title: Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks.
abstract: Cathepsin 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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
authors.forename: Jiangli
authors.initials: J
authors.lastname: Song
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Jones
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Chavarria
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Charlton-Sevcik
authors.forename: Adam
authors.initials: A
authors.lastname: Jantz
authors.forename: Audra
authors.initials: A
authors.lastname: Johansen
authors.forename: Liela
authors.initials: L
authors.lastname: Bayeh
authors.forename: Victoria
authors.initials: V
authors.lastname: Soeung
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Snyder
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Lade
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002839:Chromans / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry; D012451:Safrole / Q000031:analogs & derivatives / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry; D013764:Tetrahydronaphthalenes / Q000737:chemistry
chemical_list: D002839:Chromans; D011480:Protease Inhibitors; D011804:Quinolines; D054852:Small Molecule Libraries; D013450:Sulfones; D013764:Tetrahydronaphthalenes; C037219:quinoline; D002401:Cathepsin B; D056668:Cathepsin L; D012451:Safrole; C005746:sulfoxide