Download Design and synthesis of biologically active carboxylesterase

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.