Identification, synthesis, and biological evaluation of the metabolites of 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents.
Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago, Chicago, Illinois 60612, United States.
Lian
L
Chen
Martin
M
Conda-Sheridan
P V Narasimha
PV
Reddy
Andrew
A
Morrell
Eun-Jung
EJ
Park
Tamara P
TP
Kondratyuk
John M
JM
Pezzuto
Richard B
RB
van Breemen
Mark
M
Cushman
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D004355:Drug Stability; D005260:Female; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000187:drug effects; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C574774:3-amino-6-(3'-aminopropyl)-5H-indeno(1,2-c)isoquinoline-5,11-(6H)dione; D016588:Anticarcinogenic Agents; D007192:Indenes; D007546:Isoquinolines; D008024:Ligands; D047488:Retinoid X Receptors; C039109:isoquinoline