Goldberg I H, Kappen L S, Povirk L F, Chin D H
Drugs Exp Clin Res. 1986;12(6-7):495-505.
Neocarzinostatin (NCS) belongs to a family of antitumour protein antibiotics that selectively inhibit DNA synthesis. Replicon initiation in mammalian cells is selectively inhibited by NCS, and cells defective in DNA repair, such as ataxia telangiectasia fibroblasts, are especially sensitive to NCS as they are to X-ray. The holoantibiotic consists of a nonprotein chromophore (Mr = 659), tightly and specifically bound to an apoprotein (Mr = 10,700). The apoprotein protects the highly labile chromophore from degradation in aqueous solution; all the activity resides in the nonprotein chromophore. The latter binds specifically to DNA, especially to regions rich in T and A residues, with a tight binding site consisting of four base pairs. NCS chromophore consists of three main structural subunits: a naphthoic acid derivative, an amino-sugar and a connecting highly unsaturated middle component (C12H5) with a strained ether (probably epoxide) and cyclic carbonate. The authors have proposed that the naphthoic acid subunit intercalates DNA and the positively charged amino sugar binds electrostatically to the negatively charged sugar phosphate backbone of DNA; these two anchors serve to juxtapose the middle piece with the deoxyribose of mainly thymidylate residues in DNA. Upon activation of the drug by a thiol (which forms an adduct with the middle piece) and in the presence of O2, there is a selective oxidation of the 5'-C of deoxyribose to produce a DNA strand break with a phosphate at the 3'-end and a nucleoside 5'-aldehyde at the other. Kinetic analysis shows that one molecule of thiol adds to DNA-bound NCS chromophore even in the absence of oxygen; this is rapidly followed by the consumption of 1 mol of O2 and then another mol of thiol. The oxygen of the 5'-aldehyde is derived from O2, not H2O. Even in the absence of O2 the NCS chromophore abstracts a hydrogen from C-5' of deoxyribose in DNA, presumably generating a carbon-centred radical intermediate in the DNA (other mechanisms have not been eliminated) which can add O2 to form a peroxy derivative. The second molecule of thiol may be involved in the cleavage of this complex to form the 5'-aldehyde at the strand break. There is no evidence for the involvement of metals or a diffusible form of reduced oxygen.(ABSTRACT TRUNCATED AT 400 WORDS)
新制癌菌素（NCS）属于一类选择性抑制DNA合成的抗肿瘤蛋白抗生素。NCS可选择性抑制哺乳动物细胞中的复制子起始，而DNA修复缺陷的细胞，如共济失调毛细血管扩张症成纤维细胞，对NCS特别敏感，就像它们对X射线敏感一样。全抗生素由一个非蛋白质发色团（Mr = 659）组成，紧密且特异性地结合到一个脱辅基蛋白（Mr = 10,700）上。脱辅基蛋白保护高度不稳定的发色团在水溶液中不被降解；所有活性都存在于非蛋白质发色团中。后者特异性地结合到DNA上，尤其是富含T和A残基的区域，其紧密结合位点由四个碱基对组成。NCS发色团由三个主要结构亚基组成：一个萘酸衍生物、一个氨基糖和一个连接高度不饱和中间成分（C12H5），带有一个应变醚（可能是环氧化物）和环状碳酸酯。作者提出萘酸亚基插入DNA，带正电荷的氨基糖与DNA带负电荷的磷酸糖主链静电结合；这两个锚定物用于将中间片段与DNA中主要是胸苷酸残基的脱氧核糖并列。在硫醇（与中间片段形成加合物）激活药物并在有O2存在的情况下，脱氧核糖的5'-C会发生选择性氧化，产生一个DNA链断裂，3'-端有一个磷酸基团，另一端有一个核苷5'-醛。动力学分析表明，即使在没有氧气的情况下，一分子硫醇也会添加到与DNA结合的NCS发色团上；随后迅速消耗1摩尔O2，然后再消耗1摩尔硫醇。5'-醛的氧来自O2，而非H2O。即使在没有O2的情况下，NCS发色团也会从DNA中脱氧核糖的C-5'上夺取一个氢，大概在DNA中产生一个以碳为中心的自由基中间体（其他机制尚未排除），该中间体可以添加O2形成过氧衍生物。第二个硫醇分子可能参与该复合物的裂解，在链断裂处形成5'-醛。没有证据表明金属或可扩散形式的还原氧参与其中。（摘要截短至400字）
