DNA binding and alkylation by the "left half" of azinomycin B.
DNA binding and alkylation by the "left half" of azinomycin B.
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DOI：
10.1021/bi001998d
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发表时间：
2000-11
期刊：
影响因子：
2.9
通讯作者：
H. Zang;K. Gates
中科院分区：
文献类型：
--
作者：
H. Zang;K. Gates
Azinomycin B（也称为carzinophilin A）含有两个亲电官能团-环氧化物和氮丙啶残基-它们与双链体DNA中的亲核位点反应，在5 '-dGNT和5'-dGNC序列处形成交联。虽然azinomycin的氮丙啶残基无疑是交联形成所需的，但含有完整环氧基团但不含氮丙啶残基的类似物保留显著的生物活性。阿奇霉素环氧化物类似物（例如，5和6）由于其有效的生物活性和因为有证据表明azinomycin可在体内分解产生这样的化合物而受到关注。为了研究阿齐霉素环氧化物毒性的化学事件，研究了由阿齐霉素B（6、8和9）的合成类似物（包含含萘的抗生素“左半部分”）引起的DNA结合和烷基化。含环氧化物的azinomycin类似物（6）有效地烷基化双链DNA中的鸟苷残基。通过化合物与双螺旋的非共价结合促进6的DNA烷基化。紫外-可见吸收光谱、荧光光谱、DNA缠绕实验、粘度实验和平衡透析实验的结果表明，阿嗪霉素的萘基与DNA通过插层方式结合。平衡透析实验提供了非烷基化azinomycin类似物（9）与双链体DNA结合的估计结合常数为（1.3 +/- 0.3）x 10（3）M（-）（1）。阿齐霉素环氧化物6的DNA结合和烷基化性质为理解含有环氧化物残基但不含氮丙啶基团的阿齐霉素类似物的细胞毒性提供了基础，并且可以提供对阿齐霉素形成链间DNA交联的机制的深入了解。
Azinomycin B (also known as carzinophilin A) contains two electrophilic functional groups-an epoxide and an aziridine residue-that react with nucleophilic sites in duplex DNA to form cross-links at 5'-dGNT and 5'-dGNC sequences. Although the aziridine residue of azinomycin is undoubtedly required for cross-link formation, analogues containing an intact epoxide group but no aziridine residue retain significant biological activity. Azinomycin epoxide analogues (e.g., 5 and 6) are of interest due to their potent biological activity and because there is evidence that azinomycin may decompose in vivo to yield such compounds. To investigate the chemical events underlying the toxicity of azinomycin epoxides, DNA binding and alkylation by synthetic analogues of azinomycin B (6, 8, and 9) that comprise the naphthalene-containing "left half" of the antibiotic have been investigated. The epoxide-containing analogue of azinomycin (6) efficiently alkylates guanosine residues in duplex DNA. DNA alkylation by 6 is facilitated by noncovalent binding of the compound to the double helix. The results of UV-vis absorbance, fluorescence spectroscopy, DNA winding, viscometry, and equilibrium dialysis experiments indicate that the naphthalene group of azinomycin binds to DNA via intercalation. Equilibrium dialysis experiments provide an estimated binding constant of (1.3 +/- 0.3) x 10(3) M(-)(1) for the association of a nonalkylating azinomycin analogue (9) with duplex DNA. The DNA-binding and alkylating properties of the azinomycin epoxide 6 provide a basis for understanding the cytotoxicity of azinomycin analogues which contain an epoxide residue but no aziridine group and may provide insight into the mechanisms by which azinomycin forms interstrand DNA cross-links.