Identification of benzofused five-membered sultams, potent dual NOD1/NOD2 antagonists in vitro and in vivo

Ma, Yao; Li, Xueyuan; Pei, Yukui; Ye, Jingjia; Wei, Xiduan; Yang, Jingshu; Si, Guangxu; Tian, Jingyuan; Dong, Yunhui; Liu, Gang

doi:10.1016/j.ejmech.2020.112575

Cited by 8 publications

(4 citation statements)

References 32 publications

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“…When necessary, the reactions were performed in oven-dried glassware under a positive pressure of dry nitrogen. 1 H and 13 C APT NMR spectra were recorded on a 400 MHz. High-resolution ESI-MS spectra were performed on a Thermo LTQ Orbitrap XL mass spectrometer.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Therefore, there is ample evidence that selective inhibition of NOD1 and NOD2 signaling could be exploited in the treatment of many acute and chronic diseases. The potential of NOD ligands for cancer immunotherapy has also been highlighted recently. − A wide range of chemotypes spanning from natural compounds, such as curcumin and parthenolide, to synthetic ones, including tetrahydroisoquinolines, 2-aminobenzimidazoles, purine derivatives, benzimidazole diamides, , indolines, and benzofused five-membered sultams, are known to act as NOD antagonists downregulating the NF-κB and MAPK pathways . In the context of NOD antagonists, Liu et al reported that 1,4-benzodiazepine-2,5-diones and quinazolinones targeting both NOD1 and NOD2 were able to sensitize Lewis lung carcinoma growth in vivo and B16 tumor-bearing mice to paclitaxel treatment, respectively, via inhibition of NF-κB and MAPK (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

Russo,

Russomanno,

D’Amore

et al. 2024

J. Med. Chem.

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NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37, endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists.

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Section: ■ Conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

Russo,

Russomanno,

D’Amore

et al. 2024

J. Med. Chem.

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“…A potent NOD antagonist for inhibition of NOD activities may blunt the associated pro-inflammatory responses and decrease the rate of mortality. Recently, some dual NOD1/NOD2 antagonists that demonstrate promising inhibitory activities against NOD1/NOD2-stimulated NF-κB and MAPK signaling have been developed [104,105]. However, these compounds are still at the preclinical investigation stage, and none have shown promising activities against infection-associated complications.…”

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 99%

Nanocarriers for effective delivery: modulation of innate immunity for the management of infections and the associated complications

Zang

Zhou

et al. 2022

J Nanobiotechnol

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Innate immunity is the first line of defense against invading pathogens. Innate immune cells can recognize invading pathogens through recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). The recognition of PAMPs by PRRs triggers immune defense mechanisms and the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. However, sustained and overwhelming activation of immune system may disrupt immune homeostasis and contribute to inflammatory disorders. Immunomodulators targeting PRRs may be beneficial to treat infectious diseases and their associated complications. However, therapeutic performances of immunomodulators can be negatively affected by (1) high immune-mediated toxicity, (2) poor solubility and (3) bioactivity loss after long circulation. Recently, nanocarriers have emerged as a very promising tool to overcome these obstacles owning to their unique properties such as sustained circulation, desired bio-distribution, and preferred pharmacokinetic and pharmacodynamic profiles. In this review, we aim to provide an up-to-date overview on the strategies and applications of nanocarrier-assisted innate immune modulation for the management of infections and their associated complications. We first summarize examples of important innate immune modulators. The types of nanomaterials available for drug delivery, as well as their applications for the delivery of immunomodulatory drugs and vaccine adjuvants are also discussed.

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“…Given that only slight changes to the dipeptide moiety of MDP are permitted, all NOD2 agonists share the predominantly peptide structure of MDP, which is prone to metabolic instability and rapid elimination [ 21 , 22 ]. Similarly, while dual NOD1/2 antagonists, such as benzodiazepine [ 18 ], benzofused five-membered sultam [ 23 ], quinazoline [ 24 ], and indole [ 25 ] derivatives have been reported, the only NOD2 selective antagonists discovered to date are based on the benzimidazole structure of GSK669 ( Figure 1 , compound GSK669 and its derivative SG84 [ 26 ]), which was first discovered by an HTS campaign [ 27 ]. Therefore, novel scaffolds capable of modulating the activity of NOD2 are required.…”

Section: Introductionmentioning

confidence: 99%

Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening

Guzelj

Tomašič

2022

Biomolecules

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an innate immune pattern recognition receptor responsible for the recognition of bacterial peptidoglycan fragments. Given its central role in the formation of innate and adaptive immune responses, NOD2 represents a valuable target for modulation with agonists and antagonists. A major challenge in the discovery of novel small-molecule NOD2 modulators is the lack of a co-crystallized complex with a ligand, which has limited previous progress to ligand-based design approaches and high-throughput screening campaigns. To that end, a hybrid docking and pharmacophore modeling approach was used to identify key interactions between NOD2 ligands and residues in the putative ligand-binding site. Following docking of previously reported NOD2 ligands to a homology model of human NOD2, a structure-based pharmacophore model was created and used to virtually screen a library of commercially available compounds. Two compounds, 1 and 3, identified as hits by the pharmacophore model, exhibited NOD2 antagonist activity and are the first small-molecule NOD2 modulators identified by virtual screening to date. The newly identified NOD2 antagonist scaffolds represent valuable starting points for further optimization.

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Identification of benzofused five-membered sultams, potent dual NOD1/NOD2 antagonists in vitro and in vivo

Cited by 8 publications

References 32 publications

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

Nanocarriers for effective delivery: modulation of innate immunity for the management of infections and the associated complications

Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening

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