitate the preparation of sufficient material for progressive biological evaluation. The parent agents (KGP03 and KGP413) demonstrated profound inhibition of tubulin polymerization and potent cytotoxicity against human cancer cell lines (NCI-H460, SK-OV-3, and DU-145). The phosphate prodrug salts (KGP04 and KGP152), functioned as VDAs, evidenced (in collaborative studies) by disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor (KGP04), and in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc (KGP152). Tangential synthetic strategies provided access to a focused library of α…
author: Maguire, Casey J., 1984-
language: en
keywords: Dihydronaphthalene., Chalcone., Combretastatin A-4.
date published: 2019-05
date modified: 2026-07-24T01:07:49Z
provider: Baylor University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Baylor University.

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2104/10693