Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora

Abstract

BET proteini su epigenetski biološki targeti koji regulišu ekspresiju gena i uključeni su u patogenezu kancera. Jedan od inhibitora ovih proteina koji je opisan u literaturi je derivat tienotriazolodiazepina (+)-JQ1. Cilj ovog rada bio je dalje unapređenje osobina (+)-JQ1 derivatizacijom estarske grupe (Shema 1). U toku ovog istraživanja sintetisano je više amidnih analoga od koji je jedan pokazao 16 puta veću aktivnost u TR-FRET testu u odnosu na (+)-JQ1.

BET proteins are epigenetic biological targets that regulate gene expression and are involved in cancer pathogenesis. One of BET inhibitors described in the literature is thienotriazolodiazepine derivative (+)-JQ1. The aim of this research was to further improve the properties of (+)-JQ1 by ester group derivatization (Scheme 1). During the research several amide analogs were synthesized and one of them had 16 fold greater activity in TR-FRET assay compared to (+)-JQ1.