PYRROLO[1,4]BENZODIAZEPINE ANTITUMOR ANTIBIOTICS - EVIDENCE FOR 2 FORMS OF TOMAYMYCIN BOUND TO DNA
PYRROLO[1,4]BENZODIAZEPINE ANTITUMOR ANTIBIOTICS - EVIDENCE FOR 2 FORMS OF TOMAYMYCIN BOUND TO DNA
复制标题
DOI：
10.1021/bi00358a043
复制
发表时间：
1986-05-20
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：
BARKLEY, MD;CHEATHAM, S;HURLEY, LH
托马霉素是一种抗肿瘤化合物，属于吡咯并[1，4]苯并二氮杂类抗生素。先前的研究表明，托马霉素和该组的其他成员，包括安曲霉素、西比罗霉素和新红霉素，通过鸟嘌呤的N-2共价结合，并位于DNA的小沟内。在质子溶剂中和DNA上观察到两种荧光基态种的tomaymycin。~ 1H NMR研究表明，甲醇中的两个荧光物种为11 R，11 aS和11 S，11 aS非对映体的11-甲基醚。根据差向异构化实验和13CH_3OH中的碳-13交换到托马霉素甲醚的C-11甲氧基中，提出了它们通过10，11-脱水托马霉素相互转化的机理。耦合信息显示，这两种非对映异构体的溶液构象不同，与C-5羰基躺在更接近的11 R，11 aS非对映异构体中的芳环的平面。在甲醇中的两个发射物种的荧光激发和发射光谱分离的时间分辨荧光光谱，并与1H NMR确定的非对映体形式。在质子溶剂和DNA上的时间分辨荧光研究表明，较长寿命组分（11 R，11 aS形式）的吸收光谱相对于较短寿命组分（11 S，11 aS形式）的吸收光谱发生红移，与更广泛的共轭一致。初步确定了托麦霉素在DNA上的两种构象形式为11 S，11 aS和11 R，11 aS非对映体加合物，它们在小沟中以相反的方向结合。这一建议是支持的分子建模研究，使用6聚体的双链加合物的d（ATGCAT）2。
Tomaymycin is an antibiotic belonging to the pyrrolol[1,4]benzodiazepine groupof antitumor compounds. Previous studies have shown that tomaymycin and other members of this group, which include anthramycin, sibiromycin, and the neothramycins, binds covalently through N-2 of guanine and lie within the minor groove of DNA. Two fluorescent ground-state species of tomaymycin were observed in protic solvents and on DNA. 1H NMR studies showed that the two fluorescent species in methanol are the 11R,11aS and 11S,11aS diastereomeric 11-methyl ethers of tomaymycin. On the basis of epimerization experiments and exchange of carbon-13 from 13CH3OH into the C-11 methoxy group of the tomaymycin methyl ether, a mechanism is proposed for their interconversion via 10,11-anhydrotomaymycin. Coupling information revealed that the solution conformations of the two diastereomers differ, with the C-5 carbonyl lying closer to the plane of the aromatic ring in the 11R,11aS diastereomer. The fluorescence excitation and emission spectra of the two emitting species in methanol were separated by time-resolved fluorescence spectroscopy and were associated with the diastereomeric forms identified by 1H NMR. Time-resolved fluorescence studies of tomaymycin in protic solvents and on DNA indicated thatthe absorption spectrum of the longer lifetime component (11R,11aS form) is red-shifted relative to the absorption spectrum of the shorter lifetime component (11S,11aS form), consistent with more extensive conjugation. The two conformational formsof tomaymycin on DNA were tentatively identified as the 11S,11aS and 11R,11aS diastereomeric adducts, which bind in opposite orientation in the minor groove. This proposal is supported by molecular modeling studies using a 6-mer duplex adduct of d(ATGCAT)2.