Portugal José
Departamento de Biología Molecular y Celular, Instituto de Biología Molecular de Barcelona, CSIC, Barcelona, Spain.
Curr Med Chem Anticancer Agents. 2003 Nov;3(6):411-20. doi: 10.2174/1568011033482215.
Chartreusin and elsamicin A are structurally related antibiotics that bind to GC-rich tracts in DNA, with a clear preference for B-DNA over Z-DNA. They inhibit RNA synthesis and cause single-strand scission of DNA via the formation of free radicals. Elsamicin A can also be regarded as the most potent inhibitor of topoisomerase II reported so far. It can inhibit the formation of several DNA-protein complexes. Elsamicin A binding to the P1 and P2 promoter regions of the c-myc oncogene inhibits the binding of the Sp1 transcription factor, thus inhibiting transcription. Despite the pharmacological interest in chartreusin, elsamicin A and their derivatives, there is no experimental data on the structure of their complexes with DNA. This shortcoming has been partially solved by a theoretical approach, which provided some details about the DNA-elsamicin A interaction, and the thermodynamic characterization of the binding of chartreusin and elsamicin A to DNA. Elsamicin A but not chartreusin is being developed clinically as an anti-cancer agent. IST-622 (6-O-(3-ethoxypropylonyl)-3',4'-O-exo-benzylidene-chartreusin), a novel semi-synthetic derivative of chartreusin, which has shown a promising anti-cancer activity in a phase II study, appears to be a pro-drug with a more suitable pharmacokinetic profile than chartreusin.
赭曲菌素和埃尔斯米星A是结构相关的抗生素，它们与DNA中富含鸟嘌呤-胞嘧啶的区域结合，明显更倾向于结合B-DNA而非Z-DNA。它们抑制RNA合成，并通过自由基的形成导致DNA单链断裂。埃尔斯米星A也可被视为迄今为止报道的最有效的拓扑异构酶II抑制剂。它能抑制几种DNA-蛋白质复合物的形成。埃尔斯米星A与c-myc癌基因的P1和P2启动子区域结合会抑制Sp1转录因子的结合，从而抑制转录。尽管赭曲菌素、埃尔斯米星A及其衍生物具有药理学研究价值，但尚无关于它们与DNA复合物结构的实验数据。这一缺陷已通过理论方法得到部分解决，该方法提供了一些关于DNA-埃尔斯米星A相互作用的细节，以及赭曲菌素和埃尔斯米星A与DNA结合的热力学特征。埃尔斯米星A而非赭曲菌素正在作为抗癌药物进行临床开发。IST-622（6-O-(3-乙氧基丙酰基)-3',4'-O-外亚苄基-赭曲菌素）是一种新型的赭曲菌素半合成衍生物，在一项II期研究中显示出有前景的抗癌活性，它似乎是一种前药，其药代动力学特征比赭曲菌素更合适。
