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ChemMedChem Jul 2024Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause...
Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.
Topics: Humans; Neoplastic Stem Cells; Histone Deacetylase Inhibitors; Pyridines; Glioblastoma; Colorectal Neoplasms; Antineoplastic Agents; Cell Proliferation; Uracil; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Cell Line, Tumor; Molecular Structure; Dose-Response Relationship, Drug
PubMed: 38529661
DOI: 10.1002/cmdc.202300655 -
Accounts of Chemical Research Oct 2021Redox reactions that take place in enzymes and on the surfaces of heterogeneous catalysts often require active sites that contain multiple metals. By contrast, there are... (Review)
Review
Redox reactions that take place in enzymes and on the surfaces of heterogeneous catalysts often require active sites that contain multiple metals. By contrast, there are very few homogeneous catalysts with multinuclear active sites, and the field of organometallic chemistry continues to be dominated by the study of single metal systems. Multinuclear catalysts have the potential to display unique properties owing to their ability to cooperatively engage substrates. Furthermore, direct metal-to-metal covalent bonding can give rise to new electronic configurations that dramatically impact substrate binding and reactivity. In order to effectively capitalize on these features, it is necessary to consider strategies to avoid the dissociation of fragile metal-metal bonds in the course of a catalytic cycle. This Account describes one approach to accomplishing this goal using binucleating redox-active ligands.In 2006, Chirik showed that pyridine-diimines (PDI) have sufficiently low-lying π* levels that they can be redox-noninnocent in low-valent iron complexes. Extending this concept, we investigated a series of dinickel complexes supported by naphthyridine-diimine (NDI) ligands. These complexes can promote a broad range of two-electron redox processes in which the NDI ligand manages electron equivalents while the metals remain in a Ni(I)-Ni(I) state.Using (NDI)Ni catalysts, we have uncovered cases where having two metals in the active site addresses a problem in catalysis that had not been adequately solved using single-metal systems. For example, mononickel complexes are capable of stoichiometrically dimerizing aryl azides to form azoarenes but do not turn over due to strong product inhibition. By contrast, dinickel complexes are effective catalysts for this reaction and avoid this thermodynamic sink by binding to azoarenes in their higher-energy cis form.Dinickel complexes can also activate strong bonds through the cooperative action of both metals. Norbornadiene has a ring-strain energy that is similar to that of cyclopropane but is not prone to undergoing C-C oxidative addition with monometallic complexes. Using an (NDI)Ni complex, norbornadiene undergoes rapid ring opening by the oxidative addition of the vinyl and bridgehead carbons. An inspection of the resulting metallacycle reveals that it is stabilized through a network of secondary Ni-π interactions. This reactivity enabled the development of a catalytic carbonylative rearrangement to form fused bicyclic dienones.These vignettes and others described in this Account highlight some of the implications of metal-metal bonding in promoting a challenging step in a catalytic cycle or adjusting the thermodynamic landscape of key intermediates. Given that our studies have focused nearly exclusively on the (NDI)Ni system, we anticipate that many more such cases are left to be discovered as other transition-metal combinations and ligand classes are explored.
Topics: Coordination Complexes; Imines; Ligands; Molecular Structure; Nickel; Oxidation-Reduction; Pyridines
PubMed: 34565142
DOI: 10.1021/acs.accounts.1c00424 -
Drug Design, Development and Therapy 2021Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological... (Review)
Review
Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.
Topics: Animals; Chemistry, Pharmaceutical; Dihydropyridines; Drug Design; Drug Development; Humans; Pyridines; Structure-Activity Relationship
PubMed: 34675489
DOI: 10.2147/DDDT.S329547 -
Advances in Experimental Medicine and... 2020Ca signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular... (Review)
Review
Ca signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca signals by mobilizing Ca from intracellular stores. Inositol trisphosphate (IP) was the first messenger shown to link events at the plasma membrane to release Ca from the endoplasmic reticulum (ER), through the activation of IP-gated Ca release channels (IP receptors). Subsequently, two additional Ca mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca from acidic stores by a mechanism involving the activation of two pore channels (TPCs). In addition, other pyridine nucleotides have emerged as intracellular messengers. ADP-ribose and 2'-deoxy-ADPR both activate TRPM2 channels which are expressed at the plasma membrane and in lysosomes.
Topics: Animals; Calcium; Calcium Signaling; Cyclic ADP-Ribose; Endoplasmic Reticulum; Humans; Intracellular Space; NADP; Pyridines; Ryanodine Receptor Calcium Release Channel
PubMed: 31646518
DOI: 10.1007/978-3-030-12457-1_15 -
Organic & Biomolecular Chemistry May 2022Imidazo[1,5-]pyridine is a significant structural component of a large number of agrochemicals and pharmaceuticals. The synthesis of imidazo[1,5-]pyridine has been a... (Review)
Review
Imidazo[1,5-]pyridine is a significant structural component of a large number of agrochemicals and pharmaceuticals. The synthesis of imidazo[1,5-]pyridine has been a subject of intense research for numerous decades. A large number of transformations are now available to conveniently access imidazo[1,5-]pyridine from readily available starting materials. This review details the recent development in imidazo[1,5-]pyridine construction involving cyclocondensation, cycloaddition, oxidative cyclization, and transannulation reactions.
Topics: Cyclization; Imidazoles; Oxidation-Reduction; Pyridines
PubMed: 35394477
DOI: 10.1039/d2ob00386d -
Molecules (Basel, Switzerland) Dec 2022Chromeno[2,3-]pyridines are substances demanded in medicinal and material chemistry. (pot, atom, and step economy) and in particular approaches are key green chemistry...
Chromeno[2,3-]pyridines are substances demanded in medicinal and material chemistry. (pot, atom, and step economy) and in particular approaches are key green chemistry techniques that are applied for the synthesis of heterocyclic compounds. In this case, the approach was extended with 'component economy', as solvent was used also as reactant (solvent-involved reaction). This approach was adopted for the synthesis of previously unknown -substituted 5-alkoxy-5-chromeno[2,3-]pyridines via transformation, namely the reaction of salicylaldehydes and malononitrile dimer, with the subsequent addition of alcohol. The mechanistic studies revealed the possibility of concurrent reaction. The studies aided in optimizing the reaction conditions for the best yields (77-93%). Thus, the reaction proceeds efficient and quickly, and the work-up procedure (only simple filtering) is very convenient. The structure of synthesized chromeno[2,3-]pyridines was confirmed by 2D NMR spectroscopy.
Topics: Pyridines; Solvents; Ethanol; Heterocyclic Compounds
PubMed: 36615259
DOI: 10.3390/molecules28010064 -
Molecules (Basel, Switzerland) Apr 2024Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted... (Review)
Review
Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.
Topics: Animals; Humans; Antineoplastic Agents; Chelating Agents; Coordination Complexes; Copper; Dendrimers; Imines; Neoplasms; Pyridines; Schiff Bases
PubMed: 38675623
DOI: 10.3390/molecules29081800 -
Future Medicinal Chemistry Dec 2022Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone...
Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone derivatives exert anti-ovarian cancer activity. 21 derivatives were synthesized and assayed for their antiproliferative activities. Western blotting in A2780 cells was used to detect the effects of compound A-6 on apoptosis-related proteins. Invasion, migration and apoptosis were assayed in SKOV3 cells treated with A-6. The activity was also examined. A-6 could inhibit proliferation, invasion and migration and induce apoptosis in SKOV3 cells. Additionally, A-6 had potent inhibitory activity in a xenograft mouse model. A-6 shows potent efficacy in the treatment of ovarian cancer and may be a potential antitumor agent.
Topics: Humans; Animals; Mice; Female; Ovarian Neoplasms; Cell Line, Tumor; Antineoplastic Agents; Apoptosis; Benzimidazoles; Pyridines; Cell Proliferation
PubMed: 36373543
DOI: 10.4155/fmc-2022-0244 -
Chemistry, An Asian Journal Jun 2021Corrosion is a phenomenon that devastatingly affects innovative, industrial, and mechanical applications, especially in the oil and gas industries. The corrosion... (Review)
Review
Corrosion is a phenomenon that devastatingly affects innovative, industrial, and mechanical applications, especially in the oil and gas industries. The corrosion conceivably influences industrial equipment; it deteriorates the environment and lessens the equipment/infrastructure's lifetime. Considering the significant impact of corrosion in our daily lives, this review article aims to briefly discuss the significance of corrosion and different control methods with special attention on corrosion inhibitors. The classification of corrosion inhibitors based on types and their advantage/limitations, and heterocyclic compounds as potential corrosion inhibitors, mainly nitrogen-based compounds (pyridine (1N), pyrimidine (2N), and triazines (3N) fused ring benzimidazole, etc.), and their biological significance has been discussed in detail. The mechanism, challenges, and applications of heterocyclic compounds as corrosion inhibitors in various industrial relevant corrosive environments such as acid pickling, descaling operation in the desalination plant, oil gas industry, etc., have also been highlighted in the review.
Topics: Azoles; Corrosion; Heterocyclic Compounds; Metals; Pyridines; Pyrimidines; Triazines
PubMed: 33844882
DOI: 10.1002/asia.202100201 -
Molecules (Basel, Switzerland) Jan 2020An increasing interest in the synthesis and use of optically active pyridine -oxides as chiral controllers for asymmetric reactions has been observed in the last few... (Review)
Review
An increasing interest in the synthesis and use of optically active pyridine -oxides as chiral controllers for asymmetric reactions has been observed in the last few years. Chiral heteroaromatic -oxides can work as powerful electron-pair donors, providing suitable electronic environments in the transition state formed within the reaction. The nucleophilicity of the oxygen atom in -oxides, coupled with a high affinity of silicon to oxygen, represent ideal properties for the development of synthetic methodology based on nucleophilic activation of organosilicon reagents. The application of chiral -oxides as efficient organocatalysts in allylation, propargylation, allenylation, and ring-opening of meso-epoxides, as well as chiral ligands for metal complexes catalyzing Michael addition or nitroaldol reaction, can also be found in the literature. This review deals with stereoselective applications of -oxides, and how the differentiating properties are correlated with their structure. It contains more recent results, covering approximately the last ten years. All the reported examples have been divided into five classes, according to the chirality elements present in their basic molecular frameworks.
Topics: Catalysis; Heterocyclic Compounds; Pyridines
PubMed: 31947566
DOI: 10.3390/molecules25020330