Synthesis and biological evaluation of potential vascular disrupting and antimitotic agents utilizing benzosuberene, benzocyclooctene, and indene molecular frameworks.
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Herdman, Christine A., 1985-
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An investigational approach to cancer treatment involves the use of therapeutic agents that selectively target tumor-associated vasculature. A subset of these compounds is referred to as vascular disrupting agents (VDAs). The majority of clinically-relevant VDAs function biologically as inhibitors of tubulin polymerization, thus interfering with the dynamic instability inherent to the tubulin-microtubule protein system. As a key component of the cytoskeleton associated with eukaryotic cells, this protein system provides shape and structural stability to the endothelial cells that line the vasculature. Tumor associated vasculature provides a promising target for cancer therapeutics due to its primitive nature and abhorrent structure. Microtubule depolymerization leads to endothelial cell morphology changes (flat to round), which results in vasculature collapse and shut down of blood flow, ultimately leading to tumor necrosis. Tumors larger than 2-3 mm3 require their own vasculature for the transportation of oxygen and nutrients, as well as the disposal of waste. Selective targeting of tumor-associated vasculature results from the structural differences inherent to these vessels versus those feeding healthy tissue. The natural products combretastatin A-1 (CA1), combretastatin A-4 (CA4), and colchicine are potent inhibitors of tubulin polymerization. While toxicity associated with colchicine treatment limited its use as an anticancer therapeutic, CA1 and CA4, as their corresponding water-soluble prodrug salts CA1P and CA4P respectively, have shown promising results in clinical trials. Drawing on structural similarities inherent to these three natural products, the Pinney Research Group at Baylor University has developed a variety of potent inhibitors of tubulin polymerization that function as VDAs. A benzosuberene-based compound (referred to as KGP18) has emerged as a highly promising agent for further investigation. Using KGP18 as a model, several new analogues have been synthesized and evaluated biologically to expand the structure activity relationship (SAR) profile of the benzosuberene class of compounds and to investigate the efficacy associated with benzocyclooctene and indene ring systems bearing similar functional group motifs. The synthesized target molecules have been evaluated for their ability to inhibit tubulin polymerization (assembly) as well as their cytotoxicity against three human cancer cell lines (NCI-H460, SK-OV-3, and DU-145) in collaborative studies. In a related study, multi-walled carbon nanotubes (MWCNTs) have been evaluated for their ability to selectively deliver VDAs to tumors and/or tumor-associated vasculature. Initial studies have included dispersion assays of MWCNTs in a variety of organic solvents, as well as adsorption studies utilizing two water-soluble phosphate prodrug salts (CA4P and KGP265).