Molecular Design of Nobel DNA Alkylating Agent at GG step

Nobel DNA 烷基化剂 GG 步骤的分子设计

• 批准号: 11680588
• 负责人: NAKATANI Kazuhiko
• 金额: $ 2.3万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680588/
• 关键词: Guamine; Alkylation; Homo; GG配列; HOMO; DNA; インターカレーション; GG; 配列選択性; エポキシド

We have synthesized naphthopyranone epoxide from D-isoascorbic acid together with its three diastereoisomers. DNA alkylation of ODNs containing 5'XGT3' and 5'TGY3' by (11R, 13R)-epoxide, where X and Y are any nucleotide bases, occurred at all G residues except at G of 5'TGC3' sequence. In contrast, other three diastereoisomers showed only weak G alkylation activity. Differential ^1H NMR NOE of drug-G adduct confirmed the G-N7 alkylation at the epoxide carbon with concomitant S_N2 ring opening of the epoxide. Quantitative HPLC analysis of G alkylation efficiency by showed the order of G alkylation susceptibility as TGGT 【approximately equal】 CGT >> TGA > AGT > TGT >> TGC.The order was fully consistent with those reported for aflatoxin B_1 oxide and kapurimycin A_3, suggesting that the sequence selectivity observed for these DNA alkylating agents is not structure dependent but most likely due to the intrinsic property of DNA sequences. We found that the order of G alkylation susceptibility obtained completely matched with the calculated HOMO energy level of G-containing sequences. These results underscore that our drug is a unique molecular probe for ranking HOMO level of G-containing sequences by well-known G alkylation chemistry and suggests that the intercalation of charge neutral intercalators is a HOMO-controlled process.

我们从 D-异抗坏血酸及其三种非对映异构体合成了萘并吡喃酮环氧化物，其中包含 5'XGT3' 和 5'TGY3' 的 ODN 被 (11R, 13R)-环氧化物（其中 X 和 Y 是任何核苷酸碱基）烷基化。除 5'TGC3' 序列的 G 之外的所有 G 残基相反，其他三种非对映异构体仅显示弱 G。药物-G 加合物的微分 ^1H NMR NOE 证实了环氧化物碳上的 G-N7 烷基化以及环氧化物的 S_N2 开环，通过显示 G 烷基化敏感性的顺序为 TGGT。大致相等】 CGT >> TGA > AGT > TGT >> TGC。顺序与报道的完全一致黄曲霉毒素 B_1 氧化物和卡普霉素 A_3，表明观察到的这些 DNA 烷基化剂的序列选择性不依赖于结构，而很可能是由于 DNA 序列的内在特性，我们发现获得的 G 烷基化敏感性顺序与计算的 HOMO 完全匹配。这些结果强调了我们的药物是一种独特的分子探针，可通过众所周知的 G 烷基化化学对含 G 序列的 HOMO 水平进行排序。电荷中性嵌入剂的嵌入是 HOMO 控制的过程。