-
European Journal of Medicinal Chemistry Jul 2024Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side... (Review)
Review
Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.
Topics: Pyrroles; Humans; Antineoplastic Agents; Structure-Activity Relationship; Molecular Structure; Drug Screening Assays, Antitumor; Neoplasms; Cell Proliferation; Animals
PubMed: 38762915
DOI: 10.1016/j.ejmech.2024.116470 -
Chemical Biology & Drug Design Feb 2024A series of alkynylated pyrrole derivatives were meticulously designed, drawing inspiration from the structure of 3-alkynylpyrrole-2,4-dicarboxylates, which were...
A series of alkynylated pyrrole derivatives were meticulously designed, drawing inspiration from the structure of 3-alkynylpyrrole-2,4-dicarboxylates, which were synthesized via a cyclization process involving methylene isocyanides and propiolaldehydes under mild conditions. These derivatives were subsequently subjected to evaluation for their anticancer properties against a panel of cell lines, including U251, A549, 769-P, HepG2, and HCT-116. According to the detailed analysis of structure-activity relationship, compound 12l emerged as the most promising molecule, with IC values of 2.29 ± 0.18 and 3.49 ± 0.30 μM toward U251 and A549 cells, respectively. Subsequent mechanistic investigations revealed that compound 12l exerts its effects by arresting the cell cycle in the G0/G1 phase and inducing apoptosis specifically in A549 cells. These innovative alkynylated pyrrole derivatives hold the potential to serve as a valuable template for the discovery of novel anticancer molecules.
Topics: Antineoplastic Agents; Cell Line, Tumor; Pyrroles; Drug Screening Assays, Antitumor; Structure-Activity Relationship; Apoptosis; Cell Proliferation; Molecular Structure; Drug Design
PubMed: 38355143
DOI: 10.1111/cbdd.14484 -
Toxins May 2022Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Catalyzed by hepatic cytochrome P450...
Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Catalyzed by hepatic cytochrome P450 enzymes, PAs are metabolized into reactive pyrrolic metabolites, which can alkylate cellular proteins and DNA to form pyrrole-protein adducts and pyrrole-DNA adducts, leading to cytotoxicity, genotoxicity, and tumorigenicity. To date, the correlation between these PA-derived pyrrole-protein and pyrrole-DNA adducts has not been well investigated. Retrorsine is a representative hepatotoxic and carcinogenic PA. In the present study, the correlations among the PA-derived liver DNA adducts, liver protein adducts, and serum protein adducts in retrorsine-treated mice under different dosage regimens were studied. The results showed positive correlations among these adducts, in which serum pyrrole-protein adducts were more accessible and present in higher abundance, and thus could be used as a suitable surrogate biomarker for pyrrole-DNA adducts to indicate the genetic or carcinogenic risk posed by retrorsine.
Topics: Animals; Carcinogens; DNA; DNA Adducts; Liver; Male; Mice; Mice, Inbred ICR; Proteins; Pyrroles; Pyrrolizidine Alkaloids
PubMed: 35737038
DOI: 10.3390/toxins14060377 -
Angewandte Chemie (International Ed. in... Jul 2020Cancer possesses normoxic and hypoxia microenvironments with different levels of oxygen, needing different efficacies of photothermal and photodynamic therapies. It is...
Cancer possesses normoxic and hypoxia microenvironments with different levels of oxygen, needing different efficacies of photothermal and photodynamic therapies. It is important to precisely tune the photothermal and photodynamic effects of phototherapy nano-agents for efficient cancer treatment. Now, a series of copolymeric nanoparticles (PPy-Te NPs) were synthesized in situ by controlled oxidative copolymerization with different ratios of pyrrole to tellurophene by FeCl . The photothermal and photodynamic effects of semiconducting nano-agents under the first near-infrared (NIR) irradiation were precisely and systematically tuned upon simply varying the molar ratio of the pyrrole to tellurophene. The PPy-Te NPs were used for cancer treatment in mice, exhibiting excellent biocompatibility and therapeutic effect. This work presents a simple method to tune photothermal and photodynamic therapies effect in semiconducting nano-agents for cancer treatment.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Infrared Rays; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Photothermal Therapy; Polymerization; Polymers; Pyrroles; Reactive Oxygen Species
PubMed: 32343868
DOI: 10.1002/anie.202004181 -
Journal of Natural Products Feb 2024Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study the...
Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study the formation of trideuteromethylated artifacts of pyrrole-containing natural products was investigated, focusing on the discorhabdins. Three deuterated discorhabdins, , , and , were identified to be isolation procedure artifacts caused by the presence of DMSO during NMR sample preparation and handling. Three additional semisynthetic derivatives, -, were made during the investigation of the mechanism of formation, which was shown to be driven by trideuteromethyl radicals in the presence of water, methanol, TFA, and traces of iron in the deuterated solvent. Generation of trideuteromethylated artifacts was also confirmed for other classes of pyrrole-containing metabolites, namely, makaluvamines, tambjamines, and dibromotryptamines, which had also been dissolved in DMSO- during the structure elucidation process. Semisynthetic discorhabdins were assessed for antiproliferative activity against a panel of human tumor cell lines, and 14-trideuteromethyldiscorhabdin L () averaged low micromolar potency.
Topics: Humans; Dimethyl Sulfoxide; Pyrroles; Biological Products; Artifacts; Solvents
PubMed: 38291771
DOI: 10.1021/acs.jnatprod.3c01113 -
Journal of Natural Medicines Jan 2021Four new pyrrole alkaloids, named amokoens A-D (1-4), together with three known compounds (5-7) were isolated from the rhizomes of Amomum koenigii. Their structures and...
Four new pyrrole alkaloids, named amokoens A-D (1-4), together with three known compounds (5-7) were isolated from the rhizomes of Amomum koenigii. Their structures and absolute configurations were established by spectroscopic data, including 1D and 2D NMR, and the optical rotation calculations. All the isolates were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages. Compounds 1-7 inhibited NO production ranging from 27.1 to 82.4% at a concentration of 100 μM, and compounds 5 and 6 showed efficacious inhibitory activities with IC values of 42.2 and 69.3 µM, respectively.
Topics: Alkaloids; Amomum; Molecular Structure; Plant Extracts; Pyrroles; Rhizome
PubMed: 33084986
DOI: 10.1007/s11418-020-01461-2 -
Organic Letters Aug 2019Here we report Rh(II)-catalyzed monocyclopropanation reactions on pyrroles in the presence of aryldiazoacetates, providing the corresponding dearomatized products with...
Here we report Rh(II)-catalyzed monocyclopropanation reactions on pyrroles in the presence of aryldiazoacetates, providing the corresponding dearomatized products with high levels of enantioselectivity (up to >99% ee). Under the catalysis of Rh(-PhTPCP), a broad range of pyrrole substrates and aryldiazoacetates are shown to be compatible. Utilizing these valuable chiral building blocks, we further demonstrate the application of this transformation by synthesizing a homo-β-proline analog and a β-aminocarboxylic acid (β-ACC) derivative from the monocyclopropanated product.
Topics: Catalysis; Pharmaceutical Preparations; Pyrroles; Rhodium
PubMed: 31329451
DOI: 10.1021/acs.orglett.9b02250 -
Angewandte Chemie (International Ed. in... Apr 2016Axinellamines A and B are broad-spectrum antibacterial pyrrole-imidazole alkaloids that have a complex polycyclic skeleton. A new asymmetric synthesis of these marine...
Axinellamines A and B are broad-spectrum antibacterial pyrrole-imidazole alkaloids that have a complex polycyclic skeleton. A new asymmetric synthesis of these marine sponge metabolites is described herein, featuring an oxidative rearrangement and an anchimeric chlorination reaction.
Topics: Imidazoles; Isomerism; Pyrroles
PubMed: 27037993
DOI: 10.1002/anie.201600007 -
International Journal of Molecular... Sep 2022Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies,...
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide () or hydrazone (-) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-]pyrrole derivative was a strong inhibitor of the TET1 protein (IC = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-]pyrroles -, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.
Topics: DNA; Dioxygenases; Hydrazones; Iron; Iron Chelating Agents; Mitochondrial Proteins; Molecular Docking Simulation; Pyrroles
PubMed: 36142763
DOI: 10.3390/ijms231810850 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2021Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as...
Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
Topics: Alkylation; Chlorambucil; DNA; Imidazoles; Nylons; Pyrroles
PubMed: 33145851
DOI: 10.1002/chem.202004421