Abstract
Graphical AbstractNVP-2 (1), a potent and selective inhibitor of cyclin-dependent kinase 9 (CDK9), showed potent antitumor activity in preclinical studies. In this work, we designed and adopted a convergent synthetic route to efficiently synthesize NVP-2 (1). The key intermediate (7) was synthesized from malononitrile (2) and 1-bromo-2-(2-bromoethoxy)ethane (3) by successive cyclization, reduction, nucleophilic substitution with 2-bromo-6-fluoropyridine, and Suzuki–Miyaura reaction with (5-chloro-2-fluoropyridin-4-yl)boronic acid. Another key intermediate (11) was synthesized from (S)-1-methoxypropan-2-ol (8) by reaction with TsCl, electrophilic substitution reaction with tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate, and then by deprotection of Boc. Finally, a substitution reaction by the key intermediates (7) and (11) to afford the target product NVP-2 (1). The reaction conditions of the whole synthesis process were simple and mild, free of harsh conditions such as the microwave reaction and dangerous reagents in the original patent, and realized the efficient synthesis of NVP-2. In addition, we analyzed the binding mode of NVP-2 in the active pocket of CDK9 to provide reasonable design ideas for subsequent discovery of novel CDK9 inhibitors.
Highlights
Optimized Synthetic Route According to the literatures, the synthesis strategy of NVP-2 is divided into two parts: the first is to synthesize the key intermediates 4-(((5′-chloro-2’-fluoro-[2,4’-bipyridyl]-6yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (7) and (1r,4R)-N1-((R)-1-methoxy-2-propyl)cyclohexane-1,4-diamine
In the following step to synthesize intermediate 5, we could evade the forming of byproducts and improve the yield by slightly heating the reaction
Upon completion of the reaction, the reaction mixture cooled to ambient temperature, e54 Efficient Synthesis and Docking Analysis of Selective Cyclin-dependent kinase 9 (CDK9) Inhibitor NVP-2 Saidahmatov et al
Summary
Cyclin-dependent kinase 9 (CDK9) mainly regulates gene transcription elongation and messenger RNA (mRNA) maturation, and has emerged as an attractive therapeutic target for many malignant tumors, including hematological malignancies and solid tumors.[1,2,3,4,5] Many CDK9 inhibitors have been developed or are currently being in various stages of clinical development for cancer treatment.[6,7,8,9,10] NVP-2 (1), chemical name “4-(((5′-chloro-2’-(((1R,4r)-4-(((R)-1methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4’-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile,” is a novel selective ATP-competitive CDK9 inhibitor developed by Novartis in 2011. Keywords ► NVP-2 ► CDK9 inhibitor ► efficient synthesis ► docking analysis Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2 Saidahmatov et al e51
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