Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam

Abstract

Multidrug resistance is a widespread problem among various diseases and cancer is no exception. We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells. We have also shown that these molecules have a marked selectivity towards the MDR cells. Recent studies on the oximation of various steroid derivatives indicated remarkable increase in their antitumor activity, but there is no related bioactivity data on ecdysteroid oximes. In our present study, 13 novel ecdysteroid derivatives (oximes, oxime ethers and a lactam) and one known compound were synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and fully characterized by comprehensive NMR techniques revealing their complete H andC signal assignments. The compounds exerted moderate to strong in vitro antiproliferative activity on HeLa, SiHa, MCF-7 and MDA-MB-231 cell lines. Oxime and particularly oxime ether formation strongly increased their inhibitory activity on the efflux of rhodamine 123 by P-glycoprotein (P-gp), while the new ecdysteroid lactam did not interfere with the efflux function. All compounds exerted potent chemo-sensitizing activity towards doxorubicin on a mouse lymphoma cell line and on its MDR counterpart, and, on the latter, the lactam was found the most active. Because of its MDR-selective chemo-sensitizing activity with no functional effect on P-gp, this lactam is of high potential interest as a new lead for further antitumor studies.

Stereochemistry and complete 1H and 13C NMR signal assignment of C‐20‐oxime derivatives of posterone 2,3‐acetonide in solution state

“…The detected Δδ = 4.2 ppm syn ‐ anti parameter on the C‐21 signal in compound 3 is in good agreement with our results on C‐6 oxime derivatives of ecdysteroids and unambiguously confirmed the NMR differentiation of the E / Z isomers. Considering the detected δC‐21 (17 ppm) in compounds 6 and 7 , we can conclude that these compounds are also 20( E )‐oxime derivatives.…”

“…In particular, several poststerone derivatives, containing a substituted dioxolane (e.g., acetonide) moiety connected to their A‐ring, were found to be free from the efflux pump inhibitory activity, while acting as strong chemo‐sensitizers in combination with doxorubicin . In addition to this, ecdysteroid 6‐oximes and oxime ethers demonstrated markedly increased ABCB1 inhibitory activity, while acting as similarly potent chemo‐sensitizers as their corresponding 6‐oxo analogs …”

A Commercial Extract of Cyanotis arachnoidea Roots as a Source of Unusual Ecdysteroid Derivatives with Insect Hormone Receptor Binding Activity

“…In the context of this latter strategy, our group has investigated certain structure–activity relationships to explore the effect of these compounds on the drug resistance of cancer cell lines. 11 − 14 …”

Diversity-Oriented Synthesis Catalyzed by DAST – Preparation of New Antitumor Ecdysteroid Derivatives

“…From our previous extensive structure-activity relationship studies on the antitumor properties of ecdysteroids we found that their multidrug resistance decreasing activity does not rely on Pgp inhibition [9][10][11][12]. Because of this, our research on new antitumor ecdysteroid derivatives focuses on compounds that exert their activity without directly affecting drug efflux, and, as such, are free from the many potential problems (e.g., unwanted drug-drug interactions, altered pharmacokinetics of co-administered antitumor drugs, etc.)…”