Preparation and chemo-sensitizing activity of nitrogen-containing ecdysteroid derivatives: 6-oximes, oxime ethers, and a lactam

M Vágvölgyi; A Martins; Á Kulmány; I Zupkó; G Tóth; A Hunyadi

doi:10.1055/s-0037-1608147

Planta Medica International Open, Table of Contents

Planta Medica International Open 2017; 4(S 01): S1-S202
DOI: 10.1055/s-0037-1608147

Poster Session

Georg Thieme Verlag KG Stuttgart · New York

Preparation and chemo-sensitizing activity of nitrogen-containing ecdysteroid derivatives: 6-oximes, oxime ethers, and a lactam

M Vágvölgyi

¹Institute of Pharmacognosy, University of Szeged, Szeged, Hungary

,

A Martins

²Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary

,

Á Kulmány

³Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary

,

I Zupkó

³Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary

,

G Tóth

¹Institute of Pharmacognosy, University of Szeged, Szeged, Hungary

⁴Department of Inorganic and Analytical Chemistry, NMR Group, Budapest University of Technology and Economics, Budapest, Hungary

,

A Hunyadi

¹Institute of Pharmacognosy, University of Szeged, Szeged, Hungary

⁵Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary

› Author Affiliations

Abstract

Full Text

Ecdysteroids are a group of natural hydroxysteroids, widespread in plants and invertebrates, exerting a broad spectrum of biological functions. These nontoxic compounds are commonly valued for their beneficial, non-hormonal bioactivities also in mammals including humans. Recent studies of our group revealed that less polar ecdysteroids can strongly sensitize various cancer cell lines, including multi-drug resistant (MDR) and drug susceptible ones, to chemotherapeutics.^{[1 – 3]} Oxime functionalities can increase the antitumor activity of certain steroids; ^[4] however, no related studies on ecdysteroid oximes have been performed.

Here we report the synthesis and bioactivity testing of a set of nitrogen-containing ecdysteroid derivatives. By optimizing previously published methodology^[5], 14 compounds including 12 new derivatives (oximes, oxime ethers and a lactam) were prepared from the semi-synthetic modification of 20-hydroxyecdysone 2,3;20,22-diacetonide.

All compounds were tested for their antiproliferative activity against various cancer cells followed by determination of the chemo-sensitizing potential towards doxorubicin on a P-glycoprotein (Pgp) transfected MDR cancer cell line and on its sensitive counterpart. Moderate to strong anti-proliferative activities were observed. Each compound could considerably sensitize the studied cancer cell lines, with a noticeable selectivity towards the MDR one. The most promising results were obtained for a new ecdysteroid lactam, which showed remarkably strong chemo-sensitizing potential without interfering with the efflux function of Pgp.

This work was supported by the NKFIH, Hungary (K119770), the EU-funded Hungarian grant EFOP-3.6.1 – 16 – 2016 – 00008, and GINOP-2.3.2 – 15 – 2016 – 00012. A.H. acknowledges the János Bolyai fellowship of the Hungarian Academy of Sciences and the Kálmán Szász Prize.

[1] Martins A et al. J Med Chem 2012; 55: 5034 – 5043.

[2] Martins A et al. Biomed Res Int, 2015; 895360.

[3] Cui JG et al. Steroids 2009; 74: 62 – 72 and 2009; 74: 989 – 995.

[4] Galyautdinov IV et al. Russ J Org Chem 2006; 42: 1333 – 1339.

[5] Shafikov RV Russ J Org Chem 2009; 45: 1456 – 1463.