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;  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 , 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.
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