PYRROLO[1,4]BENZODIAZEPINE ANTIBIOTICS - PROPOSED STRUCTURES AND CHARACTERISTICS OF THE INVITRO DEOXYRIBONUCLEIC-ACID ADDUCTS OF ANTHRAMYCIN, TOMAYMYCIN, SIBIROMYCIN, AND NEOTHRAMYCIN-A AND NEOTHRAMYCIN-B
PYRROLO[1,4]BENZODIAZEPINE ANTIBIOTICS - PROPOSED STRUCTURES AND CHARACTERISTICS OF THE INVITRO DEOXYRIBONUCLEIC-ACID ADDUCTS OF ANTHRAMYCIN, TOMAYMYCIN, SIBIROMYCIN, AND NEOTHRAMYCIN-A AND NEOTHRAMYCIN-B
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DOI：
10.1021/bi00508a011
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发表时间：
1981-01-01
期刊：
影响因子：
2.9
通讯作者：
HURLEY, LH
中科院分区：
文献类型：
--
作者：
PETRUSEK, RL;ANDERSON, GL;HURLEY, LH
吡咯并[1,4]苯二氮卓类抗生素蒽霉素、茅霉素、西伯霉素以及新霉素 A 和 B 是有效的抗肿瘤药物，它们以独特的方式与 DNA 结合，导致一些不寻常的生物学后果。本文描述了推导药物（甲醇胺碳原子）和 DNA（鸟嘌呤的 N-2）之间的共价连接点的结果，以及各种药物-DNA 加合物的 Corey-Pauling-Koltun (CPK) 模型。测试了基于这些 CPK 模型的预测并报告了结果。这些测试的实验预测包括药物-DNA加合物对DNA变性的不稳定性、饱和结合限制、药物结合对DNA结构的影响、闭环超螺旋猿病毒40 (SV-40) DNA的解旋缺乏和体外链断裂、DNA二级结构对药物结合的敏感性、药物-DNA加合物的流体动力学性质、蒽霉素中的9-酚质子与DNA的氢键合、 DNA损伤的结构-活性关系和生物学后果，包括累积损伤和缓慢切除修复、修复能力强的细胞中DNA双链断裂以及线粒体中H链DNA合成的选择性抑制。结果完全符合假设的空间填充模型。
The pyrrolo[1,4]benzodiazepine antibiotics anthramycin, tomaymycin, sibiromycin and neothramycins A and B are potent antitumor agents that bind to DNA in a unique manner, resulting in some unusual biological consequences. This paper describes results on which the points of covalent linkage between the drugs (carbinolamine carbon atom) and DNA (N-2 of guanine) are deduced, as well as Corey-Pauling-Koltun (CPK) models for the various drug-DNA adducts. Predictions based upon these CPK models were tested and the results reported. These tested experimental predictions include instability of the drug-DNA adducts to denaturation of DNA, saturation binding limits, effect of drug binding on the structure of DNA, lack of unwinding and in vitro strand breakage of closed-ciruclar supercoiled simian virus 40 (SV-40) DNA, sensitivity of the secondary structure of DNA to drug binding, hydrodynamic properties of the drug-DNA adducts, hydrogen bonding of the 9-phenolic proton in anthramycin to DNA, structure-activity relationhsips and biological consequences of DNA damage, including cumulative damage and slow excision repair, double-strand breaks in DNA in repair-proficient cells and the selective inhibition of H-strand DNA synthesis in mitochondria. The results are completely in accord with postulated space-filling models.