Inhibitors of tubulin, nitric oxide synthase, and HIF-1 alpha; synthesis, biological, and biochemical evaluation.
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Hall, John Jacobs.
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Vascular disruption is an innovative method for treating cancer. By selectively altering the endothelial cells of tumor vasculature, the tumor can be destroyed by oxygen deprivation and starvation. The combretastatin (CA) family of small molecules has shown great effectiveness as vascular disrupting agents (VDAs). Structure activity relationship (SAR) studies were continued for the combretastatin family by placement of a 3,4,5-trifluoro substituted A-ring, and 2- or 3-nitro/amine substitutions on the B-ring. Indole scaffolds that are similar to the CA analogues and Oxi8006 were also prepared. The VDAs were tested for cancer cytotoxicity and their ability to inhibit tubulin polymerization. The 3′-amino stilbene 15 was the most effective of the fluoro-nitro stilbenes synthesized, having a tubulin IC50 of 2.9 µM, and a cell cytotoxicity of 0.0093 µg/mL against NCI H460 lung cancer carcinoma. Though VDAs have been effective against a variety of tumor cells, there are cancers, such as human oral squamous cell (SaS), that are resistant to combretastatin A4 phosphate (CA4P). It is believed the SaS resistance results from an increase in nitric oxide (NO) production, which can increase tumor blood supply and vascular tone. CA4P co-salts with the nitric oxide synthase (NOS) inhibitors L-NMMA and L-NAME have been shown to increase drug sensitivity. As such, L-NMMA and L-NAME co-salt formulations with Oxi8007 were prepared to increase drug sensitivity CA4 and CA1 were coupled with aromatic bioreductive triggers to increase drug response in hypoxic areas that are resistant to chemotherapeutics. These nitro-aromatic triggers are expected to only release upon reduction within the hypoxic environment, and increase drug specificity to these areas. The transcription factor HIF-1α has been labeled as a primary target in treating the hypoxic areas of tumors. Drugs that are effective at inhibiting HIF-1α may be better suited for treating hypoxic tumor cells. Approximately 20 compounds were analyzed for their ability to inhibit HIF-1α preservation. Benzosuberene 96 and benzophenone 37 were the most effective at inhibiting HIF-1α preservation. The tubulin IC50 activity of compound 96 is > 40 µM, suggesting that it is inhibiting HIF-1α preservation by a means other than microtubule disruption.