Kinetic characterization of thiosemicarbazones as cysteine protease inhibitors and their potential use as therapeutic agents against metastatic cancer and Chagas' disease.
Access rightsWorldwide access.
Access changed 7/7/15.
Chavarria Nolasco, Gustavo E.
MetadataShow full item record
Human cathepsins L and K are cysteine proteases that play important roles in physiological and pathological processes, such as cancer metastasis, bone resorption and neurodegenerative diseases. This research has focused on the evaluation of synthetic thiosemicarbazones that could inhibit their proteolytic activities with the objective of preventing cancer metastasis. In addition, cruzain, a cathepsin L-like cysteine protease found in Trypanosoma cruzi, is a validated target for pivotal roles in the parasitic invasion in Chagas' disease, a condition that could be fatal if not treated. Currently, there is no effective treatment against the disease, which is rapidly extending to non-endemic areas in the United States and Europe. More than 150 synthetic thiosemicarbazones (obtained through a collaborative study) were tested against cathepsins L, K and cruzain. This work presents preliminary in vitro analysis of these compounds in order to characterize their potency and mode of inhibition. A number of potent inhibitors was found for each enzyme. A smaller subset of thiosemicarbazones were found to be selective. Results showed that compound 1, one of the most potent inhibitors in this library is a slow binding, slowly reversible, competitive inhibitor of these targets. Furthermore, 1 was able to delay and partially inhibit the activation of procathepsin K under acidic conditions. Similar results were found with 3-bromo-3'-hydroxybenzophenone thiosemicarbazone (8). Compounds 8 and 1 inhibited the in vitro type I collagenase activity of cathepsin L in a time-dependent manner and type IV collagenase activity of cathepsin K. Analogs, 1, 8, 156, 157, and 168 were also used in cell studies. These compounds were able to delay cell migration and cell invasion in MDA-MB-231 cells, a type of carcinoma breast cancer cell line. It was determined that cell invasion and cell migration were inhibited in a concentration dependent manner. Lastly, analog 17 was also found to be a slow reversible, slow binding, competitive inhibitor of cruzain. This compound was also able to inhibit the collagenase activity of recombinant cruzain when human type I collagen was used as a substrate. Kinetic studies and molecular modeling indicate the best thiosemicarbazone inhibitors form a reversible covalent bond with each enzyme.
DepartmentChemistry and Biochemistry.
Showing items related by title, author, creator and subject.
Design and synthesis of potential serotonin-selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for the treatment of depression. Elguézabal-Torralba, Gerardo Arturo. (2010-10-08)Depression is a common disease characterized by feelings of deep sadness, guiltiness, loss of interest in once pleasurable activities, and thoughts of self-harm among others. Affecting an estimated 121 million people ...
Modeling, design, and development of potential inhibitors of γ-glutamylamine cyclotransferase and inhibitors of cruzain as therapeutic agents for Chagas' disease. Chen, Shen-En, 1981- (2008-06-11)γ-Glutamylamine cyclotransferase (γ-GACT) catalyzes cyclization of the L-glutamyl moiety in the isolated ε-(L-γ-glutamyl)-L-lysine crosslink, thereby releasing lysine. Although implicated in the degradation of the crosslink, ...
Veterans as teachers? A qualitative study of the inhibitors and enabling factors for OIF/OEF-era active duty veterans to complete a teacher education program and initial certification using military educational benefits. Moore, Brandon L., 1977- (, 2013-09-24)Over two million veterans returning from Afghanistan and Iraq may be coming to American colleges and universities as a result of the Post-9/11 GI Bill. Veterans have education benefits available to them, such as the ...