DNA alkylation by pyrrole-imidazole seco-CBI conjugates with an indole linker: sequence-specific DNA alkylation with 10-base-pair recognition through heterodimer formation.
The sequence-specific DNA alkylation by conjugates 4 and 5, which consist of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) linked with an indole linker, was investigated in the absence or presence of partner Py-Im polyamide 6. High-resolution denaturing polyacrylamide gel electrophoresis revealed that conjugate 4 alkylates DNA at the sequences 5'-(A/T)GCCTA-3' through hairpin formation, and alkylates 5'-GGAAAGAAAA-3' through an extended binding mode. However, in the presence of partner Py-Im polyamide 6, conjugate 4 alkylates DNA at a completely different sequence, 5'-AGGTTGTCCA-3'. Alkylation of 4 in the presence of 6 was effectively inhibited by a competitor 7. Surface plasmon resonance (SPR) results indicated that conjugate 4 does not bind to 5'-AGGTTGTCCA-3', whereas 6 binds tightly to this sequence. The results suggest that alkylation proceeds through heterodimer formation, indicating that this is a general way to expand the recognition sequence for DNA alkylation by Py-Im seco-CBI conjugates.
Minoshima
Masafumi
M
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
Bando
Toshikazu
T
Sasaki
Shunta
S
Shinohara
Ken-ichi
K
Shimizu
Tatsuhiko
T
Fujimoto
Jun
J
Sugiyama
Hiroshi
H
D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes; D007093:Imidazoles / Q000737:chemistry*; D007202:Indicators and Reagents; D007211:Indoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D011758:Pyrroles / Q000737:chemistry*; D012997:Solvents; D021241:Spectrometry, Mass, Electrospray Ionization; D020349:Surface Plasmon Resonance; D014966:Xanthenes
D000903:Antibiotics, Antineoplastic; D005456:Fluorescent Dyes; D007093:Imidazoles; D007202:Indicators and Reagents; D007211:Indoles; D011758:Pyrroles; D012997:Solvents; D014966:Xanthenes; C034657:Texas red; D004247:DNA