Enantioselective DNA alkylation by a pyrrole-imidazole S-CBI conjugate.
Conjugates 12S and 12R of N-methylpyrrole (Py)-N-methylimidazole (Im) seven-ringed hairpin polyamide with both enantiomers of 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) were synthesized, and their DNA alkylating activity was examined. High-resolution denaturing gel electrophoresis revealed that 12S selectively and efficiently alkylated at one match sequence, 5'-TGACCA-3', in 450-bp DNA fragments. The selectivity and efficiency of the DNA alkylation by 12S were higher than those of the corresponding cyclopropapyrroloindole (CPI) conjugate, 11. In sharp contrast, another enantiomer, 12R, showed very weak DNA alkylating activity. Product analysis of the synthetic decanucleotide confirmed that the alkylating activity of 12S was comparable with 11 and that 12S had a significantly higher reactivity than 12R. The enantioselective reactivity of 12S and 12R is assumed to be due to the location of the alkylating cyclopropane ring of the CBI unit in the minor groove of the DNA duplex. Since the CBI unit can be synthesized from commercially available 1,3-naphthalenediol, the present results open up the possibility of large-scale synthesis of alkylating Py-Im polyamides for facilitating their use in future animal studies.
Bando
Toshikazu
T
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Narita
Akihiko
A
Asada
Ken
K
Ayame
Hirohito
H
Sugiyama
Hiroshi
H
D000478:Alkylation; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D003521:Cyclopropanes; D007093:Imidazoles; D007211:Indoles; D009841:Oligonucleotides; D011758:Pyrroles; D004247:DNA; C096654:N-methylpyrrole; C018100:1-methylimidazole