Synthesis, biological evaluation and molecular docking studies of indeno [1, 2-c] pyrazol derivatives as inhibitors of mitochondrial malate dehydrogenase 2 (MDH2)

Ahmadi, Farzaneh; Engel, Matthias; Baradarani, Mehdi M.

doi:10.1016/j.bioorg.2021.104779

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…LW6 prevented anoxia-induced upregulation of the NADH to NAD+ ratio, likely by decelerating the NAD+ reduction by the Krebs cycle reactions [ 6 , 31 ]. The latter is in accordance with other studies showing that LW6 and other chemically related MDH-2 inhibitors decrease mitochondrial NADH content [ 32 ]. Under reoxygenation, we found that the ATP production increases, possibly due to the accumulated electron donors (NADH and FADH 2 ) during the previous anoxic phase when the Krebs cycle functioned, but the lack of oxygen inhibited ETC [ 6 , 31 ].…”

Section: Discussionsupporting

confidence: 93%

Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence

et al. 2022

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Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Inhibition of MDH-2 decreased reoxygenation-induced upregulation of p53 and p21, restored the levels of the proliferation marker Ki-67, and prevented the upregulation of the senescence marker beta-galactosidase and interleukin-1β production. MDH-2 inhibition reduced the reoxygenation-induced upregulation of ATP, but the alterations of critical cell metabolism enzymes allowed enough ATP production to prevent cell energy collapse. Thus, inhibition of the Krebs cycle at the level of MDH-2 protects RPTECs from anoxia-reoxygenation-induced death or senescence. MDH-2 may be a promising pharmaceutical target against ischemia-reperfusion injury.

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Section: Discussionsupporting

confidence: 93%

Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence

et al. 2022

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“…In biological signaling pathways, this usually indicates that the target is an upstream gene that plays a key role in the transmission of the signal pathway. As shown in Figure c, the key targets included mdh2, uqcrc2a, atp5d, ndufa4, and cox5ab , which are mainly involved in the processing and regulation of the TCA cycle, oxidative phosphorylation, and mitochondrial respiratory chain complex . Mitochondria are the center of cellular energy metabolism and are not only the site of the final oxidation of sugars, lipids, and amino acids to release energy but also responsible for the TCA cycle and oxidative phosphorylation in aerobic respiration .…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Figure 4c, the key targets included mdh2, uqcrc2a, atp5d, ndufa4, and cox5ab, which are mainly involved in the processing and regulation of the TCA cycle, oxidative phosphorylation, and mitochondrial respiratory chain complex. 37 Mitochondria are the center of cellular energy metabolism and are not only the site of the final oxidation of sugars, lipids, and amino acids to release energy but also responsible for the TCA cycle and oxidative phosphorylation in aerobic respiration. 38 As signaling organelles, mitochondria mediate cytoplasmic-signaling pathways through the release of ROS and TCA cycle metabolites.…”

Section: Transcriptome Analysis Of Zebrafish Liver Aftermentioning

confidence: 99%

Environmentally Relevant Concentrations of Propofol-Induced Metabolic Dysfunction in Zebrafish: Mechanistic Insights into Integrated Hepatic Transcriptomic and Metabolomic Analyses

Jiang,

Li,

Zhang

et al. 2024

ACS EST Water

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Propofol is increasingly perceived as an emerging threat to aquatic ecosystems, although the ecotoxicity and underlying mechanisms of propofol on aquatic life have not yet been clearly established. In this study, zebrafish (Danio rerio) was exposed to different concentrations of propofol (0.008, 0.04, and 0.2 mg•L −1 ) to probe the effect of propofol on functional metabolism and the ecological response mechanism in aquatic organisms. Propofol induced severe hepatic damage, including increased interstitial spaces and nuclear malformations at the tissue level. Reactive oxygen species (ROS) production and lipid peroxidation in zebrafish were induced after 28 days of exposure, while the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were substantially increased, suggesting that propofol may influence hepatic tissue injury through exacerbating oxidative damage. Exacerbated levels of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were indicative of dysregulated lipid metabolism. Comprehensive transcriptomics and metabolomics analyses showed that propofol mainly changed the glycerophospholipid metabolism, citric acid cycle, and purine metabolism, and the disorders of these pathways can aggravate lipid accumulation and oxidative damage. Overall, this study revealed the mechanisms of hepatotoxicity and metabolic dysfunction of propofol on zebrafish, providing constructive insights for a comprehensive assessment of the toxicity risk posed by propofol to aquatic environmental health.

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“…MDH2 encodes mitochondrial malate dehydrogenase 2, which converts malate into oxaloacetate using NAD + ≥ NADH, H+ as part of the citric acid cycle, and therefore regulates NADH [30]. Our molecular modeling studies suggest that the MDH2 variant found in recurrent breast cancer cases may lead to lower [NADH] and elevated NAD + , reducing oxygen consumption and ATP production during the mitochondrial respiration cycle-or, in other words, augmentation of anerobic glycolysis, which has been found to contribute to cancer cell proliferation [31,32].…”

Section: Discussionmentioning

confidence: 99%

A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree

Cannon-Albright,

Stevens,

Teerlink

et al. 2023

Cancers

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A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data. Additional breast cancer cases were assayed for a subset of candidate variants to test for co-segregation. Three-dimensional protein structure prediction methods were used to investigate how the mutation under consideration is predicted to change structural and electrostatic properties in the mutated protein. One hundred and eighty-one rare candidate predisposition variants were shared in at least one cousin pair from a high-risk pedigree. A rare variant in MDH2 was found to segregate with breast-cancer-affected relatives in one extended pedigree. MDH2 is an estrogen-stimulated gene encoding the protein malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate. The molecular simulation results strongly suggest that the mutation changes the NAD+ binding pocket electrostatics of MDH2. This small sequencing study, using a powerful approach based on recurrent breast cancer cases from high-risk pedigrees, identified a set of strong candidate variants for inherited predisposition for breast cancer recurrence, including MDH2, which should be pursued in other resources.

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Synthesis, biological evaluation and molecular docking studies of indeno [1, 2-c] pyrazol derivatives as inhibitors of mitochondrial malate dehydrogenase 2 (MDH2)

Cited by 7 publications

References 25 publications

Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence

Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence

Environmentally Relevant Concentrations of Propofol-Induced Metabolic Dysfunction in Zebrafish: Mechanistic Insights into Integrated Hepatic Transcriptomic and Metabolomic Analyses

A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree

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