title: Polyalkoxybenzenes from plants. 5. Parsley seed extract in synthesis of azapodophyllotoxins featuring strong tubulin destabilizing activity in the sea urchin embryo and cell culture assays.
abstract: A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E. These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule as the most active compound. Finally, in Jurkat cells, compound induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway.
authors.affiliation: Institute of Developmental Biology, RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Semenova
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Tsyganov
authors.forename: Leonid D
authors.initials: LD
authors.lastname: Konyushkin
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Firgang
authors.forename: Roman V
authors.initials: RV
authors.lastname: Semenov
authors.forename: Oleg R
authors.initials: OR
authors.lastname: Malyshev
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Raihstat
authors.forename: Fabian
authors.initials: F
authors.lastname: Fuchs
authors.forename: Anne
authors.initials: A
authors.lastname: Stielow
authors.forename: Margareta
authors.initials: M
authors.lastname: Lantow
authors.forename: Alex A
authors.initials: AA
authors.lastname: Philchenkov
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zavelevich
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D053143:Caspase 2 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D028528:Petroselinum / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry; D010938:Plant Oils / Q000737:chemistry; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012617:Sea Urchins / Q000187:drug effects / Q000196:embryology; D012639:Seeds / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D001372:Aza Compounds; D010936:Plant Extracts; D010938:Plant Oils; D050257:Tubulin Modulators; D053143:Caspase 2; D053453:Caspase 9; D011034:Podophyllotoxin