title: SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position.
abstract: A series of C4-N-substituted podophyllum derivatives were synthesized and tested for cytotoxicity in HeLa, BGC-823, A549, Huh7 and MCF-7 cells by MTT assay. Pharmacologically, most derivatives displayed potent cytotoxicity against at least one of the tested tumor cell lines. Structure activity relationship (SAR) analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position>4-position>5-position>6-position. Specifically, two compounds, 3g and 3h, with 2-amino-3-chloropyridine substituted into the podophyllotoxin (PPT) and 4'-O-demethylepipodophyllotoxin (DMEP) scaffolds were shown to have the most potent HeLa cells cytotoxicity compared to other synthesized derivatives or reference compounds PPT, DMEP and etoposide (VP-16). The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation. As a result of this work, we conclude that compounds 3g and 3h are more potent anticancer agents than VP-16, and that they work by different antitumor mechanisms.
authors.affiliation: School of Public Health, Wuhan University, 185 Donghu Road, Wuhan, Hubei 430071, PR China.
authors.forename: Huai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Hubei Provincial Key Laboratory of Applied Toxicology, Hubei Provincial Assessment Center for Foodstuff and Drug Safety, Wuhan, Hubei 430075, PR China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, PR China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Tang
authors.affiliation: School of Public Health, Wuhan University, 185 Donghu Road, Wuhan, Hubei 430071, PR China; Hubei Provincial Key Laboratory of Applied Toxicology, Hubei Provincial Assessment Center for Foodstuff and Drug Safety, Wuhan, Hubei 430075, PR China. Electronic address: zpyuan@whu.edu.cn.
authors.forename: Zhanpeng
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy; D011034:Podophyllotoxin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D028144:Podophyllum peltatum / Q000737:chemistry*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050257:Tubulin Modulators; D011034:Podophyllotoxin
keywords: Microtubule; N linkage; Podophyllum derivates; SAR; Topoisomerase II