Coumarin as scaffold for fluorescent kinase inhibitor

Abstract

Understanding of intracellular drug distribution and metabolism is greatly important in biological sys-tems because it provides a biological rationale for the design of new therapeutics. However, direct monitoring of drug distribution and mechanism is still challenging. The most popular method for visual monitoring of drug behavior is tethering of fluorescent dyes to drugs, yet it often causes undesired effects on in vivo activity and toxicity. Fluorescent kinase inhibitor is a novel concept that avoids the weakness of fluorescent probe and takes the advantage of using the probe. With this approach, drug distribution of fluorescent inhibitors could be readily monitored. Coumarins are the one of most important class of fluorophores. Especially, 3-heteroarylcoumarins constitute the largest class of fluorescent dyes and biologically active compounds. There-fore, we designed and synthesized a number of fluorescent 3-heteroarylcoumarins as potential c-Kit inhibitors. Rational design of inhibitors was perfomed by docking simulation and the inhibitory activities were tested over c-KIT. In the beginning, coumarin derivatives were prepared by a conventional condensation route. However, because of its limited scope of substrates, we developed an efficient synthetic method for synthesiz-ing 3-heteroarylcoumarins via direct C-H cross-coupling of 3-bromocoumarin with various heteroaryl groups. To enhance c-Kit inhibition ability, core structure was modified from 3-heteroarylcoumarins to 3-alkenylcoumarins. Some compounds showed promising inhibitory activity over wild-type c-Kit and mutant D816V c-Kit. Excellent fluorescent quantum yield and wide range absorption/emission spectrum of coumarin derivatives were also observed.