Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo.
Monoesters with the ester groups at C-2 of pyrroloquinoline quinone (PQQ) and C-9 of imidazopyrroloquinoline (IPQ) were synthesized, and radical scavenging activities of coenzyme PQQ, IPQ compounds synthesized from PQQ and various amino acids, and monoesters of PQQ and IPQ were studied in vitro and in vivo. PQQ and PQQ monoesters had strong radical scavenging activity using ESR in in vitro experiments. The IC50 value for superoxide (O2-) was from 1 to 6 x 10(-8) M and that for the hydroxy radical (.OH) was from 4 to 6 x 10(-5) M. IPQ compounds and IPQ monoesters also showed radical scavenging activity. These compounds prevented injury during in vivo experiments, such as hydrocortisone-induced cataracts, endotoxin shock and CCl4-induced liver injury (isolated hepatocytes and rats). Especially, the monoesters of PQQ and IPQ prevented liver injury in rats equally by oral or intraperitoneal administration. These results suggest that PQQ functions as a radical scavenging factor in addition to being a cofactor of quinoprotein enzymes, and monoesters with the ester groups at C-2 of PQQ and C-9 of IPQ are developed as treatment or preventive medicine for disease caused by radical compounds on the basis of strong radical scavenging activities, absorbability into cells, toxicity, safety and chemical stability.
Urakami
T
T
Biochemicals Division, Mitsubishi Gas Chemical Co., Tokyo, Japan.
Yoshida
C
C
Akaike
T
T
Maeda
H
H
Nishigori
H
H
Niki
E
E
D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D002251:Carbon Tetrachloride / Q000494:pharmacology / Q000633:toxicity; D002386:Cataract / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control; D056486:Chemical and Drug Induced Liver Injury; D002642:Chick Embryo; D003067:Coenzymes / Q000008:administration & dosage / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D004952:Esters; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D045542:PQQ Cofactor; D015363:Quinolones / Q000008:administration & dosage / Q000737:chemistry*; D011809:Quinones / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D003067:Coenzymes; D004952:Esters; D016166:Free Radical Scavengers; D005609:Free Radicals; D015363:Quinolones; D011809:Quinones; D017382:Reactive Oxygen Species; D013481:Superoxides; D017665:Hydroxyl Radical; D045542:PQQ Cofactor; D002251:Carbon Tetrachloride