Browsing by Subject "Neovascularization inhibitors."
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Item Design, synthesis and evaluation of di-nitrogen derivatives of combretastatin and novel cruzain inhibiting compounds for the treatment of Chagas disease.(2008-03-03T17:32:22Z) Ackley, J. Freeland.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Over the past years cancer statistics have continued to rise to the point that the World Health Organization said that in 2005 cancer was leading cause of death worldwide. Years of research have resulted in many new promising therapies and treatment agents and very recently the field of vascular targeting therapies has grown in a strong proportion. One especially promising technique focuses on the use of vascular disrupting agents (VDAs). This clinical approach targets the endothelial cells partially composed of the tubulin-microtubule protein system in microvessels in the tumor microenvironment. The vascular damage caused by these drugs has seen to be highly selective due, in part, to the chaotic nature of the vessels created by these rapidly proliferating endothelial cells in the tumor microenvironment. The continued success of combretastatin A4 and combretastatin A1 in human clinical development indicate the importance of preparing new synthetic analogs to further understand the role of these anti-mitotic agents. Accordingly, a small library of eleven functionalized Z-stilbenes was created containing various nitro and amine moieties substituted in a 2,3, 3,5, and 2,3 pattern. These compounds have showed impressive biological results with the leading compound 18 demonstrating an IC50 value of 2.8 [mu]M for the inhibition of tubulin assembly and in vitro GI50 values in selected human cancer cell lines that are sub-nanomolar. A separate research project has recently been focused on the design and synthesis of new cruzain inhibitors modeled around an initial small library of molecules previously prepared by the Pinney Research Group at Baylor University. These thiosemicarbazone bearing molecules were designed to target the major cysteine protease of Trypanosoma cruzi also known as cruzain. Selected compounds were successfully designed and synthesized and are awaiting biochemical and biological evaluation.Item Inhibitors of tubulin, nitric oxide synthase, and HIF-1 alpha; synthesis, biological, and biochemical evaluation.(2008-06-16T13:10:55Z) Hall, John Jacobs.; Pinney, Kevin G.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.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.