ABSTRACT
In the search for new potentially anticancer drugs, isoquinolinequinone-containing polycyclic compounds have been designed and synthesized through highly regiocontrolled cycloaddition reactions of methyl 1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate with polarized 1,3-dienes and a thiazole-o-quinodimethane. The new N-heterocyclic quinones were tested on normal human fibroblasts and four distinct human cancer cell lines. Two of the evaluated compounds displayed significant in vitro activity (IC50: 0.44-5.9 microM) comparable to that of the reference drug etoposide.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Quinones/chemical synthesis , Quinones/pharmacology , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Fibroblasts/drug effects , Humans , Quinones/chemistryABSTRACT
Boc-aminoethylindoloquinone 8, a key intermediate for the building of pentacyclic quinoneimines, analogues of kuanoniamine A, was synthesized by alkylation of 4,7-dimethoxyindole 3 with 1,2-dibromoethane followed by transformation into azide, reduction of the latter with trimethylphosphine in the presence of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile and oxydative demethylation of the Boc-amine 6 with silver(II) oxide. Quinone 8 was then treated in situ with the thiazole o-quinodimethane 10 to afford a regioisomeric mixture of the tetracyclic quinones 11. Treatment of the mixture with trifluoroacetic acid and molecular sieves 4-A provided the corresponding quinoneimines 12. Separation of the regioisomers was performed by preparative thin-layer chromatography on silica gel. The structural assignment was made by 2D 1H-13C HMBC correlations performed on the less polar regioisomer 12b. In vitro anti-leishmanial assays showed that the tested compounds possess a good potency towards two Leishmania sp. as well as against a virulent strain of Toxoplasma gondii and without any cytotoxicity against THP-1 cells.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Alkaloids/chemistry , Alkaloids/toxicity , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/toxicity , Cell Line , Humans , Inhibitory Concentration 50 , Leishmania/drug effects , Molecular Structure , Toxoplasma/drug effectsABSTRACT
The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Leishmania donovani/drug effects , Naphthoquinones/chemical synthesis , Toxoplasma/drug effects , Animals , Antiprotozoal Agents/toxicity , Furans/chemistry , Humans , Molecular Structure , Myeloid Cells/drug effects , Myeloid Cells/parasitology , Naphthoquinones/pharmacology , Parasitic Sensitivity Tests , Structure-Activity Relationship , Thiazoles/chemistry , Thiophenes/chemistryABSTRACT
We previously reported that RSV-transformed quail neuroretina cells (QNR-ts68) were highly resistant to apoptosis provoked by serum withdrawal, and that this property was due to v-Src kinase activity. The present study investigates the cytotoxic effect and the functional mechanism of carbazolequinone-mediated cell death in this system. QNR-ts68 cells were subjected to carbazolequinone treatment and both growth inhibition and cell death induction were examined using formazan assays. Cell death mechanism (both apoptosis and necrosis) was confirmed through phosphatidyl serine exposure and propidium iodide incorporation. Furthermore, the effect of active carbazolequinone was inhibited by a pan caspase inhibitor. Cytofluorimetric and immunofluorescence data demonstrated the activation of caspase-3 and the involvement of mitochondria. Therefore, this study clearly indicates that carbazolequinones could induce cell death in transformed cells displaying high levels of antiapoptotic tyrosine kinase activity. Further investigations would be necessary to elucidate the mechanisms by which these carbazolequinones act as antitumor agents.
Subject(s)
Apoptosis , Bacterial Proteins/biosynthesis , Carbazoles/pharmacology , Caspases/metabolism , DNA-Binding Proteins/biosynthesis , Quinones/pharmacology , Transcription Factors , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Bacterial Proteins/physiology , Carbazoles/chemistry , Caspase 3 , Caspase Inhibitors , Cell Division/drug effects , Cells, Cultured , Cysteine Proteinase Inhibitors/pharmacology , DNA-Binding Proteins/physiology , Drug Interactions , Enzyme Activation , Ion Channels/metabolism , L-Lactate Dehydrogenase/drug effects , L-Lactate Dehydrogenase/metabolism , Mitochondrial Membrane Transport Proteins , Mitochondrial Permeability Transition Pore , Necrosis , Quail , Quinones/chemistry , Structure-Activity RelationshipABSTRACT
Quinonic derivatives were tested against a virulent RH strain of Toxoplasma gondii maintained in cell culture in THP-1, a human myelomonocytic cell line. The derivatives were tested at various doses (0.5-4 microg/ml) and compared with the reference molecules clindamycine, sulfadiazine, pyrimethamine and atovaquone. The percentage of parasite growth inhibition was observed after 72 h of incubation. The tested derivatives are bicyclic, tricyclic or tetracyclic quinones. Eight of these compounds exhibit over 70% inhibition of parasite growth; and two were nearly equipotent to pyrimethamine. These data indicate that the most active compounds against the RH strain of T. gondii are bis-heterocyclic quinones.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Quinones/chemistry , Quinones/pharmacology , Toxoplasma/drug effects , Animals , Cell Line , Humans , Inhibitory Concentration 50 , Parasitic Sensitivity Tests/methods , Structure-Activity Relationship , Toxoplasma/growth & developmentABSTRACT
4-(Bromomethyl)-5-(dibromomethyl)thiazole (1) was prepared in good yields by bromination of 4,5-dimethylthiazole with 3.3 equiv of NBS in the presence of AIBN. Treatment of 1 with sodium iodide led to a thiazole o-quinodimethane 2 which was trapped in situ with dienophiles such as N-phenylmaleimide, DMAD, or acrylate derivatives. From the latter, 6-substituted-4,5-dihydrobenzothiazoles 7 are selectively formed. Anthra[2,3-b]thiazole-4,5-diones 13-15 were obtained from naphthoquinones. With 2- or 3-bromonaphthoquinones (11 or 12), the cycloadditions were found highly regioselective. Structural assignment of the regioisomers was made by a 2D (1)H-(13)C HMBC technique performed on the aromatized cycloadduct 15b. Calculations of HOMO and LUMO frontier orbital coefficients by the semiempirical PM3 method show that the regiochemistry observed in the cycloadditions of 2 toward acrylate dienophiles or naphthoquinones 11 and 12 did not agree with the corresponding values.