Semi-synthetic preparation, structural elucidation and pharmacological study of nitrogen-containing ecdysteroid analogs

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Ecdysteroids are specific hydroxysteroids that exert a wide a range of biological functions in the flora and the fauna. Our group has recently described that less polar ecdysteroid derivatives can strongly sensitize various cancer cell lines to certain chemotherapeutics, which can be observed both in multi-drug resistant (MDR) and drug susceptible cancer cells [1 – 2]. Recent studies also revealed that oxime groups can increase the antitumor activity of certain steroid derivatives [3], but ecdysteroid oximes have previously not been studied from this point of view. In our current work, we aimed to synthesize C6 ecdysteroid oximes of 20-hydroxyecdysone 2,3;20,22-diacetonide, optimizing the previously available methods [4]. Rotational planar chromatographic, analytical and preparative RP-HPLC and centrifugal partition chromatographic methods were developed for the purification. The diacetonides of two 14,15-anhydro ecdysteroid oxime isomers (E/Z-oximes) were obtained, and Beckmann rearrangement of the new 14,15-anhydro E-oxime yielded another new derivative containing a seven-membered lactam B-ring [5]. The ecdysteroid oximes were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their sub-cell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). Each oxime was found to be a promising modulator of resistance on the MDR cell line, and the E-oxime could also sensitize the non-MDR cells to doxorubicin. Our preliminary SAR study also revealed, that the antitumor activity of ecdysteroid diacetonides follow the ecdysteroid < Z-oxime < E-oxime order. Acknowledgement: Szeged Foundation for Cancer Research.