J.-K. Bai, W. Zhao, H.-M. Li and Y.-J. Tang Pages 927 - 936 ( 10 )
According to the structure-function relationship of podophyllotoxin (PTOX) and its analogue of 4- demethylepipodophyllotoxin (DMEP), the 4 β-substitution of sulfur-containing heterocyclic compounds with a carbon-sulfur bond at 4 position of PTOX or DMEP is an essential modification direction for improving the anti-tumor activity. So, four novel 4 β-sulfursubstituted podophyllum derivatives (i.e., 4β -(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MT-PTOX), 4β-(1,3,4- thiadiazole-2-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MTD-PTOX), 4β-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-4 -demethylepipodophyllotoxin (4-MT-DMEP), and 4β-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-4-demethylepipodophyllotoxin (4-MTD-DMEP)) were designed and then successfully biosynthesized in this work. In the novel sulfur-substituted biotransformation processes, PTOX and DMEP was linked with sulfur-containing compounds (i.e., 3-mercapto-1,2,4-triazole (MT) and 2-mercapto-1,3,4-thiadiazole (MTD)) at 4 position of cycloparaffin to produce 4-MT-PTOX (1), 4-MTD-PTOX (2), 4-MT-DMEP (3), and 4-MTD-DMEP (4) by Penicillium purpurogenum Y.J. Tang, respectively, which was screened out from Diphylleia sinensis Li (Hubei, China). All the novel compounds exhibited promising in vitro bioactivity, especially 4-MT-PTOX (1). Compared with etoposide (i.e., a 50 % effective concentration [EC50] of 25.72, 167.97, and 1.15 M), the EC50 values of 4-MT-PTOX (1) against tumor cell line BGC-823, A549 and HepG2 (i.e., 0.28, 0.76, and 0.42 M) were significantly improved by 91, 221 and 2.73 times, respectively. Moreover, the EC50 value of 4-MT-PTOX (1) against the normal human cell line HK-2 (i.e., 182.4μM) was 19 times higher than that of etoposide (i.e., 9.17 μM). Based on the rational design, four novel 4 β-sulfur-substituted podophyllum derivatives with superior in vitro anti-tumor activity were obtained for the first time. The correctness of structure-function relationship and rational drug design was strictly demonstrated by the in vitro biological activity tests.
Biological activity,biotransformation,4'-demethylepipodophyllotoxin,Podophyllotoxin,Penicillium purpurogenum Y.J. Tang,4b-sulfur-substituted,structure-function relationship,drug design,4β-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-podophyllotoxin,4β-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-podophyllotoxin,4β-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-4'-demethylepipodophyllotoxin,4β-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-4'-demethylepipodophyllotoxin
, , , Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068,China.