Late-Stage C–H Coupling Enables Rapid Identification
of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 Analogues
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Abstract
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 biofunctional molecules
