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Benzil Based Inhibitors of Carboxylesterases
Parkinson, Elizabeth
Parkinson, Elizabeth
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Text, Chemistry, Department of, Student research, Honors papers
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Abstract
Toxicity of chemotherapeutic agents is a major problem which often limits the ability to treat patients. One chemotherapeutic drug, irinotecan (CPT-11), causes diarrhea which is the dose limiting toxicity for this agent. This toxicity is thought to be caused by high levels of the active metabolite (SN-38) produced in the intestine. High levels of SN-38 exist due to the presence of carboxylesterase enzymes (CE) in this tissue that convert CPT-11 to SN-38. Therefore, identification of specific CE inhibitors that could ameliorate the delayed diarrhea associated with this agent, by reducing the amount of SN-38 produced in the intestine, may improve chemotherapy with this drug. Benzil (phenylethane-1,2-dione) was previously found to be a potent inhibitor of human CEs. Recently, two types of benzil derivatives, alkyl diones and molecules with atoms inserted between the phenyl ring and the dione, have demonstrated the necessity of hydrophobicity of these molecules for enzyme inhibition. In this study, we investigated the ability of a new set of compounds, 1-phenyl-1,2-alkyl diones, to inhibit CEs. These compounds consist of a 1,2-dione with a phenyl moiety on one side and an alkyl chain on the other. These compounds further support the link between inhibitor hydrophobicity and CE inhibition.
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Elizabeth Parkinson granted permission for the digitization of her paper. It was submitted by CD