- Novel analogs of sulfasalazine as system xc ? antiporter inhibitors: Insights from the molecular modeling studies
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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.
- Patel, Dhavalkumar,Kharkar, Prashant S.,Gandhi, Neha S.,Kaur, Ekjot,Dutt, Shilpee,Nandave, Mukesh
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p. 758 - 777
(2019/06/24)
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- Genetic incorporation of a 2-naphthol group into proteins for site-specific azo coupling
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The 2-naphthol analogue of tyrosine, 2-amino-3-(6-hydroxy-2-naphthyl) propanoic acid (NpOH), has been genetically introduced into proteins in Escherichia coli. This is achieved through the directed evolution of orthogonal aminoacyl-tRNA synthetase/tRNA pairs that selectively charge the target amino acid in response to the amber stop codon, UAG. Moreover, chemoselective azo coupling reactions have been revealed between the 2-naphthol group and diazotized aniline derivatives that are substituted with an electron donating moiety. The coupling reactions required a very mild condition (pH 7) with great reaction rate (less than 2 h at 0 C), high efficiency, and excellent selectivity.
- Chen, Shuo,Tsao, Meng-Lin
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p. 1645 - 1649
(2013/11/06)
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