Guanidiniocarbonylpyrrole-aryl derivatives: structure tuning for spectrophotometric recognition of specific DNA and RNA sequences and for antiproliferative activity.
We present a systematic study of different guanidiniocarbonylpyrrole-aryl derivatives designed to interact with DNA or RNA both through intercalation of an aromatic moiety into the base stack of the nucleotide and through groove binding of a guanidiniocarbonylpyrrole cation. We varied 1) the size of the aromatic ring (benzene, naphthalene, pyrene and acridine), 2) the length and flexibility of the linker connecting the two binding groups, and 3) the total number of positive charges present at different pH values. The compounds and their interactions with DNA and RNA were studied by UV/Vis, fluorescence and CD spectroscopy. Antiproliferative activities against human tumour cell lines were also determined. Our studies show that efficient interaction with, for example, DNA requires a significantly large aromatic ring (pyrene) connected through a flexible linker to the pyrrole moiety. However, a positive charge, as in 12, is also needed. Compound 12 allows for base-pair-selective recognition of ds-DNA at physiological pH values. The antiproliferative activities of these compounds correlate with their binding affinities towards DNA, suggesting that their biological effects are most probably due to DNA binding.
Hernandez-Folgado
Laura
L
Institute for Organic Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141 Essen, Germany.
Baretić
Domagoj
D
Piantanida
Ivo
I
Marjanović
Marko
M
Kralj
Marijeta
M
Rehm
Thomas
T
Schmuck
Carsten
C
D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011721:Pyrenes / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D012313:RNA / Q000737:chemistry* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D006146:Guanidines; D011721:Pyrenes; D011758:Pyrroles; D012313:RNA; D004247:DNA