Browsing by Subject "Chagas' disease -- Treatment."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas.(2006-05-29T01:54:54Z) Siles, Rogelio.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.In an effort to combat cancer, the development of a relatively new type of anti-cancer drugs known as vascular disrupting agents (VDAs) seems to be a promising clinical approach. VDAs selectively interfere with blood flow in the microvessels that carry nutrients and oxygen to the tumor. Blockage of these vessels will stop tumor growth, produce necrosis, and hence prevent proliferation of cancer cells through the body. The discovery of a group of VDAs known as combretastatins (CA) has sparked an exciting area of anti-cancer drug discovery due to their robust biological activity as evidenced through clinical success, particularly for combretastatin A-4 phosphate (CA-4P) and one nitrogen-based combretastatin CA-4 analogue, AVE8062 which are currently in clinical development. Herein, a small library of seventeen new synthetic oxygen and nitrogen-bearing CA-1 and CA-4 analogues is described. Three of these analogues showed significant inhibition of tubulin assembly (IC50= 2-3 μM) as well as in vitro cytotoxicity against selected human cancer cell lines and in vivo blood flow reduction in SCID mice (23-25% at 10 mg/Kg) suggesting that they have potential for further prodrug modification and development as vascular disrupting agents for the treatment of solid tumor cancers. A separate research project has concentrated on the development of cysteine protease inhibitors, primarily focused toward the inhibition of cruzain, the major cysteine protease of Trypanosoma cruzi which is the agent of the parasitic disease called Chagas’ disease. Currently there is no satisfactory treatment for this disease, and the two accepted drugs, nifurtimox and benznidazole, are associated with significant clinical toxicity. A library of fourteen small non-peptidic thiosemicarbazones has been successfully designed, synthesized and tested against cruzain and cathepsin L from which five compounds showed significant cruzain inhibition in the low namolar range. Although the most active compound synthesized, which is a bromotetrahydronaphthalene thiosemicarbazone, exhibited an IC50=12 nM against cruzain, it also showed activity against cathepsin L (IC50=134 nM). This new pharmacophore introduced may prove useful as a lead compound for further optimization. In addition, this research revealed further insights into the complex structure-activity relationship parameters which may lead to the further development of more selective cruzain inhibitors.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 human cathepsin L and cruzain as therapeutic agents.(2009-04-01T18:21:12Z) Arispe Angulo, Wara Milenka.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Increased human cathepsin L activity is linked to invasive and metastatic cancers where it promotes degradation of the extracellular matrix. This major cysteine protease found in cell lysosomes and secreted from tissues, also plays a role in the pathology of degenerative cartilage and neurological disorders, and is reported to be required for the SARS coronavirus infection. A library of 59 small non-peptidic thiosemicarbazone and α, β-unsaturated carbonyl derivatives of benzophenone, propiophenone, α- and β-tetralone, 4-chromanone, and 4-thiochromenone were evaluated as inhibitors of human cathepsin L. While most of the compounds had IC50 values in the range of 0.4 µM or greater, four were very effective inhibitors of cathepsin L: the benzophenone thiosemicarbazones 2 (IC50= 1.5 nM), 55 (IC50= 44 nM), 38 (IC50= 60 nM), 32 (IC50= 66 nM), and 37 (IC50= 140 nM) and a sulfone analog of the bromo substituted thiochroman-4-one 22 (IC50= 1 nM). Kinetics studies were used to gain understanding in enzyme-inhibitor interactions of the most potent compounds (2 and 22) and they were found to be reversible, slow, tight binding inhibitors of cathepsin L. These data support formation of a transient covalent intermediate between thiosemicarbazone inhibitors and the cathepsin L active site thiolate. Ten of the most promising lead compounds were also tested for cytotoxicity in HEK-293 cells and generated no toxicity after 24 hours. Exposure of the prostate cancer cell line DU-145 to the most promising lead compounds successfully decreased the invasiveness and mobility properties of these cells in vitro. The non-peptidic nature of these inhibitors, coupled with their cell-based activity, makes these compounds very promising leads for the development of selective cathepsin L inhibitors. A separate research project consisted of recombinant cruzain purification and evaluation of thiosemicarbazone derivatives as potential inhibitors of this parasitic cysteine protease. Cruzain is the major cysteine protease of Trypanosoma cruzi organism and is a validated therapeutic target for the development of new chemotherapy. Chagas disease, a result of Trypanosoma cruzi infection, is the third largest parasitic disease challenge worldwide after malaria and leishmania and there is an urgent need for development of new therapeutic agents against Chagas disease. From the same library of thiosemicarbazone derivatives evaluated against cathepsin L, 25 compounds were evaluated against cruzain from which six compounds were in the nanomolar range with IC50 values ranging from 170 nM to 622 nM.