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Matti, Afnan A.; Mirzaei, Joseph; Rudolph, John; Smith, Stephen A.; Newell, Jayme L.; Patel, Sarjubhai A.; Braden, M.; Bridges, Richard J.; Natale, Nicholas R.

doi:10.1016/j.bmcl.2013.08.080

Cited by 8 publications

(4 citation statements)

References 36 publications

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“…A total of 13 out of 28 compounds were able to inhibit the antiporter activity in the IC 50 range of 110-492 μM (Compound 1, IC 50 = 70 μM) (Table 1). These potency ranges (i.e., higher μM) are in accordance with the previous reports for 1 and its analogs (Matti et al, 2013;Shukla et al, 2011).…”

Section: In Vitro Sx C − Antiporter Inhibitionsupporting

confidence: 92%

“…Previously, isoxazole hydrazide inhibitors were shown to interact with Arg135 (cation-π interaction), Tyr251 (H-bonding), Ile134 (hydrophobic), Tyr244 (hydrophobic), Ser330 (H-bonding), Thr56 (H-bonding), etc. (Matti et al, 2013). Overall, similar ligand-antiporter interactions were found in our docking analyses as reported previously.…”

Section: Molecular Docking Studies and Molecular Dynamics Simulationssupporting

confidence: 89%

“…ApcT (Matti et al, 2013). We expect significant differences in the conformation of active site owing to the differences in the alignment methods and the availability of newer templates in holo-and apo-conformations.…”

Section: Synthesis Of 5-benzamido-2-hydroxybenzoic Acid (11)mentioning

confidence: 99%

“…In systematizing our design and synthesis efforts, we initiated our work with building a homology model of the xCT chain of Sx c − to rationally aid our design process. In the absence of the 3D structural information, the main emphasis was placed on building a comparative model of the antiporter which would overcome issues with similar, previously reported homology models (Matti et al, 2013).…”

mentioning

confidence: 99%

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Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

Patel

Kharkar

Gandhi

et al. 2019

Drug Development Research

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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.

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Section: In Vitro Sx C − Antiporter Inhibitionsupporting

confidence: 92%

Section: Molecular Docking Studies and Molecular Dynamics Simulationssupporting

confidence: 89%

Section: Synthesis Of 5-benzamido-2-hydroxybenzoic Acid (11)mentioning

confidence: 99%

mentioning

confidence: 99%

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Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

Patel

Kharkar

Gandhi

et al. 2019

Drug Development Research

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ChemInform Abstract: Microwave Accelerated Synthesis of Isoxazole Hydrazide Inhibitors (IV) of the System x(C^‐) Transporter: Initial Homology Model.

et al. 2014

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Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Koeberle

Kipp

Stuppner

et al. 2023

Medicinal Research Reviews

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Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapyresistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosisinducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/ glutamate antiporter system X c − that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as

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Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model

Cited by 8 publications

References 36 publications

Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

ChemInform Abstract: Microwave Accelerated Synthesis of Isoxazole Hydrazide Inhibitors (IV) of the System x(C^‐) Transporter: Initial Homology Model.

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

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Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model

Cited by 8 publications

References 36 publications

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

ChemInform Abstract: Microwave Accelerated Synthesis of Isoxazole Hydrazide Inhibitors (IV) of the System x(C‐) Transporter: Initial Homology Model.

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Contact Info

Product

Resources

About

Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

Novel analogs of sulfasalazine as system x_c⁻ antiporter inhibitors: Insights from the molecular modeling studies

ChemInform Abstract: Microwave Accelerated Synthesis of Isoxazole Hydrazide Inhibitors (IV) of the System x(C^‐) Transporter: Initial Homology Model.