Diveshkumar K V, Sakrikar Saaz, Harikrishna S, Dhamodharan V, Pradeepkumar P I
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076 (India).
ChemMedChem. 2014 Dec;9(12):2754-65. doi: 10.1002/cmdc.201402394. Epub 2014 Oct 30.
The formation of G-quadruplex structures can regulate telomerase activity and the expression of oncogenes at the transcriptional and translational levels. Therefore, stabilization of G-quadruplex DNA structures by small molecules has been recognized as a promising strategy for anticancer drug therapy. One of the major challenges in this field is to impart stabilizing molecules with selectivity toward quadruplex structures over duplex DNAs, and to maintain specificity toward a particular quadruplex topology. Herein we report the synthesis and binding interactions of indenopyrimidine derivatives, endowed with drug-like properties, with oncogenic promoters of c-myc and c-kit, telomeric and duplex DNAs. The results show specific stabilization of promoter over telomeric quadruplexes and duplex DNAs. Molecular modeling studies support the experimental observations by unraveling the dual binding mode of ligands by exploiting the top and bottom quartets of a G-quadruplex structure. This study underscores the potential of the indenopyrimidine scaffold, which can be used to achieve specific G-quadruplex-mediated anticancer activity.
G-四链体结构的形成可在转录和翻译水平上调节端粒酶活性及癌基因的表达。因此，小分子对G-四链体DNA结构的稳定作用已被视为一种有前景的抗癌药物治疗策略。该领域的主要挑战之一是使稳定分子对四链体结构具有比对双链DNA更高的选择性，并保持对特定四链体拓扑结构的特异性。在此，我们报道了具有类药物性质的茚并嘧啶衍生物与c-myc和c-kit的致癌启动子、端粒DNA及双链DNA的合成及结合相互作用。结果表明，该衍生物对启动子四链体的稳定作用比对端粒四链体和双链DNA更具特异性。分子模拟研究通过利用G-四链体结构的顶部和底部四重链揭示配体的双重结合模式，从而支持了实验观察结果。本研究强调了茚并嘧啶支架的潜力，其可用于实现特定的G-四链体介导的抗癌活性。
