Enantioselective DNA alkylation by a pyrrole-imidazole S-CIB conjugate

被引:30
作者
Bando, T
Narita, A
Asada, K
Ayame, H
Sugiyama, H [1 ]
机构
[1] Kyoto Univ, Grad Sch Sci, Dept Chem, Kyoto 6068501, Japan
[2] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Tokyo 1010062, Japan
关键词
D O I
10.1021/ja049398f
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Conjugates 12S and 12R of N-methylpyrrole (Py)-N-methylimidazole (Im) seven-ringed hairpin polyamide with both enantiomers of 1,2,9,9a-tetrahylrocyclopropa[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-by 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.
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收藏
页码:8948 / 8955
页数:8
相关论文
共 54 条
[1]   STRUCTURE + SYNTHESIS OF DISTAMYCIN A [J].
ARCAMONE, F ;
NICOLELL.V ;
PENCO, S ;
OREZZI, P ;
PIRELLI, A .
NATURE, 1964, 203 (494) :1064-+
[2]  
Bando T, 2002, CHEM-EUR J, V8, P4781, DOI 10.1002/1521-3765(20021018)8:20<4781::AID-CHEM4781>3.0.CO
[3]  
2-J
[4]   Sequence specificity, reactivity, and antitumor activity of DNA-alkylating pyrrole-imidazole diamides [J].
Bando, T ;
Iida, H ;
Tao, ZF ;
Narita, A ;
Fukuda, N ;
Yamori, T ;
Sugiyama, H .
CHEMISTRY & BIOLOGY, 2003, 10 (08) :751-758
[5]   C-H to N substitution dramatically alters the sequence-specific DNA alkylation, cytotoxicity, and expression of human cancer cell lines [J].
Bando, T ;
Narita, A ;
Iwai, A ;
Kihara, K ;
Sugiyama, H .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (11) :3406-3407
[6]   Sequence-specific DNA interstrand cross-linking by imidazole-pyrrole CPI conjugate [J].
Bando, T ;
Iida, H ;
Saito, I ;
Sugiyama, H .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2001, 123 (21) :5158-5159
[7]   Highly efficient sequence-specific DNA interstrand cross-linking by pyrrole/imidazole CPI conjugates [J].
Bando, T ;
Narita, A ;
Saito, I ;
Sugiyama, H .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125 (12) :3471-3485
[8]   AN EFFICIENT SYNTHESIS OF 1,2,9,9A-TETRAHYDROCYCLOPROPA[C]BENZ[E]INDOL-4-ONE (CBI) - AN ENHANCED AND SIMPLIFIED ANALOG OF THE CC-1065 AND DUOCARMYCIN ALKYLATION SUBUNITS [J].
BOGER, DL ;
MCKIE, JA .
JOURNAL OF ORGANIC CHEMISTRY, 1995, 60 (05) :1271-1275
[9]   SYNTHESIS OF N-(TERT-BUTYLOXYCARBONYL)-CBI, CBI, CBI-CDPI1, AND CBI-CDPI2 - ENHANCED FUNCTIONAL ANALOGS OF CC-1065 INCORPORATING THE 1,2,9,9A-TETRAHYDROCYCLOPROPA[C]BENZ[E]INDOL-4-ONE (CBI) LEFT-HAND SUBUNIT [J].
BOGER, DL ;
ISHIZAKI, T ;
KITOS, PA ;
SUNTORNWAT, O .
JOURNAL OF ORGANIC CHEMISTRY, 1990, 55 (23) :5823-5832
[10]   CHEMICAL AND STRUCTURAL COMPARISON OF N-BOC-CBQ AND N-BOC-CBI - IDENTIFICATION AND STRUCTURAL ORIGIN OF AN UNAPPRECIATED BUT PRODUCTIVE STABILITY OF THE CC-1065 AND DUOCARMYCIN SA ALKYLATION SUBUNITS [J].
BOGER, DL ;
MESINI, P ;
TARBY, CM .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1994, 116 (14) :6461-6462