• Jiangli Song, Lindsay M Jones, Gustavo E Chavarria, Amanda K Charlton-Sevcik, Adam Jantz, Audra Johansen, Liela Bayeh, Victoria Soeung, Lindsey K Snyder, Shawn D Lade, David J Chaplin, Mary Lynn Trawick, and Kevin G Pinney.
• Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
• Bioorg. Med. Chem. Lett. 2013 May 1; 23 (9): 2801-7.

AbstractCathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl-alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure-activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500 nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164 nM. All of the compounds evaluated were inactive (IC50 >10,000 nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.Copyright © 2012 Elsevier Ltd. All rights reserved.

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