Synthesis and hepatic transport of strongly fluorescent cholephilic dipyrrinones.
A new class of highly fluorescent (phi(F) 0.3-0.8) low molecular weight water-soluble cholephilic compounds has been synthesized in two steps from dipyrrinones. The dipyrrinone nitrogens are first bridged by reaction with 1,1'-carbonyldiimidazole to form an N,N'-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidine-3,5-dione) nucleus, and a sulfonic acid group is then introduced at C(8) by reaction with concd H(2)SO(4). The resulting sulfonated N,N'-carbonyl-bridged dipyrrinones ("sulfoglows") are isolated as their sodium salts. When the alkyl substituents of the lactam ring are lengthened from ethyl to decyl, sulfoglows become increasingly lipophilic while maintaining water solubility. Low molecular weight sulfoglows were rapidly excreted intact in both bile and urine after intravenous infusion into rats, but higher molecular weight sulfoglows were excreted more selectively in bile. Hepatobiliary excretion of sulfoglows was partially, but not completely, blocked in mutant rats deficient in the multidrug-resistance associated transport protein Mrp2 (ABCC2). These observations point to the feasibility of developing simple sulfoglows with clinical diagnostic potential that are normally excreted in bile but appear in urine when hepatic elimination is impaired by cholestatic liver disease.
Woydziak
Zachary R
ZR
Department of Chemistry, University of Nevada, Reno, Nevada 89557, USA.
Boiadjiev
Stefan E
SE
Norona
Wilma S
WS
McDonagh
Antony F
AF
Lightner
David A
DA
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives / Q000737:chemistry; D003078:Colchicine / Q000032:analysis* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D011744:Pyrimidinones / Q000032:analysis / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011911:Rats, Gunn; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013050:Spectrometry, Fluorescence; D013451:Sulfonic Acids / Q000032:analysis / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014556:Urine / Q000737:chemistry
C511257:3-n-heptyl-2,7,9-trimethyl-N,N'-carbonyl-(10H)-dipyrrin-1-one-8-sulfonic acid; D005456:Fluorescent Dyes; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D011744:Pyrimidinones; D011758:Pyrroles; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D013451:Sulfonic Acids; C511256:xanthoglow; C013337:xanthobilirubic acid; D001663:Bilirubin; D003078:Colchicine