Chemical and microbial semi-synthesis of tetrahydroprotoberberines as inhibitors on tissue factor procoagulant activity

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• 作者：Hai-Xia Ge^a ; ^c ; ^&dagger ; ; Jian Zhang^a ; ^&dagger ; ; Ling Chen^b ; Jun-Ping Kou^b ; ^{junpingkou@163.com} ; Bo-Yang Yu^a ; ^{boyangyu59@163.com}
• 关键词：Tissue factor ; Tetrahydroprotoberberines ; Biotransformation ; Structure and activity relationship (SAR) ; Cardiovascular diseases
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：21
• 期：1
• 页码：62-69
• 全文大小：1255 K

文摘

To discover new inhibitors on tissue factor procoagulant activity, 21 tetrahydroprotoberberines were screened on the model of human THP-1 cells stimulated by lipopolysaccharide. Among these tetrahydroprotoberberines, several unique compounds were synthesized through microbial transformation: compound 6 (l-corydalmine) was obtained through regio-selective demethylation by Streptomyces griseus ATCC 13273, whereas compounds 4a, 4b, 5h, and 5i were microbial glycosylation products by Gliocladium deliquescens NRRL1086. The bioassay results showed that compounds 3 (tetrahydroberberine), 10 (tetrahydroberberrubine), and 5f (cinnamyl ester of 5) and 5i (glycosidic product of 5), exhibited the most potential effects, with IC₅₀ values of 8.35, 6.75, 3.75, and 8.79 nM, respectively. The preliminary structure and activity relationship analysis revealed that the 2,3-methylenedioxy group of the A ring was essential for the strong inhibitory effects, and the R configuration of the chiral center C-14 showed higher activity than S-form products. The formation of fatty acid or aromatic acid esters of compound 5, except the cinnamyl esters, would weaken its effects. It is also interesting to note that the glycosylation of tetrahydroprotoberberines will maintain and even enhance the inhibitory effects. Because of the importance of glycochemistry in new drug discovery and development, this deserves further exploration and may provide some guide on the semi-synthesis of tetrahydroprotoberberines as tissue factor pathway inhibitors. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.