Antitumor Activity, X-ray Crystal Structure, and DNA Binding Properties of Thiocoraline A, a Natural Bisintercalating Thiodepsipeptide
详细信息 查看全文
- 作者：Ana Negri ; Esther Marco ; Veró ; nica Garcí ; a-Herná ; ndez ; Alberto Domingo ; Antonio L. Llamas-Saiz ; Silvia Porto-Sandá ; Ricardo Riguera ; William Laine ; Marie-Hé ; lè ; ne
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：July 12, 2007
- 年：2007
- 卷：50
- 期：14
- 页码：3322 - 3333
- 全文大小：550K
- 年卷期：v.50,no.14(July 12, 2007)
- ISSN：1520-4804
文摘
The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolarconcentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystalsof this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendenthydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the twochromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding toDNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNaseI footprinting experiments and determination of the melting temperatures of several custom-designedfluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when modelsof thiocoraline clamping a central step embedded in several octanucleotides were built and studied by meansof unrestrained molecular dynamics simulations in aqueous solution.