Perry P J, Read M A, Davies R T, Gowan S M, Reszka A P, Wood A A, Kelland L R, Neidle S
Cancer Research Campaign Biomolecular Structure Unit and Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, U.K.
J Med Chem. 1999 Jul 15;42(14):2679-84. doi: 10.1021/jm990084q.
Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthesis and biological evaluation of a series of analogous fluorenone-based compounds with the specific aims of, first, determining if the anthraquinone chromophore is a prerequisite for activity and, second, whether the conventional cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad range of telomerase inhibitory activity, with the most potent inhibitors displaying levels of activity (8-12 microM) comparable with other classes of G-quadruplex-interactive agents. Comparisons with analogous anthraquinone-based compounds reveal a general reduction in the level of cellular cytotoxicity. Molecular modeling techniques have been used to compare the interaction of fluorenone- and analogous anthraquinone-based inhibitors with a human G-quadruplex structure and to rationalize their observed biological activities.
端粒酶是新型抗癌药物合理设计的一个主要新靶点。我们之前已鉴定出基于蒽醌的分子，它们能够通过稳定由端粒DNA折叠形成的G-四链体结构来抑制端粒酶。在本研究中，我们描述了一系列类似的基于芴酮的化合物的合成及生物学评价，其具体目的一是确定蒽醌发色团是否是活性的先决条件，二是基于蒽醌的分子固有的传统细胞毒性是否可通过合理设计来降低。该芴酮系列化合物表现出广泛的端粒酶抑制活性，最有效的抑制剂显示出的活性水平（8 - 12微摩尔）与其他类G-四链体相互作用剂相当。与类似的基于蒽醌的化合物比较发现细胞毒性水平普遍降低。分子建模技术已用于比较芴酮和类似的基于蒽醌的抑制剂与人类G-四链体结构的相互作用，并对观察到的生物学活性作出合理解释。
