Dicationic diarylfurans as anti-Pneumocystis carinii agents.
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.
Boykin
D W
DW
Department of Chemistry, Georgia State University, Atlanta 30303.
Kumar
A
A
Spychala
J
J
Zhou
M
M
Lombardy
R J
RJ
Wilson
W D
WD
Dykstra
C C
CC
Jones
S K
SK
Hall
J E
JE
Tidwell
R R
RR
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002412:Cations; D016054:DNA, Protozoan / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016829:Giardia lamblia / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000378:metabolism; D011010:Pneumocystis / Q000187:drug effects* / Q000378:metabolism*; D016720:Pneumocystis Infections / Q000188:drug therapy; D011067:Poly dA-dT / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000935:Antifungal Agents; D002412:Cations; D016054:DNA, Protozoan; D005663:Furans; D009841:Oligonucleotides; D059005:Topoisomerase II Inhibitors; D011067:Poly dA-dT