Thielavins as glucose-6-phosphatase (G6Pase) inhibitors: producing strain, fermentation, isolation, structural elucidation and biological activities.
High-throughput screening of microbial extracts using rat hepatic microsomal glucose-6-phosphatase (G6Pase) led us to find thielavin B as a G6Pase inhibitor with inhibition of glucose output from glucagon-stimulated hepatocytes. Further searching for more potent analogs identified 11 new thielavins F-P in addition to the known thielavins A and B from a fungus Chaetomium carinthiacum ATCC 46463. Thielavin G showed the strongest activity as a G6Pase inhibitor (IC50=0.33 microM), while the IC50 of thielavin B was 5.5 microM. According to the structure-activity relationship, including authentic thielavins C, D and 3 partial hydrolysates from thielavins A and B, 3 benzoic acid-units and carboxylic acid functions are essential for G6Pase inhibition.
Sakemi
Shinichi
S
Exploratory Medicinal Sciences, Pfizer Global Research and Development (PGRD)-Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Shinichi.Sakemi@japan.pfizer.com
Hirai
Hideo
H
Ichiba
Toshio
T
Inagaki
Taisuke
T
Kato
Yoshinao
Y
Kojima
Nakao
N
Nishida
Hiroyuki
H
Parker
Janice C
JC
Saito
Toshiyuki
T
Tonai-Kachi
Hiroko
H
VanVolkenburg
Maria A
MA
Yoshikawa
Nobuji
N
Kojima
Yasuhiro
Y
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002597:Chaetomium / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005285:Fermentation; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D062385:Hydroxybenzoates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D001565:Benzoates; D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; C471244:thielavin G; C033794:thielavin A; C033795:thielavin B; D005934:Glucagon; D005952:Glucose-6-Phosphatase; D005947:Glucose