154-09-6Relevant articles and documents
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KARRER,PORTMANN
, p. 1034 - 1034 (1949)
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Tryptophanol‐derived oxazolopyrrolidone lactams as potential anticancer agents against gastric adenocarcinoma
Espadinha, Margarida,Barcherini, Valentina,Gon?alves, Lídia M.,Molins, Elies,Antunes, Alexandra M. M.,Santos, Maria M. M.
, (2021)
Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol‐derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol‐derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA‐MB‐231, A‐549, DU‐145, and MG‐63). More importantly, the compounds were non‐toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono‐ and di‐hydroxylation of the indole ring.
Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
Baumann, Georg,Meckel, Tobias,B?hm, Kevin,Shih, Yung-Hsin,Dickhaut, Mirco,Reichardt, Torben,Pilakowski, Johannes,Pehl, Ulrich,Schmidt, Boris
, (2021/04/12)
NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
Total syntheses of Hexahydropyrrolo[2,3-b]indole Alkaloids, (+)-pseudophrynamine 270 and (+)-pseudophrynamine 272A
Maity, Arindam,Munda, Mintu,Niyogi, Sovan,Kumar, Nivesh,Bisai, Alakesh
, (2021/12/09)
A general strategy for asymmetric approach to the hexahydropyrrolo[2,3-b]indole alkaloids sharing a vicinal quaternary-tertiary centers has been disclosed via Pd(0)-catalyzed N-deacylative allylations (N-DaA) (dr > 20:1). Utilizing this strategy, asymmetric total syntheses of pseudophrynamines 270 (3c) and 272A (3b) have been achieved from a 3-substituted N-acyl indole 8 (pro-nucleophile) with allyl alcohol (pro-electrophile).
