Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors

Xie, Yuxin; Tummala, Padmaja; Oakley, A.J.; Deora, Girdhar Singh; Nakano, Yuji; Rooke, Melissa; Cuellar, Matthew E.; Strasser, Jessica M.; Dahlin, Jayme L.; Walters, Michael A.; Casarotto, Marco G.; Board, Philip G.; Baell, Jonathan B.

doi:10.1021/acs.jmedchem.9b01391

Cited by 14 publications

(8 citation statements)

References 61 publications

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“…257 They used the GSTO1-1 inhibitor C1-27 to show that inhibition of GSTO1-1 had a protective effect in an ECE mouse model, and a more advanced form of inhibitor, designated 25, was reported in a follow-up study. 258 In addition, artemisinin 259 targeted NEK7-NLRP3 interactions to suppress inflammasome activity in a T2DM disease model.…”

Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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“…Other notable reactions included rhodium-catalyzed conjugate addition of arylboronic acids, [162] catalytic hydrogenation of the double bond, [339] or its reduction with Et 3 SiH. [339] Cycloaddition reactions of alkenyl sulfonyl fluorides provide a convenient entry to (partially) saturated (hetero)cyclic adducts bearing the SO 2 F group. In particular, [4 + 2], [340] [3 + 2], [144,341] [2 + 2], [291,342,343] and [2 + 1] [180] cycloadditions were reported.…”

Section: Synthesis Of Saturated Sulfonyl Fluoridesmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well-overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp 3 -enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non-classical sp 3 -enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gemdifluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.

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“…Compound 25 has the highest intracellular inhibitory activity with a K inact /K I value of 2.3 × 10 4 M −1 S −1 , while its elimination rate is slower than compounds C1-27, 3d, and 22e. Therefore, compound 25 is considered the most potent GSTO1-1 inhibitor reported up to date [214]. [214]; (H) compound 3d [214]; (I) compound 22e [214].…”

Section: Gstm Inhibitorsmentioning

confidence: 99%

Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

Lv,

Huang,

Huang

et al. 2023

Antioxidants

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Glutathione S-transferases (GSTs) are a major class of phase II metabolic enzymes. Besides their essential role in detoxification, GSTs also exert diverse biological activities in the occurrence and development of various diseases. In the past few decades, much research interest has been paid to exploring the mechanisms of GST overexpression in tumor drug resistance. Correspondingly, many GST inhibitors have been developed and applied, solely or in combination with chemotherapeutic drugs, for the treatment of multi-drug resistant tumors. Moreover, novel roles of GSTs in other diseases, such as pulmonary fibrosis and neurodegenerative diseases, have been recognized in recent years, although the exact regulatory mechanisms remain to be elucidated. This review, firstly summarizes the roles of GSTs and their overexpression in the above-mentioned diseases with emphasis on the modulation of cell signaling pathways and protein functions. Secondly, specific GST inhibitors currently in pre-clinical development and in clinical stages are inventoried. Lastly, applications of GST inhibitors in targeting cell signaling pathways and intracellular biological processes are discussed, and the potential for disease treatment is prospected. Taken together, this review is expected to provide new insights into the interconnection between GST overexpression and human diseases, which may assist future drug discovery targeting GSTs.

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Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors

Cited by 14 publications

References 61 publications

An update on the regulatory mechanisms of NLRP3 inflammasome activation

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

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