1028-11-1Relevant articles and documents
Novel analogs of sulfasalazine as system xc ? antiporter inhibitors: Insights from the molecular modeling studies
Patel, Dhavalkumar,Kharkar, Prashant S.,Gandhi, Neha S.,Kaur, Ekjot,Dutt, Shilpee,Nandave, Mukesh
, p. 758 - 777 (2019/06/24)
System xc ? (Sxc ?), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc ?. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sxc ? antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sxc ? inhibitory activity following in vitro Sxc ? inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.
Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains
Zhang, Guangtao,Plotnikov, Alexander N.,Rusinova, Elena,Shen, Tong,Morohashi, Keita,Joshua, Jennifer,Zeng, Lei,Mujtaba, Shiraz,Ohlmeyer, Michael,Zhou, Ming-Ming
, p. 9251 - 9264 (2014/01/06)
BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.
In vivo and in vitro anti-leishmanial activities of 4-nitro-N-pyrimidinand N-pyrazin-2-ylbenzenesulfonamides, and N2-(4-nitrophenyl)-N 1propylglycinamide
Auxiliadora Dea-Ayuela,Castillo, Encarna,Gonzalez-Alvarez, Marta,Vega, Celeste,Rolón, Miriam,Bolas-Fernández, Francisco,Borras, Joaquín,Eugenia González-Rosende
experimental part, p. 7449 - 7456 (2011/02/23)
A series of compounds containing the nitrobenzene and sulfonamido moieties were synthesized and their leishmanicidal effect was assessed in vitro against Leishmania infantum promastigotes. Among the compounds evaluated, the p-nitrobenzenesulfonamides 4Aa
