Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks

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.     

Palm and sole interdigital ridge-count correlations

Correlations among the twelve palm and sole interdigital ridge-counts were calculated for samples of Europeans of German, Austrian, Finnish and Polish ancestry, for Bantu speaking Black Africans from Angola and the Republic of South Africa, for Japanese and Tibetans and for Indians and Coloureds from the Republic of South Africa. Canonical correlation and factor analyses were used to discern patterning in the correlations. Generally, within palm and within sole correlations are stronger than palm-sole correlations. However, the results show an unequivocal positive relationship between palm and sole ridge-counts. A consistent feature was a stronger relationship of palm c-d counts to sole a-b counts. We suggest that this pattern of correlation may reflect early morphogenetic pattern formation prior to commitment of cells to hands and feet.