Molecular Design of Autitumor Autibiotic by DNA double Crosslinking.

通过 DNA 双交联进行自肿瘤自生素的分子设计。

• 批准号: 08555228
• 负责人: SAITO Isao
• 金额: $ 6.59万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08555228/
• 关键词: Kapurmycin A3; DNA alkylation; guanine N7; epoxide; cross-linking; DNA; 抗腫瘍性抗生物質; オキシラニルメトキシアントランセン; メ-ジャーグループ

The compound which effectively crosslink DNA is know to be a strong antitumor agent. We have envisioned to develop a novel antitumor agent by means of producing dimer of DNA alkylation agent showing antitumor activity. Antitumor antibiotic kapurimycin A_3 (1), ^1 having a structure closely related to pluramycin family, ^2 alkylates DNA by the attack of the epoxide subunit on the aguanine N7 to result in a formation of kapurimycin-DNA adduct, ^3 The high efficiency for the selective guanine N7 alkylation indicated that the epoxide subunit would be placed in the major groove of DNA with an appropriate alignment to the guanine N7 through a precovalent intercalation of the aromatic moiety. We have designed a "dimeric model" of kapurimycin A3 by means of introducing two epoxide moiety on anthracene structure. We have investigated synthesis of such compounds starting from 1,5-dihydroxyanthracene and 1,8-dihydroxyanthracene, but it turned out to be difficult to obtain proposed intermediate 1,5-dihydroxy-2,6-anthracenedialdehyde and 1,8-dihydroxy-2,7-anthracenedialdehyde. In contrast, simplified analog oxyranylmethoxyanthracene was found to be effective DNA alkylating agent with comparable reactivity with kapurimycin A3. We are now investigate a dimeric model of this compound.

已知有效交联 DNA 的化合物是一种强效抗肿瘤剂。我们设想通过生产具有抗肿瘤活性的DNA烷基化剂二聚体来开发一种新型抗肿瘤剂。抗肿瘤抗生素卡普利霉素 A_3 (1), ^1 具有与多霉素家族密切相关的结构, ^2 通过鸟嘌呤 N7 上的环氧化物亚基的攻击使 DNA 烷基化, 形成卡普利霉素-DNA 加合物, ^3 选择性鸟嘌呤 N7 烷基化的高效率表明环氧化物亚基将被置于 DNA 的主沟通过芳香族部分的预共价插入与鸟嘌呤 N7 适当对齐。我们通过在蒽结构上引入两个环氧化物部分，设计了卡普霉素A3的“二聚模型”。我们研究了从1,5-二羟基蒽和1,8-二羟基蒽开始合成此类化合物，但结果很难获得所提出的中间体1,5-二羟基-2,6-蒽二醛和1,8-二羟基-2,7-蒽二醛。相比之下，简化的类似物氧基甲氧基蒽被发现是有效的 DNA 烷化剂，其反应活性与卡普霉素 A3 相当。我们现在正在研究该化合物的二聚体模型。

项目成果

斎藤 烈: "CASSCF,MP2,and CASMP2 studies on Addition Reaction of Singlet Molecular Oxygen to Ethylene Molecule" Int.Journal of Quantum Chem.65. 787-801 (1997)

Retsu Saito：“单线态分子氧与乙烯分子的加成反应的 CASSCF、MP2 和 CASMP2 研究”Int.Journal of Quantum Chem.65 (1997)。

齋藤 烈: "Design of Photochemical DNA-Cleaving Molecules via Electron Transfer." Potochem.Photobiol.A.Chemistry. 106. 141-144 (1997)

Retsu Saito：“通过电子转移设计光化学 DNA 切割分子。”Potochem.Photobiol.A.Chemistry 106. 141-144 (1997)

"Design of Photochemical DNA-Cleaving Molecules via Electron Transfer" Photochem.Photobiol.A.Chemistry. 106. 141-144 (1997)

“通过电子转移设计光化学 DNA 切割分子”Photochem.Photobiol.A.Chemistry。

齋藤,烈: "Theoretical Studies of GG-Specific Photocleavage of DNA via Electron Transfer" J.Am.Chem.Soc.118. 7063-7068 (1996)

Retsu Saito：“通过电子转移对 DNA 进行 GG 特异性光裂解的理论研究”J.Am.Chem.Soc.118 (1996)。

斎藤 烈: "Structure of Cobalt(III)-Pepleomycin and Cobalt(III)-Degycopopleomg con (Green fanus) determined by NMR studies." Eur.J.Biochem.244. 818-828 (1997)

Retsu Saito：“通过 NMR 研究确定钴 (III)-Pepleomycin 和 Cobalt (III)-Degycopopleomg con (Green fanus) 的结构。”Eur.J.Biochem.244 (1997)。