Molecular Design of Autitumor Autibiotic by DNA double Crosslinking.

这种能有效交联DNA的化合物被认为是一种强大的抗肿瘤药物。我们希望通过生产具有抗肿瘤活性的DNA烷基化试剂二聚体来开发一种新型的抗肿瘤药物。抗肿瘤抗生素Kapurimycin A_3(1)，^1具有与多柔比星家族密切相关的结构，^2通过环氧化物亚基对鸟嘌呤N7的攻击使DNA烷基化，形成Kapurimycin-DNA加合物，^3选择性鸟嘌呤N7烷基化反应的高效率表明，环氧化物亚基将通过芳香族部分的预共价插层作用放置在DNA的主沟中，与鸟氨酸N7适当地对齐。通过在菲结构上引入两个环氧基团，设计了卡普里霉素A3的“二聚体模型”。我们以1，5-二羟基菲和1，8-二羟基菲为起始原料合成了这类化合物，但很难得到所提出的中间体1，5-二羟基-2，6-蒽二醛和1，8-二羟基-2，7-蒽二醛。相反，简化的类似物氧甲氧基蒽被发现是有效的DNA烷基化试剂，其反应活性与卡普里霉素A3相当。我们现在正在研究这种化合物的二聚体模型。

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.