BINDING OF METALLOBLEOMYCIN TO SYNTHETIC DNA

金属博莱霉素与合成 DNA 的结合

• 批准号: 6279869
• 负责人: DAVID H PETERING
• 金额: $ 0.54万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6279869
• 关键词: bioengineering /biomedical engineering; biological products; biomedical resource; proteins

Among the agents used to treat human cancer, at least three require metals for their activity, i.e., cis-diamminedichloro Pt(II), bleomycin (Blm), and adriamycin. Of the three, Blm has the most elaborate structure and most complicated chemistry. Blm causes double-strand scission in cells and, because double-strand scission is correlated with inhibition of cell proliferation and is poorly repaired, this type of DNA damage is likely to be responsible for anticancer properties of this compound. In 1997, a new project with graduate student C. Xia was initiated. ESR spectra over time for O2 Co(II) Blm bound to 10-mers with a specific GC binding site or a nonspecific AT binding site were obtained to determine the viability of the O2 Co(II) Blm-DNA adduct for NMR studies. It was found that the half-like for the conversion of O2 Co(II) Blm to H O2 Co(III) Blm is days under our conditions. This reaction corresponded with a change from fast-exchanage data to slow-exchange data from the NMR studies. A second EPR study with graduate student Chunwu Xia was completed to follow the time course of the cyanide adduct of Fe(III) Blm, NC-Fe(III) Blm, upon addition of 10-mers with specific and nonspecific binding sites for FeBlm. Cyanide was slowly released upon binding drug to the 10-mer with the specific, GC, binding site as determined by formation of the low-spin ESR signal for Fe(III) Blm bound toDNA. The low-spin signal did not form over time upon addition of the nonspecific, AT, 10-mer to NC-Fe(III) Blm. Since Fe(III) Blm bound to DNA can bind nitric oxide, carbon monoxide, and hydrogen peroxide, it is not clear why cyanide is released upon binding of the specific, GC, 10-mer.

在用于治疗人类癌症的药物中，至少有三种 它们的活性需要金属，即顺式二氨基二氯铂(II)， 博莱霉素(BLM)和阿霉素。在这三家公司中，BLM拥有最多 精细的结构和最复杂的化学。博莱姆引起的 细胞中的双链断裂，因为双链断裂是 与细胞增殖抑制相关，且表现不佳 修复后，这种类型的DNA损伤很可能是 该化合物的抗癌性能。1997年，一个新的项目， 研究生夏志强是启蒙的。O2随时间变化的ESR谱 与10-MERS结合的具有特定GC结合位点或 获得非特异的AT结合位点以确定其活性 O2Co(II)BLm-DNA加合物用于核磁共振研究。结果发现， O2-Co(II)BLm转化为H-O2-Co(III)BLm的半相似反应 在我们的条件下是几天。这种反应相当于一种 从快速交换数据到核磁共振慢交换数据的转变 学习。对研究生夏春武的第二次EPR研究是 完成跟踪Fe(III)的氰化物加合物的时间过程 BLm，NC-Fe(III)BLm，在添加具有特定和 FeBlm的非特异性结合位点。氰化物被缓慢释放到 将药物结合到具有特定GC结合部位的10-聚体 由Fe(III)BLM的低自旋ESR信号的形成所确定 与DNA结合。低自旋信号不是在相加时随时间而形成的 非特异性的AT，10-聚体对NC-Fe(III)BLm。由于Fe(III)BLm 与DNA结合可以结合一氧化氮、一氧化碳和氢气 过氧化氢，尚不清楚为什么氰化物在结合时被释放 特异性，GC，10-聚体。