Synthesis and evaluation of esters and carbamates to identify critical functional groups for esterase-specific metabolism.
In an effort to develop novel prodrugs for viral directed enzyme prodrug therapy (VDEPT) approaches to chemotherapy, eleven esters and carbamates of o-nitrophenol, p-nitrophenol, and beta-naphthol were synthesized and characterized as substrates for rabbit (rCE) and human liver (hCE1) carboxylesterases. All of the esters of o-, p-nitrophenols, and beta-naphthols showed moderate hydrolysis by both rCE and hCE1. Esters of beta-naphthols exhibited higher hydrolysis rates compared to esters of p-nitrophenols by rCE. Of the carbamates, 4-benzyl-piperazine-1-carboxylic acid 2-nitrophenol showed preferential hydrolysis by rCE compared to hCE1 with a V(max) of 54.4 micromoles/min/mg, and a K(m) value of 1071 microM. Substrate metabolism by a specific CE or inhibition of CEs by each compound depended on several factors, including the types of functional groups and linking moieties.
Yoon
Kyoung Jin P
KJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Morton
Christopher L
CL
Potter
Philip M
PM
Danks
Mary K
MK
Lee
Richard E
RE
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004950:Esterases / Q000378:metabolism*; D004952:Esters; D006801:Humans; D011817:Rabbits
D002219:Carbamates; D004952:Esters; D004950:Esterases