Design and synthesis of non-peptidic thiosemicarbazone derivatives as inhibitors of cathepsins L and K.

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dc.contributor.advisor Pinney, Kevin G. Song, Jiangli. 2012-08
dc.identifier.citation Song, J. L., Jones, L. M., Kishore Kumar, G. D., Conner, E. S., Bayeh, L., Chavarria, G. E., Charlton-Sevcik, A. K., Chen, S. E., Chaplin, D. J., Trawick, M. L., Pinney, K. G. "Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L." ACS Med. Chem. Lett. 3, 6 (2012); 450–453. en_US
dc.description.abstract Cathepsin L, a member of the lysosome cysteine proteases, is ubiquitously expressed in tissue and is responsible for protein turnover. An overexpression of cathepsin L by certain tumor types is associated with enhanced tumor expansion through degradation of the extracellular matrix and the invasion and migration of cancer cells. Therefore, the inhibition of cathepsin L has emerged as a therapeutic strategy against metastatic cancer. Cathepsin K is involved in osteoclastic bone resorption because it is selectively expressed in osteoclasts and is capable of degrading bone matrix. In this project, a small library of thiosemicarbazone derivatives containing thiochromanone, 2,3-dihydroquinoline-4-one, and dibenzoylbenzene scaffolds has been successfully designed and synthesized as potential inhibitors of cathepsin L and other homologous cathepsins (B and K). Through a collaborative study, ten compounds from this library were found to be potent inhibitors (IC50 < 300 nM) of cathepsin L, and nine compounds were potent inhibitors of cathepsin K. None of these inhibitors showed activity against cathepsin B. For example, 6,7-difluorothiochromanone thiosemicarbazone 4 (IC50 = 46 nM) was the most potent inhibitor against cathepsin L from this group, while the 6-trifluoromethyl derivative 28 (IC50 = 21 nM) was the most potent inhibitor against cathepsin K. Structure activity relationship (SAR) studies centered on the thiochromanone thiosemicarbazone scaffold demonstrated that electron-withdrawing functionalities, incorporated primarily at the 6-position of the thiochromanone scaffold, showed good inhibition against cathepsin L in comparison to related analogues bearing electron-donating groups. Collectively, these results expand the known SAR regarding molecular structures and their inhibitory activity against cathepsins L and K. en_US
dc.rights Baylor University theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact for inquiries about permission. en_US
dc.subject Cathepsin K. en_US
dc.subject Cathepsin L. en_US
dc.subject Non-peptidic thiosemicarbazone derivatives. en_US
dc.subject Inhibitors. en_US
dc.subject Lysosome cysteine proteases. en_US
dc.subject Metastatic cancer. en_US
dc.title Design and synthesis of non-peptidic thiosemicarbazone derivatives as inhibitors of cathepsins L and K. en_US
dc.type Thesis en_US Ph.D. en_US
dc.rights.accessrights No access - Contact en_US
dc.contributor.department Chemistry and Biochemistry. en_US
dc.contributor.schools Baylor University. Dept. of Chemistry and Biochemistry. en_US

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