Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Design and synthesis of biologically active carboxylesterase inhibitors based upon the tanshinone scaffold for modulation of esterified drug metabolism Randall J. Binder, M. Jason Hatfield, Philip M. Potter Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital [email protected] Recently, we determined that extracts of Danshen (Salvia miltiorrhiza) can inhibit carboxylesterases (CEs), resulting in reduced drug hydrolysis. Since both anticancer agents (e.g. irinotecan) and antiviral drugs (e.g. Tamiflu) require these enzymes for conversion to their active metabolite, potentially, inhibitors of these proteins may result in significant drug:drug interactions. The local toxicity associated with the former agent is known to be dose-limiting. As previous results indicated that the inhibition of CEs from extracts of Danshen occurs due to the presence of tanshinones. Thus, we sought to develop novel isozyme-specific inhibitors to selectively modulate metabolism of the administered agent. Therefore, libraries of tanshinones have been synthesized using a unified approach, amenable to parallel synthesis, and rapid screening. By applying a synthetic strategy based upon palladium-catalyzed Suzuki couplings, we have developed routes for the syntheses of two distinct series of analogues. Gratifyingly, these molecules demonstrate Ki values in the low nM range for inhibition of both liver and intestinal CEs. In summary, this facile synthetic approach for tanshinone analogues has resulted in a panel of biological activity CE inhibitors molecules that will allow for a detailed understanding of esterified drug metabolism by which dosing regimens may be improved with the aid of a co-drug.