基于反苯环丙胺的 LSD1 抑制剂的纯非对映异构体：酶选择性和细胞内研究
Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies.
作者信息
Valente Sergio, Rodriguez Veronica, Mercurio Ciro, Vianello Paola, Saponara Bruna, Cirilli Roberto, Ciossani Giuseppe, Labella Donatella, Marrocco Biagina, Ruoppolo Giovanni, Botrugno Oronza A, Dessanti Paola, Minucci Saverio, Mattevi Andrea, Varasi Mario, Mai Antonello
机构信息
Department of Drug Chemistry and Technologies, Sapienza University of Roma , P.le A. Moro 5, 00185 Roma, Italy.
Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milano, Italy.
出版信息
ACS Med Chem Lett. 2014 Dec 8;6(2):173-7. doi: 10.1021/ml500424z. eCollection 2015 Feb 12.
Abstract
The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2-aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts.
摘要
反式苄基（1-((4-(2-氨基环丙基)phenyl)氨基)-1-氧代-3-苯基丙烷-2-基）氨基甲酸酯盐酸盐11的四种纯非对映异构体（11a-d），我们之前将其描述为LSD1抑制剂，通过对映体特异性合成/手性HPLC分离方法获得。在LSD1和MAO测定中进行测试，11b（S,1S,2R）和11d（R,1S,2R）是针对LSD1最有效的异构体，对MAO-A活性较低，对MAO-B几乎无活性。在细胞中，所有四种非对映异构体均诱导NB4细胞中Gfi-1b和ITGAM基因表达，与其对LSD1的抑制作用一致，并且11b和11d抑制小鼠早幼粒细胞的集落形成潜能。
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