14223-47-3Relevant articles and documents
Synthesis and leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
Díaz, Marta,de Lucio, Héctor,Moreno, Esther,Espuelas, Socorro,Aydillo, Carlos,Jiménez-Ruiz, Antonio,Toro, Miguel ángel,Gutiérrez, Killian Jesús,Martínez-Merino, Victor,Cornejo, Alfonso,Palop, Juan Antonio,Sanmartín, Carmen,Planoa, Daniel
, (2019)
A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.
Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity
Chen, Zhao,Li, Di,Xu, Ning,Fang, Jinzhang,Yu, Yan,Hou, Wei,Ruan, Haoqiang,Zhu, Panpan,Ma, Renchao,Lu, Shiying,Cao, Danhui,Wu, Rui,Ni, Mowei,Zhang, Wei,Su, Weike,Ruan, Benfang Helen
, p. 589 - 603 (2019/01/10)
Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, we explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)ethyl sulfide and CB839 analogues with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles. The resulting selenadiazole compounds showed enhanced KGA inhibition, more potent induction of reactive oxygen species, improved inhibition of cancer cells, and higher cellular and tumor accumulation than the corresponding sulfur-containing molecules. However, both CB839 and its selenium analogues show incomplete inhibition of the tested cancer cells, and a partial reduction in tumor size was observed in both the glutamine-dependent HCT116 and aggressive H22 liver cancer xenograft models. Despite this, tumor tissue damage and prolonged survival were observed in animals treated with the selenium analogue of CB839.
Selenoureido-iminosugars: A new family of multitarget drugs
Olsen, Jacob Ingemar,Plata, Gabriela B.,Padrón, José M.,López, óscar,Bols, Mikael,Fernández-Bola?os, José G.
, p. 155 - 160 (2016/08/01)
Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki= 1.6–5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Kiup to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2(Kcat/Kuncatup to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.
