Ali Asfa, Bhattacharya Santanu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 064, India.
Bioorg Med Chem. 2014 Aug 15;22(16):4506-21. doi: 10.1016/j.bmc.2014.05.030. Epub 2014 May 24.
Cancer has always been a dreadful disease and continues to attract extensive research investigations. Various targets have been identified to restrain cancer. Among these DNA happens to be the most explored one. A wide variety of small molecules, often referred to as 'ligands', has been synthesized to target numerous structural features of DNA. The sole purpose of such molecular design has been to interfere with the transcriptional machinery in order to drive the cancer cell toward apoptosis. The mode of action of the DNA targeting ligands focuses either on the sequence-specificity by groove binding and strand cleavage, or by identifying the morphologically distinct higher order structures like that of the G-quadruplex DNA. However, in spite of the extensive research, only a tiny fraction of the molecules have been able to reach clinical trials and only a handful are used in chemotherapy. This review attempts to record the journey of the DNA binding small molecules from its inception to cancer therapy via various modifications at the molecular level. Nevertheless, factors like limited bioavailability, severe toxicities, unfavorable pharmacokinetics etc. still prove to be the major impediments in the field which warrant considerable scope for further research investigations.
癌症一直是一种可怕的疾病，并且持续吸引着广泛的研究。人们已经确定了各种抑制癌症的靶点。其中，DNA是研究最为深入的靶点之一。人们合成了各种各样的小分子，通常称为“配体”，以靶向DNA的众多结构特征。这种分子设计的唯一目的是干扰转录机制，从而促使癌细胞走向凋亡。靶向DNA的配体的作用方式要么通过沟槽结合和链切割实现序列特异性，要么通过识别形态上不同的高阶结构（如G-四链体DNA）来发挥作用。然而，尽管进行了广泛的研究，但只有极少数分子能够进入临床试验，且只有少数几种用于化疗。本综述试图记录DNA结合小分子从其诞生到通过分子水平的各种修饰用于癌症治疗的历程。尽管如此，生物利用度有限、严重毒性、不良药代动力学等因素仍然是该领域的主要障碍，这为进一步的研究提供了相当大的空间。
