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

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 [EC(50)] of 25.72, 167.97, and 1.15 M), the EC(50) 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 EC(50) value of 4-MT-PTOX (1) against the normal human cell line HK-2 (i.e., 182.4 μM) 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.

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

“…In addition, the expression of TUBB3 (a key member of β-tubulin) and TOPIIA (a key nuclease in DNA replication) was inhibited in tumor cells after MPTOX treatment. Furthermore, Bai et al (2012) and Zhao et al (2015Zhao et al ( , 2019) demonstrated that the carbon-sulfur bond at the 4-position (C-4) of the carbon ring of PTOX reduced the inhibitory effect of dose on tubulin polymerization, thereby enhancing its therapeutic effect. They synthesized 4β-NH-(6aminoindole)-4-deoxy-PTOX Compound 25 (Figure 7) that can target the α-tubulin binding site and colchicine binding domain, as confirmed by X-ray crystallographic analysis.…”

Facile Synthesis, Characterization and Antimicrobial Activities of Novel 6-AminoTriazolo-Thiadiazoles Integrated with Benzofuran and Pyrazole Moieties

“…The numbers of triazoles fused to thiadiazoles exhibit various therapeutically important property probably due to the existence of N-C-S fragment in ring. Literature survey has revealed that the 6-amino thiadiazole structure plays vital role in biologically active compounds consequently represents fascinating moiety for therapeutic chemistry.1,3,4thiadiazoles are vital classes of azoles with significant pharmacological activities such antimicrobial [1][2][3][4][5][6] , antioxidant 7 , antituberculosis 8 , anticancer [9][10][11] , analgesic 12 , anti-inflammatory 13 , antiviral [14][15] , antifungal [16][17][18][19] , antitumor 20 , urease inhibitor 21 , analgesic and anti-inflammatory 22 , antidepressant 23 , anticonvulsant 24 , antimycotic 25 , diuretic 26 , cytotoxic 27 , corrosion inhibition effect 28 , antiproliferative 29 , anthelmintic 30 . Moreover, nowadays researchers desire to yield fused or hybrids of various heteroatom ring to improve the medicinal property.…”

Novel Beta-Tubulin-Immobilized Nanoparticles Affinity Material for Screening β-Tubulin Inhibitors from a Complex Mixture

“…The microtubules in tumor cells are heterodimers composed of α- and β-tubulins. Microtubule damage can induce cell cycle arrest at the G 2 /M stage and lead to formation of abnormal mitosis spindle, which can ultimately lead to cell apoptosis. − Additional research on drug design, biosynthesis, and structural modification with tubulin as the target site are current ongoing projects. Natural products are an excellent source for many active compounds, including microtubule-targeting compounds.…”