Novel Library of Selenocompounds as Kinase Modulators

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.

Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer

“…Se-compounds are thought to modulate several kinases. The PI3K/AKT pathway appears as a common target for Se-compounds, but they may modulate different kinases at the same time and their effectiveness depends on the genetic background of the tumor cells [ 61 , 62 ]. All the Se-compounds did not exhibit kinase inhibitory activity.…”

Novel N,N′-Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

“…During the implementation of our scientific program based in the synthesis and biological evaluation of Se compounds, we have synthetized and observed the antioxidant and anticancer activity of closely related imidoselenocarbamates [26][27][28][29][30][31][32][33][34], seleno-quinazoline, and pyrido [2,3-d]pyrimidine derivatives [33,[35][36][37]. Some evidence has pointed out that relatively simple selenoureas ( Figure 1A) might possess a superoxide radical scavenging activity accompanied by a low toxicity in human cells [38].…”

Library of Seleno-Compounds as Novel Agents against Leishmania Species

“…The results obtained for the reference drug, meglumine antimonate, were included in all cases for comparison. Biological data evidenced that half of the screened compounds (compounds 8,9,10,11,13,15,17,18,20,21,24,26,29,33,35,37,38,42,43,44,45,46, 47, and 48) showed high levels of bioactivity against L. infantum, presenting greater potency than the reference drug, meglumine antimonate, against both forms (IC 50 s, 18.0 M for promastigotes and 24.2 M for amastigotes).…”

“…The differences between meglumine antimonate and the tested compounds are clearly revealed. Twelve compounds (compounds 8,10,11,15,20,21,26,31,35,44,45, and 48) presented notable selectivity index values (SIs Ͼ 7) for both forms. These derivatives exhibited substantially better SI values than the reference drug for L. infantum, and in the most remarkable case, the SI of compound 8 for the intracellular form of L. infantum exceeded that of meglumine antimonate by 237-fold, a relevant data point, which was by far the best SI value.…”