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

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 Full article

Journal

Journal of Medicinal Chemistry
ISSN: 0022-2623 , E-ISSN: 1520-4804

Output data

Year: 2011, Volume: 54, Number: 20, Pages: 7138-7149 Pages count : 12 DOI: 10.1021/jm200737s

Authors

Semenova Marina N. ^1,2 , Kiselyov Alex S. ³ , Tsyganov Dmitry V. ⁴ , Konyushkin Leonid D. ⁴ , Firgang Sergei I. ⁴ , Semenov Roman V. ⁴ , Malyshev Oleg R. ⁴ , Raihstat Mikhail M. ⁴ , Fuchs Fabian ⁵ , Stielow Anne ⁵ , Lantow Margareta ^6,5 , Philchenkov Alex A. ⁷ , Zavelevich Michael P. ⁷ , Zefirov Nikolay S. ⁸ , Kuznetsov Sergei A. ⁵ , Semenov Victor V. ^1,4

Affiliations

1	Chemical Block Ltd., 3 Kyriacou Matsi, 3723 Limassol, Cyprus
2	Institute of Developmental Biology, RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation
3	CHDI Foundation, 6080 Center Drive, Suite 100, Los Angeles California 90045, United States
4	N. D. Zelinsky Institute of Organic Chemistry, RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation
5	Institute of Biological Sciences, University of Rostock, 3 Albert-Einstein-Strasse, D-18059 Rostock, Germany
6	Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 Archer Road, Gainesville Florida 32610, United States
7	R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl’kivska Street, 03022 Kyiv, Ukraine
8	Lomonosov Moscow State University, GSP-1, Leninskie Gory, 119991, Moscow, Russian Federation

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.

Semenova M.N. , Kiselyov A.S. , Tsyganov D.V. , Konyushkin L.D. , Firgang S.I. , Semenov R.V. , Malyshev O.R. , Raihstat M.M. , Fuchs F. , Stielow A. , Lantow M. , Philchenkov A.A. , Zavelevich M.P. , Zefirov N.S. , Kuznetsov S.A. , Semenov V.V.
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
Journal of Medicinal Chemistry. 2011. V.54. N20. P.7138-7149. DOI: 10.1021/jm200737s WOS Scopus OpenAlex

Web of science:	WOS:000296205900010
Scopus:	2-s2.0-80054885068
OpenAlex:	W2095442296

DB	Citing
OpenAlex	62
Scopus	59
Web of science	58