作为强效和选择性端粒酶抑制剂的三取代吖啶衍生物

Trisubstituted acridine derivatives as potent and selective telomerase inhibitors.

作者信息

Harrison R John, Cuesta Javier, Chessari Gianni, Read Martin A, Basra Sanji K, Reszka Anthony P, Morrell James, Gowan Sharon M, Incles Christopher M, Tanious Farial A, Wilson W David, Kelland Lloyd R, Neidle Stephen

机构信息

Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, U.K.

出版信息

J Med Chem. 2003 Oct 9;46(21):4463-76. doi: 10.1021/jm0308693.

DOI:10.1021/jm0308693

PMID:14521409

Abstract

The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.

摘要

本文描述了三个相关系列的合理设计的三取代吖啶衍生物的端粒酶抑制和四链体DNA结合特性的合成与评估。这些衍生物在吖啶环的2,6,9；2,7,9；和3,6,9位进行了取代。通过表面等离子体共振方法评估了几种最有效的化合物与分子内G-四链体DNA相互作用并使其稳定的能力，发现亲和力与端粒酶测定中的效力相关。通过分子建模方法模拟了许多化合物与平行四链体DNA结构的相互作用。将计算得到的相互作用能与端粒酶活性进行比较，结果表明四链体亲和力与端粒酶抑制之间通常具有一致的相关性。这些数据支持了这些化合物的作用模型，即通过稳定中间四链体结构来抑制肿瘤细胞中端粒酶对端粒DNA的延伸。