title: Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents.
abstract: A series of novel 4-oxa-podophyllotoxin derivatives 7 featuring the intact lactone ring D and various substituents in rings B and E has been synthesized and evaluated in a phenotypic sea urchin embryo assay along with the representative 4-aza-analogs 5 for their antimitotic and microtubule destabilizing activity. The most active compounds exhibited myristicin-derived or a 3',5'-dimethoxy substitution pattern in the ring E and a 6-methoxy moiety replacing the methylenedioxy ring A. Compounds 5xb, 5xe, 5yb, 7xa, 7xb, and 7xc showed potent antiproliferative effects in the NCI60 cytotoxicity screen. Notably, growth of the multi-drug resistant NCI/ADR-RES cells was more affected by these agents than the parent OVCAR-8 cell line. Although generally 4-oxa-podophyllotoxins were less potent than the respective 4-aza-derivatives in these assays, stability of the former series towards oxidation may prove to be of interest for the development of anticancer agents with in vivo activity.
authors.affiliation: N D Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991 Moscow, Russia. info@chemblock.com
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Chernysheva
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Tsyganov
authors.forename: Alex A
authors.initials: AA
authors.lastname: Philchenkov
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zavelevich
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Roman V
authors.initials: RV
authors.lastname: Semenov
authors.forename: Marina N
authors.initials: MN
authors.lastname: Semenova
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
mesh_terms: D000081248:Allylbenzene Derivatives; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D001593:Benzyl Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004148:Dioxolanes / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004625:Embryo, Nonmammalian / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011748:Pyrogallol / Q000031:analogs & derivatives / Q000737:chemistry; D012617:Sea Urchins; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000081248:Allylbenzene Derivatives; D000972:Antineoplastic Agents, Phytogenic; D001593:Benzyl Compounds; D004148:Dioxolanes; D050257:Tubulin Modulators; D011748:Pyrogallol; C005246:myristicin; D011034:Podophyllotoxin