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

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• 作者：Marina N. Semenova ; Alex S. Kiselyov ; Dmitry V. Tsyganov ; Leonid D. Konyushkin ; Sergei I. Firgang ; Roman V. Semenov ; Oleg R. Malyshev ; Mikhail M. Raihstat ; Fabian Fuchs ; Anne Stielow ; Margareta Lantow ; Alex A. Philchenkov ; Michael P. Zavelevich ; Nikolay S. Zefirov ; Sergei A. Kuznetsov ; Victor V. Semenov
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7138-7149
• 全文大小：1103K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

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 (4e, 6e, and 8e). 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 8e as the most active compound. Finally, in Jurkat cells, compound 8e 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.