Chen Jhong-Min, Shepherd Micah D, Horn Jamie, Leggas Markos, Rohr Jürgen
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536-0596 (USA).
Chembiochem. 2014 Dec 15;15(18):2729-35. doi: 10.1002/cbic.201402426. Epub 2014 Nov 3.
Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure-activity relationships of the gilvocarcin group of antitumor antibiotics due to a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O-methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2'-OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important hydrogen bond donor for the interaction with histone H3, and converting 3'-OH into an OCH3 group improved the bioactivity. Bis-methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two hydrogen bond donors in the sugar are necessary for optimal binding.
多卡菌素V是多形链霉菌产生的一种聚酮类天然产物，由于其化学结构与该类抗肿瘤抗生素的主要化合物吉尔vocarcin V相似，生物活性相当，且其糖部分可被辅助O-甲基转移酶进行酶促修饰，因此被选用于研究吉尔vocarcin类抗肿瘤抗生素的构效关系。此类酶被用于改变药物与组蛋白H3的相互作用，组蛋白H3是与糖部分相互作用的生物学靶点。细胞毒性试验表明，糖部分的游离2'-OH基团对于维持多卡菌素V的生物活性至关重要，显然它是与组蛋白H3相互作用的重要氢键供体，将3'-OH转化为OCH3基团可提高生物活性。双甲基化的多卡菌素衍生物显示出比母体化合物较弱的活性，表明糖中至少有两个氢键供体对于最佳结合是必要的。
