911062-24-3Relevant academic research and scientific papers
Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase
Huff, Sarah E.,Mohammed, Faiz Ahmad,Yang, Mu,Agrawal, Prashansa,Pink, John,Harris, Michael E.,Dealwis, Chris G.,Viswanathan, Rajesh
, p. 666 - 680 (2018)
Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 ? X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC50 of 5.3 ± 1.8 μM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial enzyme.
SUBSTITUTED TRIAZOLE DERIVATIVES AS OXYTOCIN ANTAGONISTS
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Page/Page column 56, (2010/11/24)
The present invention relates to a class of substituted triazoles of formula (I) with activity as oxytoci antagonists, uses thereof, processes for the preparation thereof and compositions containing sai inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction particularly premature ejaculation (P.E.).
