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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 -
Bioorganic Chemistry May 2022Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development...
Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4-c]pyrrole derivative, identified as DPP(PyMe), that showed very promising results as G4 stabilizing ligand. The data obtained from UV-Vis and fluorescence experiments suggest that DPP(PyMe) presents high affinity to G4 structures. Docking studies and molecular dynamics simulations unraveled the binding modes of the ligand with four G4 structures. The obtained results also allowed us to conclude that the DPP(PyMe) ligand binds into the top G-tetrad or in a mixed binding mode depending on the GQ structure. A remarkable selectivity of DPP(PyMe) for c-MYC and KRAS 32R in the presence of ds26 was observed by circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting experiments. CD titrations revealed a stabilization higher than 30 °C in the case of c-MYC G4 structure and, for the same sequence, DPP(PyMe) showed the ability to block the activity of Taq polymerase in a dose-dependent manner. The subcellular localization obtained with confocal microscopy corroborates the results obtained by the other techniques and the obtained data suggest that DPP(PyMe) is an attractive ligand for the development of G4 labelling probes.
Topics: DNA; G-Quadruplexes; Ligands; Pyrroles; Telomere
PubMed: 35248982
DOI: 10.1016/j.bioorg.2022.105703 -
European Journal of Medicinal Chemistry Jul 2022An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active...
An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.
Topics: Animals; Antitubercular Agents; Humans; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrroles; Structure-Activity Relationship
PubMed: 35486992
DOI: 10.1016/j.ejmech.2022.114404 -
Biochemical and Biophysical Research... Oct 2022Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT)...
Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.
Topics: Alkylating Agents; Cell Line, Tumor; Humans; Imidazoles; Male; Nylons; Prostatic Neoplasms, Castration-Resistant; Pyrroles; Receptors, Androgen
PubMed: 35868070
DOI: 10.1016/j.bbrc.2022.07.042 -
Marine Drugs Jul 2022Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge collected in the South China Sea. Compound is the first...
Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge collected in the South China Sea. Compound is the first identified precursor metabolite of the classic 5/7/5 tricyclic skeleton with unesterified guanidine and carboxyl groups, compounds - and - belong to the spongiacidin-type pyrrole imidazole alkaloids (PIAs). - and -configurations of the spongiacidin-type PIAs often appeared concomitantly and were distinguished by the chemical shift analysis of C NMR spectra. The structures of all twelve new compounds were determined by NMR, MS, and ECD analysis combined with single-crystal data of compounds , , and . In the aldose reductase (ALR2) inhibitory assay, six 5/7/5 tricyclic compounds (-, -) displayed significant activities. Compounds and , as the representative members of spongiacidin-PIAs, demonstrated their ALR2-targeted activities in SPR experiments with K values of 12.5 and 6.9 µM, respectively.
Topics: Alkaloids; Animals; Magnetic Resonance Spectroscopy; Molecular Structure; Porifera; Pyrroles
PubMed: 35877747
DOI: 10.3390/md20070454 -
Marine Drugs Dec 2018Two new sceptrin derivatives (,) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge . By a combination of...
Two new sceptrin derivatives (,) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge . By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin () and ageleste C (), were determined to be structural analogs of each other that differ at the imidazole moiety. Dioxysceptrin was also found to exist as a mixture of α-amido epimers. The sceptrin alkaloids exhibited weak cytotoxicity against cancer cells. Compounds and also moderately exhibited anti-angiogenic and isocitrate lyase-inhibitory activities, respectively.
Topics: Agelas; Alkaloids; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Assays; Human Umbilical Vein Endothelial Cells; Humans; Isocitrate Lyase; Pyrroles; Stereoisomerism
PubMed: 30563015
DOI: 10.3390/md16120513 -
Molecules (Basel, Switzerland) Mar 2016In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the... (Review)
Review
In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the modification of β-pyrrolic positions leading to pyrrole-modified porphyrins containing four-, five-, six- or seven-membered heterocycles. Azeteoporphyrins, porpholactones and morpholinoporphyrins are representative examples of such porphyrinoids. These porphyrin derivatives have recently gained an increasing interest due to their potential application in PDT, as multimodal imaging contrast agents, NIR-absorbing dyes, optical sensors for oxygen, cyanide, hypochlorite and pH, and in catalysis.
Topics: Catalysis; Contrast Media; Humans; Molecular Structure; Multimodal Imaging; Porphyrins; Pyrroles
PubMed: 27005605
DOI: 10.3390/molecules21030320 -
Toxins Oct 2021Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between...
Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole-protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of (containing one PA: monocrotaline) and (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole-protein adducts formed in the rats' livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole-protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole-protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole-protein adducts-which directly correlated with the elevation of serum ALT activity-was a common insult leading to PA-ILI, suggesting a potential for using pyrrole-protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.
Topics: Alanine Transaminase; Animals; Asteraceae; Chemical and Drug Induced Liver Injury; Crotalaria; Liver; Male; Plant Extracts; Proteins; Pyrroles; Pyrrolizidine Alkaloids; Rats, Sprague-Dawley; Rats
PubMed: 34679016
DOI: 10.3390/toxins13100723 -
Chemistry (Weinheim An Der Bergstrasse,... May 2020The degradation of chlorophyll, the omnipresent green pigment, has been investigated intensively over the last 30 years resulting in many elucidated tetrapyrrolic...
The degradation of chlorophyll, the omnipresent green pigment, has been investigated intensively over the last 30 years resulting in many elucidated tetrapyrrolic degradation products. With a comparison to the degradation of the structurally similar heme, we hereby propose a novel additional chlorophyll degradation mechanism to mono- and dipyrrolic products. This is the first proof of the occurrence of a family of mono- and dipyrrols in leaves that are previously only known as heme degradation products. This product family is also found in spit and feces of herbivores with specific metabolomic patterns reflecting the origin of the samples. Based on chromatographic and mass spectrometric evidence as well as on mechanistic considerations we also suggest several tentative new degradation products. One of them, dihydro BOX A, was fully confirmed as a novel natural product by synthesis and comparison of its spectroscopic data.
Topics: Chlorophyll; Herbivory; Plant Leaves; Plants; Pyrroles
PubMed: 31971638
DOI: 10.1002/chem.201905236 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2022In this study, a novel La(III)-based two-dimensional (2D) metal-organic framework, [La (qptca) ] (referred to as SLX-2), from LaCl and...
In this study, a novel La(III)-based two-dimensional (2D) metal-organic framework, [La (qptca) ] (referred to as SLX-2), from LaCl and 1,1' : 4',1'' : 4'',1''' : 4''',1''''-quinquephenyl]-2,2'',2'''',5''-tetracarboxylic acid (H qptca) was synthesized by conventional solvothermal method and thoroughly characterized by using X-ray single-crystal diffraction, powder X-ray diffraction, and thermogravimetric analyses. The 2D SLX-2 features a unique lanthanum center exposed to the skeleton and was used as an efficient Lewis acid catalyst for the Friedel-Crafts alkylation of indole and pyrrole with β-nitrostyrene along with a wide substrate scope, giving the desired products in good-to-high yields under the optimal reaction conditions. Furthermore, the catalyst was used for twenty cycles, with nearly no effect on its activity, and the reaction was heterogeneous in nature. Moreover, compared to the previous hydrogen-bond-donating MOF catalysts for such alkylation reactions, SLX-2 showed an excellent stability toward harsh acidic and basic environment, and gave comparable catalytic activities.
Topics: Lewis Acids; Metal-Organic Frameworks; Catalysis; Alkylation; Pyrroles
PubMed: 36082763
DOI: 10.1002/chem.202202441