Singh Arshdeep, Kaur Navdeep, Singh Gurpreet, Sharma Pooja, Bedi Pms, Sharma Sahil, Nepali Kunal
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India.
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
Recent Pat Anticancer Drug Discov. 2016;11(4):401-423. doi: 10.2174/0929866523666160720095940.
Topoisomerases are a set of nuclear enzymes that play a vital role in handling of topological consequences of DNA during various genetic activities necessary for vitality of cell. Inhibition of these enzymes consequently leads to the blockage of ligation step of the cell cycle which generates single and double strand breakage in DNA strand. Introduction of these breaks subsequently leads to programmed cell death (Apoptosis).
In the past several years, topoisomerases have become one of the most expedient and strategic molecular targets for anticancer drugs and numerous patents have been filed and published on topoisomerase inhibitors. This review compiles the patent literature up to 2016 embracing topo I and II inhibitors as well as dual inhibitors which are structurally adjacent to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. The present assemblage can be extremely advantageous for the medicinal chemists who are in crave for the development of potential anticancer agents targeting topoisomerases.
Recent patents indicated that some of the nitrogen containing heteroaromatic compounds have immense potential to inhibit topoisomerase enzyme. In particular, fused N-Heterocycles can be anticipated for their promising therapeutic potential alone or in combination with other anticancer agents. Naphthyridinone and indenoisoquinoline derivatives, described in the preceding sections of this review, are endowed with significant potency against topoisomerase I which clearly indicates the need of preclinical and clinical studies to place them in forefront as potential future drug candidates.
拓扑异构酶是一组核酶，在细胞活力所必需的各种基因活动过程中，对于处理DNA的拓扑结构后果起着至关重要的作用。抑制这些酶会导致细胞周期连接步骤的阻断，从而在DNA链中产生单链和双链断裂。这些断裂的产生随后导致程序性细胞死亡（凋亡）。
在过去几年中，拓扑异构酶已成为抗癌药物最便捷且具战略意义的分子靶点之一，并且已提交和发表了许多关于拓扑异构酶抑制剂的专利。本综述汇编了截至2016年的专利文献，涵盖拓扑异构酶I和II抑制剂以及双重抑制剂，这些抑制剂在结构上与喜树碱（CPT）相邻、包括诸如片螺素之类的天然产物以及合成的三取代吡啶。对于渴望开发靶向拓扑异构酶的潜在抗癌药物的药物化学家而言，目前的汇编可能极具优势。
近期的专利表明，一些含氮杂环化合物具有极大的抑制拓扑异构酶的潜力。特别是，稠合N-杂环无论是单独使用还是与其他抗癌药物联合使用，都有望展现出其有前景的治疗潜力。在本综述前文部分所描述的萘啶酮和茚并异喹啉衍生物，对拓扑异构酶I具有显著的活性，这清楚地表明需要进行临床前和临床研究，以便将它们作为潜在的未来药物候选物置于前沿位置。
