Novel Biotransformation Process of Podophyllotoxin to 4 -Sulfur-Substituted Podophyllum Derivates with Anti-Tumor Activity by Penicillium purpurogenum Y.J. Tang

Author(s): J.-K. Bai, W. Zhao, H.-M. Li, Y.-J. Tang.

Journal Name: Current Medicinal Chemistry

Volume 19 , Issue 6 , 2012

Become EABM
Become Reviewer

Abstract:

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.

Keywords: 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

Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 6
Year: 2012
Page: [927 - 936]
Pages: 10
DOI: 10.2174/092986712799034914
Price: $58

Article Metrics

PDF: 11