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The Journal of Organic Chemistry Mar 2018The binding interactions between the azide anion (N) and the strapped calix[4]pyrroles 2 and 3 bearing auxiliary hydrogen bonding donors on the bridging moieties, as...
The binding interactions between the azide anion (N) and the strapped calix[4]pyrroles 2 and 3 bearing auxiliary hydrogen bonding donors on the bridging moieties, as well as of normal calix[4]pyrrole 1, were investigated via H NMR spectroscopic and isothermal titration calorimetry analyses. The resulting data revealed that receptors 2 and 3 have significantly higher affinities for the azide anion in organic media as compared with the unfunctionalized calix[4]pyrrole 1 and other azide receptors reported to date. Single crystal X-ray diffraction analyses and calculations using density functional theory revealed that receptor 2 binds CsN in two distinct structural forms. As judged from the metric parameters, in the resulting complexes one limiting azide anion resonance contributor is favored over the other, with the specifics depending on the binding mode. In contrast to what is seen for 2, receptor 3 forms a CsN complex in 20% CDOD in CDCl, wherein the azide anion is bound only vertically to the NH protons of the calix[4]pyrrole and the cesium cation is complexed within the cone shaped-calix[4]pyrrole bowl. The bound cesium cation is also in close proximity to a naphthobipyrrole subunit present in a different molecule, forming an apparent cation-π complex.
Topics: Azides; Calixarenes; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Pyrroles
PubMed: 29441791
DOI: 10.1021/acs.joc.7b03135 -
The Journal of Physical Chemistry. A Oct 2022Zinc-complexed porphyrin and chlorophyll derivatives form functional aggregates with remarkable photophysical and optoelectronic properties. Understanding the type and...
Zinc-complexed porphyrin and chlorophyll derivatives form functional aggregates with remarkable photophysical and optoelectronic properties. Understanding the type and strength of intermolecular interactions between these molecules is essential for designing new materials with desired morphology and functionality. The dimer interactions of a molecular set composed of porphyrin derivatives obtained by substitutional changes starting from free-base porphyrin is studied. It is found that the B97M-rV/def2-TZVP level of theory provides a good compromise between the accuracy and cost to get the dimer geometries and interaction energies (IEs). The neglect of the relaxation energy due to the change in the monomer configurations upon complex formation causes a more significant error than the basis set superposition error. The metal complexation increases the binding energy by about -6 to -8 kcal/mol, and the introduction of keto and hydroxy groups further stabilizes the dimers by about -20 kcal/mol. Although the saturation of one of the pyrrol double bonds does not change the IE, the addition of R groups increases it.
Topics: Chlorophyll; Metalloporphyrins; Models, Molecular; Porphyrins; Thermodynamics; Zinc
PubMed: 36194887
DOI: 10.1021/acs.jpca.2c03692 -
Journal of Medicinal Chemistry Dec 2022We synthesized new aroyl diheterocyclic pyrrole (ARDHEP) that exhibited the hallmarks of ferroptosis. Compound strongly inhibited U-87 MG, OVCAR-3, and MCF-7 cancer...
We synthesized new aroyl diheterocyclic pyrrole (ARDHEP) that exhibited the hallmarks of ferroptosis. Compound strongly inhibited U-87 MG, OVCAR-3, and MCF-7 cancer cells, induced an increase of cleaved PARP, but was not toxic for normal human primary T lymphocytes at 0.1 μM. Analysis of the levels of lactoperoxidase, malondialdehyde, lactic acid, total glutathione, and ATP suggested that the in vivo inhibition of cancer cell proliferation by went through stimulation of oxidative stress injury and Fe accumulation. Quantitative polymerase chain reaction analysis of the mRNA expression in U-87 MG and SKOV-3 tumor tissues from -treated mice showed the presence of //// genes correlated with ferroptosis in both groups. Immunofluorescence staining revealed significantly lower expressions of proteins Ki67, CD31, and ferroptosis negative regulation proteins glutathione peroxidase 4 (GPX4) and FTH1. Compound was found to be metabolically stable when incubated with human liver microsomes.
Topics: Humans; Animals; Female; Mice; Tubulin Modulators; Tubulin; Pyrroles; Ovarian Neoplasms; Apoptosis; Cell Line, Tumor
PubMed: 36395526
DOI: 10.1021/acs.jmedchem.2c01457 -
British Journal of Pharmacology Jul 2017The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT and...
BACKGROUND AND PURPOSE
The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT and MT receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.
EXPERIMENTAL APPROACH
We therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.
KEY RESULTS
Among the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT and MT receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the G /cAMP and ERK pathway and β-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between G /cAMP signalling of the MT receptor initiated at the cell surface and neuronal mitochondria.
CONCLUSIONS AND IMPLICATIONS
We report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.
Topics: Animals; Carbocyanines; Cell Membrane Permeability; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Ethylamines; HEK293 Cells; Humans; Indoles; Ligands; Mice; Molecular Structure; Pyrroles; Receptors, Melatonin; Structure-Activity Relationship
PubMed: 28493341
DOI: 10.1111/bph.13856 -
Molecules (Basel, Switzerland) Sep 2023Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to...
Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC values below 10 μM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.
Topics: Humans; Acridines; Pyrroles; Thiazolidines; Spectroscopy, Fourier Transform Infrared; Antineoplastic Agents; HCT116 Cells
PubMed: 37764394
DOI: 10.3390/molecules28186616 -
Annals of Oncology : Official Journal... May 2018
Topics: Alkylation; Aminoquinolines; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Ellipticines; Humans; Mutation; Neoplasms; Protein Binding; Protein Interaction Domains and Motifs; Pyrazoles; Pyrroles; Quinuclidines; Structure-Activity Relationship; Thiosemicarbazones; Tumor Suppressor Protein p53
PubMed: 29462239
DOI: 10.1093/annonc/mdy057 -
Journal of Hepatology Aug 2017Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive...
BACKGROUND & AIMS
Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions.
METHODS
Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia.
RESULTS
Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton.
CONCLUSIONS
Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia.
LAY SUMMARY
Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.
Topics: Acute-On-Chronic Liver Failure; Animals; Bile; Bilirubin; Biliverdine; Cholestasis; Glutathione; Heme; Hemodynamics; Hep G2 Cells; Humans; Hyperbilirubinemia; In Vitro Techniques; Liver; Liver Circulation; Male; Oxidation-Reduction; Pyrroles; Rats; Rats, Wistar
PubMed: 28412296
DOI: 10.1016/j.jhep.2017.03.037 -
International Journal of Oral Science Mar 2017Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes...
Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy.
Topics: Aminoacyltransferases; Bacterial Adhesion; Bacterial Proteins; Benzofurans; Biofilms; Computer Simulation; Cysteine Endopeptidases; Dental Caries; Pyrroles; Streptococcus mutans; Thiadiazoles
PubMed: 28358034
DOI: 10.1038/ijos.2016.58 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2022The recent discovery of calix[3]pyrrole, a porphyrinogen-like tripyrrolic macrocycle, has provided an unprecedented strain-induced ring expansion reaction into...
The recent discovery of calix[3]pyrrole, a porphyrinogen-like tripyrrolic macrocycle, has provided an unprecedented strain-induced ring expansion reaction into calix[6]pyrrole. Here, we synthesized calix[n]furan[3-n]pyrrole (n=1∼3) macrocycles to investigate the reaction scope and mechanism of the ring expansion. Single crystal X-ray analysis and theoretical calculations revealed that macrocyclic ring strain increases as the number of inner NH sites increases. While calix[1]furan[2]pyrrole exhibited almost quantitative conversion into calix[2]furan[4]pyrrole within 5 minutes, less-strained calix[2]furan[1]pyrrole and calix[3]furan were inert. However, N-methylation of calix[2]furan[1]pyrrole induced a ring-expansion reaction that enabled the isolation of a linear reaction intermediate. The mechanism analysis revealed that the ring expansion consists of regioselective ring cleavage and subsequent cyclodimerization. This reaction was further utilized for synthesis of calix[6]-type macrocycles.
Topics: Calixarenes; Pyrroles
PubMed: 35137995
DOI: 10.1002/chem.202200056 -
Molecules (Basel, Switzerland) Oct 2022Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in...
Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.
Topics: Pyrroles; Lewis Acids; Aziridines; Biological Products; Water
PubMed: 36296466
DOI: 10.3390/molecules27206869