Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents

Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents Full article

Journal

Bioorganic & Medicinal Chemistry Letters
ISSN: 1464-3405 , E-ISSN: 0960-894X

Output data

Year: 2012, Volume: 22, Number: 7, Pages: 2590-2593 Pages count : 4 DOI: 10.1016/j.bmcl.2012.01.128

Authors

Chernysheva Natalia B. ¹ , Tsyganov Dmitry V. ¹ , Philchenkov Alex A. ² , Zavelevich Michael P. ² , Kiselyov Alex S. ³ , Semenov Roman V. ¹ , Semenova Marina N. ^4,5 , Semenov Victor V. ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991 Moscow, Russia
2	R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NASU, Vasyl’kivska Street, 45, 03022 Kyiv, Ukraine
3	CHDI Foundation, 6080 Center Drive, Suite 100, Los Angeles, CA 90045, USA
4	Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334 Moscow, Russia
5	Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus

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.

Chernysheva N.B. , Tsyganov D.V. , Philchenkov A.A. , Zavelevich M.P. , Kiselyov A.S. , Semenov R.V. , Semenova M.N. , Semenov V.V.
Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents
Bioorganic & Medicinal Chemistry Letters. 2012. V.22. N7. P.2590-2593. DOI: 10.1016/j.bmcl.2012.01.128 WOS Scopus OpenAlex

Web of science:	WOS:000301846100045
Scopus:	2-s2.0-84858701682
OpenAlex:	W2074279398

DB	Citing
OpenAlex	28
Scopus	28
Web of science	26