Dicationic Diarylfurans as Anti-Pneumocystis carinii Agents
| Autor: | Jarosław Spychała, Arvind Kumar, Lombardy Rj, Susan Jones, Christine C. Dykstra, W. D. Wilson, Zhou M, R R Tidwell, David W. Boykin, James Edwin Hall |
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| Rok vydání: | 1995 |
| Předmět: |
Models
Molecular Antifungal Agents Stereochemistry Molecular Sequence Data Oligonucleotides Oligomer Structure-Activity Relationship chemistry.chemical_compound Poly dA-dT Cations Drug Discovery Animals Topoisomerase II Inhibitors Structure–activity relationship Binding site Furans Binding Sites Base Sequence biology Pneumocystis Chemistry Topoisomerase Biological activity DNA Protozoan Rats Pneumocystis Infections Pneumocystis carinii biology.protein Nucleic Acid Conformation Molecular Medicine Giardia lamblia Topoisomerase-II Inhibitor DNA |
| Zdroj: | Journal of Medicinal Chemistry. 38:912-916 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00006a009 |
| Popis: | Seven dicationic 2,5-diarylfurans have been synthesized, and their interactions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)2 were evaluated by Tm measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by these furans, and the effectiveness of these compounds against Pneumocystis carinii in the immunosuppressed rat model have been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the compounds. An X-ray structure for the complex of the dicationic amidine derivative, 2,5-bis(4-guanylphenyl)furan (1), with the oligomer demonstrates the snug fit of these compounds with the AATT minor-groove binding site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inhibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibition with the biological activity of these compounds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more active and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dication first binds in the minor groove of DNA and forms a complex that results in the inhibition of the microbial topoisomerase II enzyme. |
| Databáze: | OpenAIRE |
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