Browsing by Subject "Tubulins."
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Item Design and synthesis of dihydronaphthalene vascular disrupting agents and indolequinone-based bioreductives.(2007-03-08T15:41:24Z) Dogra, Abhishek.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Cancer remains a deadly affliction for millions across the United States, and the number of new cases is only expected to rise in the years to come. In the field of anticancer research, vascular disrupting agents (VDAs) that preferentially target the tumor vasculature show great promise. The naturally occurring combretastatins, especially combretastatin A-4 (CA4) and combretastatin A-1 (CA1), in suitable prodrug form, have proven to be highly effective VDAs. In this study, efforts were directed towards the synthesis of two combretastatin analogs bearing key features of CA4 on a dihydronaphthalene framework: Oxi 6196 and a beta-dihydronaphthalene analog. In addition to VDAs, another class of exciting anticancer drugs is bioreductive agents that are selectively targeted towards the hypoxic region of tumors. These compounds are chemically reduced selectively and intracellularly to form active cytotoxic compounds. This study also presents the design and synthesis of two analogs of indolequinone-based prodrugs, which can be triggered to release an attached VDA upon bioreductive activation from the 3- or the 2-position, as well as the attempted synthesis of a CA4-tirapazamine bioconjugate drug.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.Item Structure-activity relationships and thermodynamics of combretastatin A-4 and A-1 derivatives as potential inhibitors of tubulin polymerization.(2006-05-29T01:59:46Z) Mugabe, Benon E.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Inhibition of tubulin polymerization has been identified as a significant characteristic of potential anticancer agents. Tubulin is a heterodimeric protein of a and b polypepetide chains, each with a molecular weight of 50kDa and is the biochemical target for several clinically used anticancer drugs. Tubulin was purified from calf brain by a method that uses a series of selective polymerizations induced by a temperature jump in the presence of GTP followed by cold depolymerization. Protein purity was determined by SDS-PAGE and the ability of tubulin to polymerize into microtubules. As part of a program to identify vascular disrupting agents (VDAs), we have determined the effect of more than 78 combretastatin A-4 and A-1 analogs on tubulin polymerization. Combretastatin analogs with substitutions in both the trimethoxyphenyl and phenolic rings were analyzed. These included bromo, chloro, fluoro, mono and di-nitro, di-amino and di-amino hydrochloride, serinamides, serinamide hydrochloride salts of CA-4 and CA-1 derivatives many of which showed good antitubulin activities (IC50 = 1.1 – 3.0 µM) which were comparable to those of CA-1 and CA-4. Generally, water soluble combretastatin phosphate salts analyzed did not show significant inhibitory activity on tubulin polymerization. Our research also explored the application of isothermal titration calorimetry in determining the thermodynamic parameters of binding of CA-1, CA-4 and some of their derivatives. Microcalorimetric studies of the interactions between tubulin and combretastatin analogs were designed to directly determine the enthalpy, binding affinity and the number of binding sites involved upon interaction. We have defined the various thermodynamic signatures that characterize interaction of these compounds with tubulin. All tubulin-combretastatin analog interactions were exothermic and showed favorable free energies and binding affinity constants (0.1 – 9.8 x 105 M-1). The binding affinity constants, stoichiometry, and the thermodynamic signatures suggested hydrogen bonding and hydrophobic contacts for the stronger binding interactions between CA-1 and its analogs which were both enthalpy and entropy driven whereas 2,3 di-amino CA-1 and others showed low binding constants, with evidence of conformational changes upon binding.Item Synthesis of protected amino thymidines and new thiol derivatives of the vascular targeting agent combretastatin A-4.(2007-03-08T05:06:14Z) Ramirez, Daniel A.; Kane, Robert R.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Protected amino thymidines were synthesized as part of a project aimed at developing reagents for the site-specific, sequence selective DNA cleavage. Modified DNA oligonucleotides have the capacity to behave like artificial restriction enzymes in addition to being agents for the targeted scission of DNA and RNA in antiviral and gene therapy. Sulfur-containing analogues of the vascular targeting agent (VTA) Combretastatin A4 (CA4) were also synthesized. Vascular targeting agents are a class of anticancer compounds made to target and restrict tumor neovasculature. Disruption of these new tumor-associated capillaries prevents the blood flow necessary to feed the tumor, resulting in tumor cell starvation, the build-up of toxins, and massive necrotic cell death. One of the best characterized small molecule vascular targeting agents is Combretastatin A-4 (CA4), which is currently in Phase II clinical trials.