Abstract
Although the causes of cancer lie in mutations or epigenic changes at the genetic level, their molecular manifestation is the dysfunction of biochemical pathways at the protein level. The 518 protein kinases encoded by the human genome play a central role in various diseases, a fact that has encouraged extensive investigations on their biological function and three dimensional structures. Selenium (Se) is an important nutritional trace element involved in different physiological functions with antioxidative, antitumoral and chemopreventive properties. The mechanisms of action for selenocompounds as anticancer agents are not fully understood, but kinase modulation seems to be a possible pathway. Various organosulfur compounds have shown antitumoral and kinase inhibition effects but, in many cases, the replacement of sulfur by selenium improves the antitumoral effect of compounds. Although Se atom possesses a larger atomic volume and nucleophilic character than sulfur, Se can also formed interactions with aminoacids of the catalytic centers of proteins. So, we propose a novel chemical library that includes organoselenium compounds as kinase modulators. In this study thirteen selenocompounds have been evaluated at a concentration of 3 or 10 µM in a 24 kinase panel using a Caliper LabChip 3000 Drug Discover Platform. Several receptor (EGFR, IGFR1, FGFR1…) and non-receptor (Abl) kinases have been selected, as well as serine/threonine/lipid kinases (AurA, Akt, CDKs, MAPKs…) implicated in main cancer pathways: cell cycle regulation, signal transduction, angiogenesis regulation among them. The obtained results showed that two compounds presented inhibition values higher than 50% in at least four kinases and seven derivatives selectively inhibited one or two kinases. Furthermore, three compounds selectively activated IGF-1R kinase with values ranging from −98% to −211%. In conclusion, we propose that the replacement of sulfur by selenium seems to be a potential and useful strategy in the search of novel chemical compound libraries against cancer as kinase modulators.
Highlights
Nowadays, malignancies are still crucial problems in the healthcare system in many aspects which include efficacy of therapeutic modalities, quality of patients’ life and cost of treatments
Compounds of C series were synthesized from the appropriate ortho-aromatic diamine and selenium dioxide [36] and transformed into amides by reaction of the carboxylic acid with thionyl chloride and the appropriate amine or diamine
The diselenide compound E was synthesized by addition of selenium dioxide to malononitrile in DMSO followed by reaction with ortho-amino benzoic acid
Summary
Malignancies are still crucial problems in the healthcare system in many aspects which include efficacy of therapeutic modalities, quality of patients’ life and cost of treatments. It is known that several protein kinase pathways play essential roles in mediating mitogenic and antiapoptotic signals and can regulate cell proliferation and survival [7] At present it is difficult, if not impossible, to consider a wide kinase panel to describe a multikinase inhibition route that encompasses all the connections and combinations that are possibly implicated in cancer modulation [8]. Several reports have recently highlighted that selenocompounds are able to induce tumor cell apoptosis through distinct mechanisms according to cell type and compound pattern These mechanisms include survival pathways modulation, among which the PI3K/AKT pathway appears as a common target for the selenocompounds studied [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. This approach is based on the promising cytotoxic activity of compounds previously reported by our group [34,35,36,37,38] and will be considered, as a starting point for a new strategy, in the design and development of new anticancer candidates
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