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.

Synthesis of new derivatives of Alkylselanyl[1,2,4]triazolo[4,3‐a]pyrimidine asselenium‐containingheterocyclic system

“…5-Bromo-2-chloro-6-methylpyrimidine-4-selenolate is produced through the reduction reaction of selenocyanatopyrimidine (2) with sodium borohydride at the temperature of 0-5 C in methanol, followed by the nucleophilic substitution reaction with various alkyl halides for 30 min [47][48][49]. The corresponding heterocyclic alkyl selenides (3a-e) were prepared in 86%-90% yields.…”

Selenization of Small Molecule Drugs: A New Player on the Board

“…It was also observed that, even though the toxicity toward the healthy cells was slightly raised, the potency of one of the selenoderivatives reported was enhanced up to 30-fold, thus increasing the overall SI. 254 In summary, even though in most cases, Se incorporation may enhance the toxicity of a molecule toward normal cells, it can also more significantly increase the toxicity toward cancer cells, thus increasing the overall TI. The lower dose requirements to achieve a similar or better efficacy as compared to the parent compounds could thus also ensure better target selectivity for a Se containing small molecule.…”

Selenonium Salt as a Catalyst for Nucleophilic Substitution Reactions in Water: Synthesis of Thiocyanites and Selenocyanates

“…5-(selenocyanatomethyl)benzo[d][ 1 , 3 ]dioxole ( 10b ) [ 52 ] was purified by silica gel chromatography column (hexanes/AcOEt = 9/1) to afford a yellow solid, 97.2 mg (81% yield); m.p. = 70.0–71.5 °C; 1 H NMR (CDCl 3 , 400 MHz) δ = 6.82–6.81 (m, 2H), 6.77–6.75 (m, 1H), 5.96 (s, 2H), 4.23 (s, 2H).…”