2731-06-8Relevant articles and documents
Optimization and scale-up of the Grandberg synthesis of 2-methyltryptamine
Slade, Joel,Parker, David,Girgis, Michael,Wu, Raeann,Joseph, Scott,Repic, Oljan
, p. 721 - 725 (2007)
An efficient, safe, and cost-effective synthesis of 2-methyltryptamine (2), a key starting material in the synthesis of the histone deacetylase inhibitor LBH589 (1) is described. The reaction of Phenylhydrazine (7) with a stoichiometric amount of 5-chloro-2-pentanone (8) in aqueous ethanol at reflux furnished crude 2-methyltryptamine (2). The product 2 was obtained in 47% yield and >99% purity after crystallization from toluene.
Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor
Skwarska, Anna,Calder, Ewen D.D.,Sneddon, Deborah,Bolland, Hannah,Odyniec, Maria L.,Mistry, Ishna N.,Martin, Jennifer,Folkes, Lisa K.,Conway, Stuart J.,Hammond, Ester M.
, p. 1258 - 13,1270 (2021/09/16)
Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
Novel Myocyte Enhancer Factor 2 (MEF2) modulators
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Paragraph 0238; 0241-0242, (2019/08/20)
The present disclosure provides novel compounds capable of functioning as Myoctye Enhancer Factor 2 (MEF2) modulators, as well as compositions, pharmaceutical formulations, methods of synthesis and kits. Also provided are methods of treating a condition regulatable by MEF2 and/or MEF2 cofactors using the compounds, compositions, pharmaceutical formulations, and kits provided herein.
5-(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations
Li, Xiangdong,Golz, Christopher,Alcarazo, Manuel
supporting information, p. 9496 - 9500 (2019/06/27)
The synthesis of 5-(cyano)dibenzothiophenium triflate 9, prepared by activation of dibenzo[b,d]thiophene-5-oxide with Tf2O and subsequent reaction with TMSCN is reported, and its reactivity as electrophilic cyanation reagent evaluated. The scalable preparation, easy handling and broad substrate scope of the electrophilic cyanation promoted by 9, which includes amines, thiols, silyl enol ethers, alkenes, electron rich (hetero)arenes and polyaromatic hydrocarbons, illustrate the synthetic potential of this reagent. Importantly, Lewis acid activation of the reagent is not required for the transfer process. We additionally report herein biomimetic cyanocyclization cascade reactions, which are not promoted by typical electrophilic cyanation reagents, demonstrating the superior ability of 9 to trigger challenging transformations.