Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

Abstract

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI₅₀ = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.

Keywords: P-gp; antioxidant; antiproliferative; organoselenium; phenolics.

Figure 1

General structure of the chalcogen-polyphenol conjugates prepared herein.

Scheme 1

Attempted esterification of hydroxytyrosol 1.

Scheme 2

Synthesis of symmetrical phenolic disulfides and diselenides.

Scheme 3

Synthesis of phenolic aryl selenide 18 and selenocyanate 20.

Scheme 4

Synthesis of catechol-ebselen hybrid 26.

Scheme 5

Preparation of O-protected phenolic-based selenides, selenocyanates and diselenides.

Scheme 6

Preparation of O-protected selenocyanato 45 and diselenide 46.

Figure 2

GI₅₀ range plot of active compounds against human solid tumor cell lines and GI₅₀ values against human fibroblasts (red bars). Cisplatin (CDDP) was used as reference anticancer drug. Ebselen was used as reference parental drug. Green colour indicates GI₅₀ < 10 µM for all cell lines. Yellow colour indicates GI₅₀ > 10 µM for some or all cell lines.