Synthesis of novel benzils and benzoins as selective inhibitors of mammalian carboxylesterases designed to ameliorate the delayed diarrhea associated with CPT-11 treatment.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5530 The anticancer prodrug CPT-11 is activated by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I poison. Delayed diarrhea, which is the dose limiting toxicity for this drug, is thought to arise from direct conversion of the drug to the active metabolite in the small intestine. Therefore, we have screened for, and identified, a series of selective CE inhibitors that may have utility in ameliorating diarrhea. Benzil has been identified as a potent inhibitor of these enzymes. The essential characteristics required for inhibitory activity by the benzil and its analogs include: (i) the dione moiety, (ii) the aromatic rings; and (iii) substitution on the rings which does not impede access of inhibitor to the enzyme active site. Halogen substitution has been shown to increase the Ki values for these small compounds toward three mammalian CEs, human intestinal CE (hiCE), rabbit CE (rCE), and human liver CE (hCE1). We have synthesized and assessed the ability of symmetrical benzils and their related benzoins with different degrees of fluorine substitution in the o-, m-, or p- position of the aromatic ring, to inhibit these enzymes. Following determination of the Ki values for CE enzyme inhibition with these fluorobenzil analogs, a variety of computational molecular modeling methods have been applied in an attempt to correlate these results with physical parameters of these compounds. These include the assessment of the atomic charge on both the oxygen and carbon atoms of the carbonyl group and the pka of the hydroxyl group of the benzoins. In addition, molecular modeling of the movement of the aromatic rings around the 1,2-dione dihedral angle of the benzil and the pseudo-dione dihedral angle of the benzoin indicated that the ability for these molecules to inhibit CEs was due, partially, to rotational restrictions enforced by this dihedral angle. Hence these studies may prove useful as a predictive tool to assess the potency of fluorinated benzils and benzoins as potent inhibitors of mammalian CEs. We envisage that these compounds could be used to inhibit hiCE in vivo, preventing the conversion of CPT-11 to SN-38 in the gut, therefore reducing the side effect, diarrhea, associated with drug treatment. This work was funded by the American Lebanese Syrian Associated Charities.