Ecdysteroids: from insect molting hormones to potent chemo-sensitizers in cancer

Phytoecdysteroids are herbal analogs of the insect molting hormone and play a highly complex ecological role among different Kingdoms of Nature [1]. In mammals, beneficial bioactivities have been attributed to these compounds. Non-hormonal anabolic and adaptogenic effects are among such bioactivities, and these properties led to the production and worldwide marketing of ecdysteroid-containing plant extracts as food supplements [2].

In our recent studies on commercial extracts of Cyanotis arachnoidea, a particularly rich source of structurally diverse natural ecdysteroids, several compounds could be isolated in sufficient amounts to permit various semi-synthetic transformations.

We discovered that certain ecdysteroids can strongly sensitize multi-drug resistant (MDR) and susceptible cancer cell lines to chemotherapeutics [3]. Based on these results, a wide variety of chemical modifications of selected ecdysteroids have been performed in order to further extend and explore the available chemical space. Such modifications included base-catalyzed autoxidation, oxidative side-chain cleavage, oxime, oxime-ether and lactame formation, fluorination, and preparation of dioxolane rings. SAR for more than 120 compounds revealed that a C-20,22 side-chain cleavage together with introducing a 2,3-dioxolane moiety confers ecdysteroids a strong chemo-sensitizing activity against MDR cancer cell lines, without any detectable functional inhibition of drug efflux [4], which could lead to various side effects during possible in vivo applications. Based on our results, several promising lead compounds have been identified that can be further developed to be used in the treatment of MDR cancer.

Support from the NKFIH, Hungary (K119770), EFOP-3.6.1 – 16 – 2016 – 00008, GINOP-2.3.2 – 15 – 2016 – 00012, the János Bolyai fellowship of the Hungarian Academy of Sciences, and the Kálmán Szász Prize are acknowledged.

[1] Hornok et al. Sci. Rep. 2016, 6: 23390

[2] Hunyadi et al. Sci. Rep. 2016, 6: 37322

[3] Martins et al. J. Med. Chem. 2012, 55: 5034 – 43

[4] Hunyadi et al. Molecules 2017, 22: 199