ABSTRACT
A novel series of thiazolopyrimidines and fused thiazolopyrimidines was designed and synthesized as topoisomerase II alpha inhibitors. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compound 3a was found to be the most potent inhibitor on renal cell line (A-498) causing 83.03% inhibition (IC50 = 1.89 µM). DNA-flow cytometric analysis showed that compound 3a induce cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Moreover, fused thiazolopyrimidines 3a showed potent topoisomerase II inhibitory activity (IC50 = 3.19 µM) when compared with reference compound doxorubicin (IC50 = 2.67 µM). Docking study of all the synthesized compounds showed that compound 3a interacts in a similar pattern to etoposide and stabilizing the topoisomerase cleavage complex (Top2-cc) that accounts for its high potency.
Subject(s)
Antineoplastic Agents/chemical synthesis , DNA Topoisomerases, Type II/metabolism , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Pyrimidines/chemical synthesis , Thiazoles/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Heterocyclic Compounds, Fused-Ring/pharmacology , Humans , Molecular Docking Simulation , Molecular Structure , Pyrimidines/pharmacology , Topoisomerase II Inhibitors/pharmacologyABSTRACT
A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 µg/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 µg ml-1), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 µg ml-1). These compounds have no hemolytic activity and are low cytotoxic. Replacement of the pentathiepine ring with 1,3-dithiolan-2-one or 1,3-dithiolane moieties leads to loss of antimicrobial activity. Based on the QSAR analysis and molecular docking data, bacterial DNA ligase might be one of the targets for the antibacterial activity of substituted benzopentathiepin-6-amines against S. aureus.
Subject(s)
Anti-Infective Agents/pharmacology , Heterocyclic Compounds, Fused-Ring/pharmacology , Sulfides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/drug effects , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Quantitative Structure-Activity Relationship , Sulfides/chemical synthesisABSTRACT
A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes.
Subject(s)
Green Chemistry Technology/methods , Heterocyclic Compounds, Fused-Ring/chemistry , Nitrogen/chemistry , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Nitriles/chemistry , Pyrazines/chemistry , Pyrimidines/chemistryABSTRACT
The divergent total syntheses of three types of heteropolycyclic natural products, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. A strategy involving a late-stage pluripotent common synthetic intermediate prepared via original and innovative transformations was employed. A brief description of the philosophy and criteria for choosing the synthetic targets and common synthetic precursors, as well as details regarding the development of the overall synthetic schemes from a common intermediate are discussed.
Subject(s)
Biological Products/chemical synthesis , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
The post-cyclization strategy rather than the conventional ante-cyclotetramerization method was employed for the synthesis of multinuclear phthalocyanine-fused molecular nanoarrays. Reaction of 2,3,9,10,16,17-hexakis(2,6-dimethylphenoxy)-23,24-diaminophthalocyaninato zinc(II) with 2,7-di-tert-butylpyrene-4,5-dione, 2,7-di-tert-butylpyrene-4,5,9,10-tetraone, and hexaketocyclohexane in refluxing acetic acid afforded the corresponding mono-, bi-, and trinuclear phthalocyanine-fused zinc complexes (Pz-pyrene){Zn[Pc(OC8 H9 )6 ]} (1), (Pz2 -pyrene){Zn[Pc(OC8 H9 )6 ]}2 (2), {(HAT){Zn[Pc(OC8 H9 )6 ]}3 } (3) in 46, 13, and 25 % yield, respectively, which extend the scope of multinuclear phthalocyanine-fused nanoarrays with different molecular skeletons. The self-assembly behavior of trinuclear phthalocyanine 3 in THF/CH3 CN was investigated by electronic absorption spectroscopy and SEM, and the fabricated nanorods showed interesting semiconducting properties, which suggest good application potential of these multinuclear phthalocyanine-fused molecular nanoarrays.
Subject(s)
Coordination Complexes/chemical synthesis , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Indoles/chemical synthesis , Nanostructures/chemistry , Zinc/chemistry , Electrochemical Techniques/methods , Isoindoles , Microscopy, Electron, Scanning , Molecular Structure , Nanotubes/chemistry , Semiconductors , Spectrum AnalysisABSTRACT
The combinatorial syntheses of a library of novel dihydrothiophenone-engrafted dispiro oxindole/indenoquinoxaline-pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles have been realized through a chemo-, regio-, and stereoselective multicomponent 1,3-dipolar cycloaddition strategy.
Subject(s)
Heterocyclic Compounds, Fused-Ring/chemical synthesis , Small Molecule Libraries/chemical synthesis , Spiro Compounds/chemical synthesis , Thiophenes/chemical synthesis , Combinatorial Chemistry Techniques , Cycloaddition Reaction , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of novel 4H-benzo[h]chromenes 4, 6-11, 13, 14; 7H-benzo[h]chromeno[2,3-d]pyrimidines 15-18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 19a-e, 24 was prepared. The structures of the synthesized compounds were characterized on the basis of their spectral data. Some of the target compounds were examined for their antiproliferative activity against three cell lines; breast carcinoma (MCF-7), human colon carcinoma (HCT-116) and hepatocellular carcinoma (HepG-2). The cytotoxic behavior has been tested using MTT assay and the inhibitory activity was referenced to three standard anticancer drugs: vinblastine, colchicine and doxorubicin. The bioassays demonstrated that some of the new compounds exerted remarkable inhibitory effects as compared to the standard drugs on the growth of the three tested human tumor cell lines. The structure-activity relationships (SAR) study highlights that the antitumor activity of the target compounds was significantly affected by the lipophilicity of the substituent at 2- or 3- and fused rings at the 2,3-positions.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Antineoplastic Agents/chemistry , Benzopyrans/chemistry , Cell Proliferation/drug effects , Cell Survival , Drug Screening Assays, Antitumor , HCT116 Cells , Hep G2 Cells , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Heterocyclic Compounds, Fused-Ring/chemistry , Heterocyclic Compounds, Fused-Ring/pharmacology , Humans , MCF-7 Cells , Molecular Structure , Structure-Activity RelationshipABSTRACT
Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.
Subject(s)
Drug Discovery/methods , Glutamic Acid/analogs & derivatives , Glutamic Acid/chemical synthesis , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Pyrans/chemical synthesis , Receptors, AMPA/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Glutamic Acid/chemistry , Glutamic Acid/pharmacology , Heterocyclic Compounds, Fused-Ring/chemistry , Heterocyclic Compounds, Fused-Ring/pharmacology , Ligands , Mice , Molecular Structure , Pyrans/chemistry , Pyrans/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Since 1979, synthetic studies of bioactive heterocyclic natural products and condensed heteroaromatic compounds based on the thermal electrocyclic reaction of 6π-electron or aza-6π-electron systems incorporating the double bond of the principal aromatic or heteroaromatic ring have been conducted by our research group. In this review, five types of electrocyclic and azaelectrocyclic reaction are described: 1) the synthesis of the carbazole alkaloids hyellazole and 6-chlorohyellazole through the electrocyclic reaction of 2,3-bisalkenylindoles; 2) synthetic studies of the pyridocarbazole alkaloids ellipticine and olivacine through the electrocyclic reactions of the indole-2,3- and pyridine-3,4-quinodimethane intermediates; 3) synthetic studies of polysubstituted carbazole alkaloids through the allene-mediated electrocyclic reactions involving the indole 2,3-bond; 4) synthetic studies of fused pyridine rings through the azaelectrocyclic reaction of the 1-aza-6π-electron system using the oxime or oxime ether; and 5) synthetic studies of fused pyridine rings through the azaelectrocyclic reaction of the 2-aza-6π-electron system using a carbodiimide or isocyanate.
Subject(s)
Biological Products/chemistry , Biological Products/chemical synthesis , Electrons , Heterocyclic Compounds, Fused-Ring/chemistry , Heterocyclic Compounds, Fused-Ring/chemical synthesis , Alkaloids/chemical synthesis , Carbazoles/chemical synthesis , Carbodiimides/chemistry , Isocyanates/chemistry , Organic Chemistry PhenomenaABSTRACT
The progesterone receptor (PR) is a ligand-activated steroid receptor in the nuclear receptor (NR) superfamily of transcription factor. Besides gynecological and obstetrical indications, the involvement/mechanism of PR in many other diseases, such as oncology, neurology, immunology, etc. has been revealed and studied in recent decades. Therapeutic agents that selectively activate or inhibit PR have been developed. PR agonists have generally been used in oral contraception and postmenopausal hormone replacement therapy (HRT), typically in combination with estrogens. PR antagonists and selective PR modulators (SPRMs) can be useful therapies for hormone dependent breast and prostate cancers, nonmalignant chronic conditions such as fibroids, and endometriosis. This review provides an overview and detailed discussions about the recent development of chemical structures of the PR ligands, their structural characteristics (particularly those contributing to their activity and selectivity), in vitro/in vivo studies and clinical trial outcomes, and the synthetic methodologies.