Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship was written by Vianello, Paola;Sartori, Luca;Amigoni, Federica;Cappa, Anna;Faga, Giovanni;Fattori, Raimondo;Legnaghi, Elena;Ciossani, Giuseppe;Mattevi, Andrea;Meroni, Giuseppe;Moretti, Loris;Cecatiello, Valentina;Pasqualato, Sebastiano;Romussi, Alessia;Thaler, Florian;Trifiro, Paolo;Villa, Manuela;Botrugno, Oronza A.;Dessanti, Paola;Minucci, Saverio;Vultaggio, Stefania;Zagarri, Elisa;Varasi, Mario;Mercurio, Ciro. And the article was included in Journal of Medicinal Chemistry in 2017.SDS of cas: 224309-64-2 This article mentions the following:
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. The authors have previously described the identification of thieno[3,2-b]pyrrole-5-carboxamides, as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound (I) with biochem. IC50 = 160 nM. The authors now report the structure-guided optimization of this chem. series, based on multiple ligand/KDM1A-CoRest co-crystal structures, which led to several extremely potent inhibitors. In particular, compounds N-[3-(methoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]- methoxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]-pyrrole-5-carboxamide hydrochloride (46), 4-ethyl-N-[3-(methoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]-methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide (49) and N-[3-(ethoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]methoxy]-phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide hydrochloride (50) showed single digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells these compounds transcriptionally affected the expression of genes regulated by KDM1A, such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anti-clonogenic cell growth effect on MLL-AF9 human leukemia cells. In the experiment, the researchers used many compounds, for example, tert-Butyl (4-hydroxycyclohexyl)carbamate (cas: 224309-64-2SDS of cas: 224309-64-2).
tert-Butyl (4-hydroxycyclohexyl)carbamate (cas: 224309-64-2) belongs to alcohols. A strong base can deprotonate an alcohol to yield an alkoxide ion (R―O−). For example, sodamide (NaNH2), a very strong base, abstracts the hydrogen atom of an alcohol. Grignard and organolithium reagents are powerful tools for organic synthesis, and the most common products of their reactions are alcohols.SDS of cas: 224309-64-2
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