Fragment‐Based Discovery of 5‐Arylisatin‐Based Inhibitors of Matrix Metalloproteinases 2 and 13

Agamennone, Mariangela; Belov, Dmitry S.; Laghezza, Antonio; Ivanov, Vladimir N.; Novoselov, Anton M.; Андреев, Иван А.; Ратманова, Нина К.; Altieri, Andrea; Tortorella, Paolo; Kurkin, Alexander V.

doi:10.1002/cmdc.201600266

Cited by 12 publications

(16 citation statements)

References 44 publications

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“…For instance, infusion of specific antagonists to MMPs into the brain would be helpful in determining if MMP‐9 or another MMP is responsible for promoting EtOH consumption before and after the development of dependence, similar to what has been done with studies on cocaine relapse in rats (Agamennone et al., ; Levin et al., ; Smith et al., ). Conditional knockout or overexpression of PN proteins, such as aggrecan, brevican, neurocan, and tenascins in a site‐specific and cell type‐specific manner would also be useful, as it is currently not clear how these proteins affect behaviors related to AUD.…”

Section: Future Directions and Gaps In Knowledgementioning

confidence: 96%

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

Lasek

2016

Alcoholism Clin & Exp Res

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The brain extracellular matrix (ECM) occupies the space between cells and is involved in cell-matrix and cell-cell adhesion. However, in addition to providing structural support to brain tissue, the ECM activates cell signaling and controls synaptic transmission. The expression and activity of brain ECM components are regulated by alcohol exposure. This review will discuss what is currently known about the effects of alcohol on the activity and expression of brain ECM components. An interpretation of how these changes might promote alcohol use disorder (AUD) will be also provided. Ethanol exposure decreases levels of structural proteins involved in the interstitial matrix and basement membrane, with a concomitant increase in proteolytic enzymes that degrade these components. In contrast, ethanol exposure generally increases perineuronal net (PN) components. Because the ECM has been shown to regulate both synaptic plasticity and behavioral responses to drugs of abuse, regulation of the brain ECM by alcohol may be relevant to the development of alcoholism. Although investigation of the function of brain ECM in alcohol abuse is still in early stages, a greater understanding of the interplay between ECM and alcohol might lead to novel therapeutic strategies for treating AUD.

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Section: Future Directions and Gaps In Knowledgementioning

confidence: 96%

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

Lasek

2016

Alcoholism Clin & Exp Res

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“…Currently, ~500 papers investigating the role of MMP inhibition in myocardial ischemia are available from the last 2 decades in PubMed database. There are several papers that describe the non-zinc binding, allosteric (e.g., π-π stacking) interactions of MMP-2 with selected inhibitors (Di Pizio et al, 2013 ; Agamennone et al, 2016 ; Ammazzalorso et al, 2016 ; Adhikari et al, 2018 ). Most of these papers employ MMP-2 as a potential biomarker for ischemic heart diseases or as a therapeutic target to evoke cardioprotection.…”

Section: Discussionmentioning

confidence: 99%

Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

et al. 2018

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The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.

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“…5‐Bromoindoline‐2,3‐dione: [26a] In a round‐bottom flask was added isatin (3 g, 20 mmol) and AcOH (41 mL) and the mixture was stirred at room temperature. Br 2 (1.1 mL, 22 mmol, 1.1 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Accessing New 5‐α‐(3,3‐Disubstituted Oxindole)‐Benzylamine Derivatives from Isatin: Stereoselective Organocatalytic Three Component Petasis Reaction

et al. 2020

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A one‐step, three‐component Petasis reaction of isatin derived 5‐arylboronate‐3‐substituted oxindole derivatives with salicylaldehydes and secondary amines affords new enantiomerically pure structurally diverse 5‐α‐(3‐substituted‐oxindole)‐benzylamine derivatives. The reaction shows good substrate and reagent scope affording the products with good to excellent yields (up to >99 % yield) and enantioselectivities (up to 99 % ee) using cheap and readily available (R)‐BINOL as the organocatalyst. A diastereoselective version of the reaction was also developed where moderate yields (37 to 55 % yield), excellent enantioselectivities (up to 99 % ee) and good diastereoselectivities (up to 86 % de) were obtained for new 5‐α‐(3‐hydroxy‐oxindole)‐benzylamine derivatives, having two stereocenters. The reaction is also feasible on gram‐scale.

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Fragment‐Based Discovery of 5‐Arylisatin‐Based Inhibitors of Matrix Metalloproteinases 2 and 13

Cited by 12 publications

References 44 publications

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

Accessing New 5‐α‐(3,3‐Disubstituted Oxindole)‐Benzylamine Derivatives from Isatin: Stereoselective Organocatalytic Three Component Petasis Reaction

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