Dicationic Diarylfurans as Anti-Pneumocystis carinii Agents

Abstract

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.

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

“…Poly(dA^dT) 2 and poly(dA)^poly(dT) were purchased from Midland Certi¢ed Reagent Company (Midland, TX, USA). GL020924 was synthesized at Genelabs (Dr. C. Roberts, manuscript in preparation) and veri¢ed by NMR and mass spectrometry (MS).…”

“…Binding of GL020924 to sequence homogeneous polymeric DNA (poly(dA^dT) 2 and poly(dA)^poly(dT)) was monitored using a Jasco J-600 CD polarimeter. At each ligand concentration, the CD signal was obtained as an average of at least two scans over the range of 200^400 nm.…”

Principais métodos de síntese de amidinas

“…Como exemplo, temos a distamicina, extraída a partir de Streptomyces, que apresenta significante atividade antiviral 4 (Esquema 3). Na química medicinal, muitas substâncias contendo este grupo funcional têm apresentado atividade contra vários agentes patogênicos como Giardia lamblia 5 , Leishmania sp [6][7][8][9] , Pneumocystis carinii [10][11][12][13][14] , Candida albicans 15,16 , Cryptococcus neoformans 15,16 , 17 , Trypanosoma sp [18][19][20][21] , Cryptosporidium sp 22 , Acanthamoeba polyphaga 23 e Plasmodium sp 24 . Além disso, o grupo amidina está presente em diversos compostos com atividade antitrombótica [25][26][27][28] .…”

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

“…Recent reports [10,11] have suggested that 2,5-bis[(4-amidino)phenyl]furan also binds in the major groove of DNA in addition to binding in the minor groove, however this view has been questioned [12]. The crystal structure of a complex between 2,5-bis[(4-amidino)phenyl]furan and d(CGCGAATTCGCG) 2 was recently solved and clearly illustrates the minor-groove-binding mode [13]. A method of calculating the radius of curvature of groove-binding molecules has been developed by Cory et al [14], which expands upon the isohelicity concept [16].…”

“…Pentamidine and its analogs [19], dicationic bis-benzimidazoles [20,21], and more recently dicationic 2,5-diarylfurans [13] (the latter give calculated radius of curvature values of approximately 15 Å) have been shown to be effective in treating Pneumocystis carinii pneumonia (PCP) and topoisomerase II inhibition may be involved in their mode of action. Collectively, these observations led us to evaluate dicationic 2,4-diarylpyrimidines, which give radius of curvature values in the range predicted to be effective DNA binding agents [17] and which have been demonstrated to strongly bind to AT-rich DNA [14], for effectiveness against PCP.…”