Neidle Stephen
UCL School of Pharmacy, University College London , 29-39 Brunswick Square, London WC1N 1AX, U.K.
J Med Chem. 2016 Jul 14;59(13):5987-6011. doi: 10.1021/acs.jmedchem.5b01835. Epub 2016 Feb 16.
Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be effectively resolved by helicase action. Mutated helicases in cancer cells are unable to unwind quadruplexes, which are impediments to transcription, translation, or replication, depending on their location within a particular gene. Small molecules that can stabilize quadruplex structures augment these effects and produce cell and proliferation growth inhibition. This article surveys the chemical biology of quadruplexes. It critically examines the major classes of quadruplex-binding small molecules that have been developed to date and the various approaches to discovering selective agents. The challenges of requiring (and achieving) small-molecule targeted selectivity for a particular quadruplex are discussed in relation to the potential of these small molecules as clinically useful therapeutic agents.
四链体形成序列在人类和其他基因组（包括细菌基因组）中广泛存在。这些序列在真核生物的端粒、启动子和5'非翻译区中过度富集。它们可以形成四链体结构，在正常细胞的许多情况下，这种结构可能是短暂的，因为它们可以通过解旋酶的作用有效地解开。癌细胞中发生突变的解旋酶无法解开四链体，而四链体根据其在特定基因中的位置，会对转录、翻译或复制造成阻碍。能够稳定四链体结构的小分子会增强这些影响，并抑制细胞和增殖生长。本文综述了四链体的化学生物学。它批判性地审视了迄今为止已开发的主要类别的四链体结合小分子以及发现选择性药物的各种方法。结合这些小分子作为临床有用治疗药物的潜力，讨论了针对特定四链体要求（并实现）小分子靶向选择性所面临的挑战。
