FR900482, a close cousin of mitomycin C that exploits mitosene-based DNA cross-linking.
FR900482, a close cousin of mitomycin C that exploits mitosene-based DNA cross-linking.
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FR900482，丝裂霉素 C 的近亲，利用基于丝裂霉素的 DNA 交联。
DOI：
10.1016/s1074-5521(97)90256-8
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发表时间：
1997
影响因子：
--
通讯作者：
Rollins,SB
中科院分区：
文献类型：
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作者：
Williams,RM;Rajski,SR;Rollins,SB
背景：包括FR 900482在内的抗肿瘤抗生素类与丝裂霉素具有非常接近的结构相似性，其中之一丝裂霉素C已在临床上广泛使用超过20年。与丝裂霉素C一样，这些抗肿瘤抗生素在体内被还原活化，并由于还原时产生的丝裂霉素部分的活性而共价交联DNA。由于丝裂霉素和FR 900482之间的结构差异和伴随的生物还原活化机制差异，FR 900482在还原活化期间不产生外源超氧自由基阴离子，因此不表现出DNA的氧化性断链。据推测，FR 900482相对于丝裂霉素C的低临床毒性是导致高反应性DNA交联丝裂素的生物还原活化的机制差异的直接表现。使用Fe（II）-EDTA足迹法，我们发现两种天然产物FR 900482（1）和二氢FR 66979（3），以及半合成衍生的三乙酸FK 973（2），对DNA的5′脱氧CG序列显示出显著的选择性，并且当缺失任一参与鸟苷残基的环外N2胺时，这种选择性消失。此外，我们研究了单烷基化能力的FR 66979相对于一些肌苷取代的oligonuclectides和观察到的FR 900482类化合物能够产生容易分离的方向异构体，其各自的crosslinks.Conclusions：FR 900482类抗肿瘤抗生素交联DNA的方式类似于丝裂霉素。交联反应产生两种取向的异构体，它们具有非常不同的电泳迁移率，并且在与限制性内切酶1反应时也表现出根本不同的DNA-蛋白质识别特性。此外，FR 66979对DNA的单烷基化显示出对丝裂霉素所必需的共价前相互作用的依赖性很小（如果有的话）。这些见解支持了这样的提议，即FR 900482类化合物代表了丝裂霉素C的令人信服的临床替代品，因为其大大降低了宿主毒性和上级DNA链间交联功效。
Background:The class of antitumor antibiotics that includes FR900482 has a very close structural analogy to the mitomycins, one of which, mitomycin C, has been in widespread clinical use for more than 20 years. Like mitomycin C, these antitumor antibiotics are reductively activatedin vivoand covalently cross-link DNA as a result of activity of the mitosene moiety generated on reduction. Owing to differences in structure and the attendant mechanistic differences in bioreductive activation between the mitomycins and FR900482, FR900482 does not produce an adventitious superoxide radical anion during reductive activation and thus does not exhibit oxidative strand scission of DNA. It is postulated that the low clinical toxicity of FR900482 relative to mitomycin C is a direct manifestation of the mechanistic differences of bioreductive activation leading to the highly reactive DNA cross-linking mitosenes.Results:Using Fe(II)-EDTA footprinting, we showed that the two natural products FR900482 (1) and dihydro, FR66979 (3), and the semi-synthetically derived triacetate FK973 (2), display remarkable selectivity for 5′ deoxy-CG sequences of DNA, and that this selectivity is abolished upon deletion of the exocyclic N2 amine of either participating guanosine residue. In addition, we investigated the mono alkylation abilities of FR66979 with respect to a number of inosine-substituted oligonuclectides and observed that the FR900482 class of compounds were able to give rise to easily separable orientation isomers of their respective cross-links.Conclusions:The FR900482 class of antitumor antibiotics cross-link DNA in a fashion analogous to the mitomycins. The cross-linking reaction yields two orientation, isomers which are of vastly different electrophoretic mobility and which also exhibit radically different DNA-protein recognition properties upon reaction withAlul restriction endonuclease. In addition, mono-alkylation of DNA by FR66979 shows little, if any, dependence upon pre-covalent interactions deemed necessary for the mitomycins. These insights support the proposal that the FR900482 class of compounds represents a compelling clinical replacement for mitomycin C, given its greatly reduced host toxicity and superior DNA interstrand cross-linking efficacy.