TY - JOUR AU - Saidahmatov, Abdusaid; Liang, Xue-Wu; Shi, Yu-Qiang; Han, Xu; Liu, Hong TI - Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2 SN - 2628-5088 SN - 2628-5096 PY - 2021 JF - Pharmaceutical Fronts LA - EN VL - 03 IS - 02 SP - e50 EP - e55 DA - 2021/09/02 KW - NVP-2 KW - CDK9 inhibitor KW - efficient synthesis KW - docking analysis AB - 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. PB - Georg Thieme Verlag KG DO - 10.1055/s-0041-1735144 UR - http://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0041-1735144 ER -