MAN-DESIGNED BLEOMYCIN WITH ALTERED SEQUENCE SPECIFICITY IN DNA CLEAVAGE

被引:124
作者
OTSUKA, M
MASUDA, T
HAUPT, A
OHNO, M
SHIRAKI, T
SUGIURA, Y
MAEDA, K
机构
[1] UNIV TOKYO,FAC PHARMACEUT SCI,BUNKYO KU,TOKYO 113,JAPAN
[2] INST MICROBIAL CHEM,SHINAGAWA KU,TOKYO 141,JAPAN
[3] KYOTO UNIV,INST CHEM RES,UJI,KYOTO 611,JAPAN
关键词
D O I
10.1021/ja00158a052
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The synthetic approach to the concerted antitumor mechanism of bleomycin is studied by introducing a dynamic change into the O2-activation moiety and DNA-binding site. A model PYML(6)-bleomycin previously reported, possessing an oxygen-activating methoxypyridine moiety and a DNA-binding bithiazole moiety, exhibits a nucleotide cleavage mode virtually identical with that of bleomycin. Herein reported is a newly designed bleomycin analogue, PYML(6)-(4R-APA)-distamycin, wherein the 4-methoxypyridine moiety and a DNA-binding distamycin component are connected through an (R)-4-aminopentanoic acid linker moiety. Synthesis of PYML(6)-(4R-APA)-distamycin is carried out by condensation of the hydroxyhistidine-pentanoic acid fragment with the methoxypyridine moiety, followed by introduction of the distamycin moiety. PYML(6)-(4RAPA)-distamycin cleaves a G4 phage DNA fragment (100 base pairs) at 1 μ:mM concentration in the presence of Fe(II), oxygen, and dithiothreitol and induces dramatically altered adenine/thymine specificity. It is indicated that the specific recognition of base sequences for the cleavage is mainly controlled by the DNA affinity site and that the (R)-4-aminopentanoic acid linker seems to determine the proper arrangement of the iron-oxygen site and the distamycin moiety on DNA. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:838 / 845
页数:8
相关论文
共 37 条
[21]   SYNTHETIC COBALT BLEOMYCIN MODELS AS A PHOTOCHEMICAL DNA CLEAVER [J].
SAITO, I ;
MORII, T ;
OBAYASHI, T ;
SERA, T ;
SUGIYAMA, H ;
MATSUURA, T .
JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1989, (06) :360-362
[22]  
SAITO S, 1984, THESIS U TOKYO
[23]  
SCHNABEL E, 1967, LIEBIGS ANN CHEM, V702, P88
[24]   A RAPID SYNTHESIS OF OLIGOPEPTIDES DERIVATES WITHOUT ISOLATION OF INTERMEDIATES [J].
SHEEHAN, JC ;
PRESTON, J ;
CRUICKSHANK, PA .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1965, 87 (11) :2492-+
[25]   DIPHENYLPHOSPHORYL AZIDE - NEW CONVENIENT REAGENT FOR A MODIFIED CURTIUS REACTION AND FOR PEPTIDE SYNTHESIS [J].
SHIOIRI, T ;
YAMADA, S ;
NINOMIYA, K .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1972, 94 (17) :6203-&
[26]   SYNTHESES OF (S)-5-SUBSTITUTED 4-AMINOPENTANOIC ACIDS - NEW CLASS OF GAMMA-AMINOBUTYRIC ACID TRANSAMINASE INACTIVATORS [J].
SILVERMAN, RB ;
LEVY, MA .
JOURNAL OF ORGANIC CHEMISTRY, 1980, 45 (05) :815-818
[27]   SYNTHESIS OF A SEQUENCE-SPECIFIC DNA-CLEAVING PEPTIDE [J].
SLUKA, JP ;
HORVATH, SJ ;
BRUIST, MF ;
SIMON, MI ;
DERVAN, PB .
SCIENCE, 1987, 238 (4830) :1129-1132
[28]   MECHANISMS OF BLEOMYCIN-INDUCED DNA-DEGRADATION [J].
STUBBE, J ;
KOZARICH, JW .
CHEMICAL REVIEWS, 1987, 87 (05) :1107-1136
[29]   TRANSITION-METAL BINDING-SITE OF BLEOMYCIN - A SYNTHETIC ANALOG EQUIVALENT TO BLEOMYCIN IN ACTIVATING MOLECULAR-OXYGEN [J].
SUGANO, Y ;
KITTAKA, A ;
OTSUKA, M ;
OHNO, M ;
SUGIURA, Y ;
UMEZAWA, H .
TETRAHEDRON LETTERS, 1986, 27 (31) :3635-3638
[30]  
SUGIURA Y, 1985, MET IONS BIOL SYST, V19, P81