1H-2-benzopyran-1-one derivatives, microbial products with pharmacological activity. Relationship between structure and activity in 6-[[1(S)-(3(S),4- dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]-amino]-4(S), 5(S)-dihydroxy-6-oxo-3(S)-ammoniohexanoate.
In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for protective activity against stress-induced ulcers in rats. Neither the chromophore, [1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]ammonium chloride (2), nor the side-chain moiety, 4-amino-2,3-dihydroxyhexanedioic acid (4), as separate fragments alone showed any significant activity. Hydrolysis of the lactone ring of the 1H-2-benzopyran-1-one skeleton, to give 6-[[1-(2-carboxy-3-hydroxyphenyl)-2-hydroxy-5-methylhex-3-yl]amino]-4, 5-dihydroxy-6-oxo-3-ammoniohexanoate (5), led to a considerable decrease in activity. The formation of a gamma-lactone ring in the side chain, 4-[1-hydroxy-2-[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl) -3-methylbutyl]-amino]-2-oxoethyl]butan-4-olid-3-yl]ammonium chloride (6), resulted in a small decrease in activity. Selective acetylation at the primary amine position of 6, to give 4-[1-hydroxy-2- [[1-(3,4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-2-oxoethyl]-3- (acetylamino)butan-4-olide (7), led to a considerable decrease in activity. Both di- and triacetylated derivatives of 6, 4-[1-acetoxy-2 -[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl] amino]-2-oxoethyl]-3-(acetylamino)butan-4-olide (8) and 4-[1-acetoxy-2- [[1-(3,4- dihydro-8-acetoxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-2- oxoethyl]-3-(acetylamino)butan-4-olide (9), were inactive. Selective methylation of the phenolic hydroxyl group of to give 1, 6-[[1-(3,4-dihydro-8-methoxy-1-oxo-1H-2-benzopyran-3-yl) -3-methylbutyl]amino]-4,5-dihydroxy-6-oxo-3-ammoniohexanoate (15), resulted in a small decrease in activity. On the other hand, conversion of the carboxyl group of the side chain to an amide, to give [6-[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)- 3-methylbutyl]amino]-4,5-dihydroxy-6-oxo-3-hexanamido]ammonium chloride (10), caused a considerable increase in both activity and toxicity. The findings showed that modifications at the position of the amino acid moiety of 1 significantly influenced the activity and that the 1H-2-benzopyran-1-one skeleton was also required for activity to occur.
D000818:Animals; D003374:Coumarins / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D049934:Isocoumarins; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008722:Methods; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000517:prevention & control; D013329:Structure-Activity Relationship
D003374:Coumarins; D007202:Indicators and Reagents; D049934:Isocoumarins; C039360:AI 77B