939-90-2Relevant articles and documents
Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1
Zhou, Chao,Wu, Fangrui,Lu, Lianghao,Wei, Liping,Pai, Eric,Yao, Yuan,Song, Yongcheng
, (2017/02/15)
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1.Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity.
Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent
Vianello, Paola,Botrugno, Oronza A.,Cappa, Anna,Dal Zuffo, Roberto,Dessanti, Paola,Mai, Antonello,Marrocco, Biagina,Mattevi, Andrea,Meroni, Giuseppe,Minucci, Saverio,Stazi, Giulia,Thaler, Florian,Trifiró, Paolo,Valente, Sergio,Villa, Manuela,Varasi, Mario,Mercurio, Ciro
, p. 1501 - 1517 (2016/03/08)
We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.
Nickel-Catalyzed Reductive Carboxylation of Cyclopropyl Motifs with Carbon Dioxide
Moragas, Toni,Martin, Ruben
, p. 2816 - 2822 (2016/08/26)
A nickel-catalyzed reductive carboxylation technique for the synthesis of cyclopropanecarboxylic acids has been developed. This user-friendly and mild transformation operates at atmospheric pressure of carbon dioxide and utilizes either organic halides or alkene precursors, thus representing the first example of catalytic reductive carboxylation of secondary counterparts lacking adjacent π-components.
