Hiromi Sekizawa, Kazuma Amaike, Yukihiro Itoh,  Takayoshi Suzuki, Kenichiro Itami, and Junichiro Yamaguchi

ACS. Med. Chem. Lett. 2014, just accepted. DOI: 10.1021/ml500024s

Power of C–H coupling technology for medicinal chemistry

We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C–H coupling reaction,  we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C–H coupling approach to rapidly identify novel and highly active/selective bio-functional molecules.