1H-2-Benzopyran-1-one derivatives, microbial products with pharmacological activity. Conversion into orally active derivatives with antiinflammatory and antiulcer activities.
1H-2-Benzopyran-1-one derivatives, microbial products with pharmacological activity. Conversion into orally active derivatives with antiinflammatory and antiulcer activities.
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DOI：
10.1021/jm00379a002
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发表时间：
1985
影响因子：
7.3
通讯作者：
Y. Shimojima;T. Shirai;T. Baba;H. Hayashi
中科院分区：
文献类型：
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作者：
Y. Shimojima;T. Shirai;T. Baba;H. Hayashi
从短小芽孢杆菌AI-77的发酵液中分离出一种新的胃保护物质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)，对其进行化学修饰，使其具有口服给药活性。化合物1被内酯化，然后在伯胺位置上单烷基化。合成了6个N-烷基化的γ-内酯衍生物1(烷基链为甲基5a、乙基5b、正丙基5c、正丁基5d、正戊基5e或正己基5f)，并比较了它们的8个化合物(1和γ-内酯衍生物2)的胃保护作用和大鼠口服后的血药浓度。此外，还比较了5a-f的氯仿-水分配系数作为衡量脂类溶解度的指标。这些化合物对应激性溃疡的保护作用与血液中脱烷基化合物(1和2)的水平相互关联。给药后1h在血液中检测到母体化合物1。当服用5b或5c时，与服用5a或5d时相比，观察到高活性和高水平的血1。由于5e和5f在肠液中的溶解度和凝集性极低，在没有特殊配方的情况下，口服给药在血液中检测不到任何数量的5e和5f。有趣的是，5b和5c除了具有较强的抗溃疡作用外，还具有抗炎活性。
A novel gastroprotective substance, 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), isolated from a culture broth of Bacillus pumilus AI-77, was chemically modified to prodrugs that are active by oral dosing. Compound 1 was lactonized and then monoalkylated at the primary amine position. Six N-alkylated gamma-lactone derivatives of 1 (with alkyl chains being methyl 5a, ethyl 5b, n-propyl 5c, n-butyl 5d, n-pentyl 5e, or n-hexyl 5f) were synthesized and eight compounds including 1 and gamma-lactone derivative 2 were compared for their gastroprotective activities and blood levels after oral administration in rats. Further, chloroform-water partition coefficients of 5a-f were also compared as a measure of lipid solubility. The protective effects of these compounds on stress ulcers were mutually related to blood levels of dealkylated compounds (1 and 2). Parent compound 1 was detected in blood at 1 h after each of 5a-d was administered. When 5b or 5c was administered, high activity and high blood levels of 1 were observed in comparison with those levels obtained with 5a or 5d. Neither 5e nor 5f were detected in any amount in blood by oral administration without special formulation due to extremely low solubilities and agglutinative properties in intestinal fluid. Interestingly, 5b and 5c were found to have antiinflammatory activities in addition to potent antiulcerogenicity action.