Browsing by Subject "Protease inhibitors."
Now showing 1 - 2 of 2
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 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.