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
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.