Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity.
The dose-limiting toxicity of the highly effective anticancer agent 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (irinotecan; CPT-11) is delayed diarrhea. This is thought to be caused by either bacteria-mediated hydrolysis of the glucuronide conjugate of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) or direct conversion of CPT-11 to SN-38 by carboxylesterases (CE) in the small intestine. After drug administration, a very high level of CPT-11 is present in the bile; this is deposited into the duodenum, the region of the gut with the highest levels of CE activity. Hence, it is likely that direct conversion of the drug to SN-38 is partially responsible for the diarrhea associated with this agent. In an attempt to ameliorate this toxicity, we have applied Target-Related Affinity Profiling to identify novel CE inhibitors that are selective inhibitors of the human intestinal enzyme (hiCE). Seven inhibitors, all sulfonamide derivatives, demonstrated greater than 200-fold selectivity for hiCE compared with the human liver CE hCE1, and none was an inhibitor of human acetylcholinesterase or butyrylcholinesterase. Quantitative structure-activity relationship (QSAR) analysis demonstrated excellent correlations with the predicted versus experimental Ki values (r2 = 0.944) for hiCE. Additionally, design and synthesis of a tetrafluorine-substituted sulfonamide analog, which QSAR indicated would demonstrate improved inhibition of hiCE, validated the computer predictive analyses. These and other phenyl-substituted sulfonamides compounds are regarded as lead compounds for the development of effective, selective CE inhibitors for clinical applications.
Wadkins
Randy M
RM
Department of Chemistry and Biochemistry, University of Mississippi, University, USA.
Hyatt
Janice L
JL
Yoon
Kyoung Jin P
KJ
Morton
Christopher L
CL
Lee
Richard E
RE
Damodaran
Komath
K
Beroza
Paul
P
Danks
Mary K
MK
Potter
Philip M
PM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007422:Intestines / Q000201:enzymology; D000077146:Irinotecan; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin