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Natural Product as Anti-Cancerous Therapeutic Molecules Targeted towards Topoisomerases.
Current Protein & Peptide Science ( IF 1.9 ) Pub Date : 2020-09-18 , DOI: 10.2174/1389203721666200918152511
Swati Singh 1 , Veda P Pandey 1 , Kusum Yadav 1 , Anurag Yadav 2 , U N Dwivedi 1
Affiliation  

Topoisomerases are reported to resolve the topological problem of DNA during several cellular processes such as DNA replication, transcription, recombination, and chromatin remodeling. Two types of topoisomerases (Topo I and II) accomplish their designated tasks by introducing single- or double-strand breaks within the duplex DNA molecule, and thus maintain the proper structural conditions of DNA to release the topological torsions, which is generated by unwinding of DNA to access coded information, in the course of replication, transcription, and other processes. Both the topoisomerases have been looked as crucial targets against various types of cancers such as lung, melanoma, breast, and prostate cancers. Con ceptually, targeting topoisomerases will disrupt both DNA replication and transcription, thereby leading to inhibition of cell division and consequently stopping the growth of actively dividing cancerous cells. Since the discovery of camptothecin (an alkaloid) as an inhibitor of Topo I in 1958, a number of derivatives of camptothecin were developed as potent inhibitors of Topo I. Two such derivatives of camptothecin, namely, topotecan and irinotecan, have been commonly used as US Food and Drug Administration (FDA) approved drugs against Topo I. Similarly, the first Topo II inhibitor, namely, etoposide, an analogue of podophyllotoxin, was developed in 1966 and got FDA approval as an anti-cancer drug in 1983. Subsequently, several other inhibitors of Topo II such as doxorubicin, mitoxantrone, and teniposide were developed. These drugs have been reported to cause accumulation of cytotoxic non-reversible DNA double-strand breaks (cleavable complex). Thus, the present review describes the anticancer potential of plant derived secondary metabolites belonging to alkaloids, flavonoids and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made in the field of computer aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of these potent anti-canceroustherapeutic molecules.

中文翻译:

天然产物,是针对拓扑异构酶的抗癌治疗分子。

据报道,拓扑异构酶可在几种细胞过程中解决DNA的拓扑问题,例如DNA复制,转录,重组和染色质重塑。两种拓扑异构酶(拓扑I和II)通过在双链DNA分子内引入单链或双链断裂来完成其指定的任务,从而维持DNA的适当结构条件以释放拓扑扭曲,该扭曲是由解链DNA在复制,转录和其他过程中访问编码信息。两种拓扑异构酶均已被视为抵抗各种类型癌症(例如肺癌,黑色素瘤,乳腺癌和前列腺癌)的重要靶标。从概念上讲,靶向拓扑异构酶会破坏DNA复制和转录,从而导致细胞分裂的抑制,并因此阻止了活跃分裂的癌细胞的生长。自从喜树碱(一种生物碱)作为Topo I的抑制剂于1958年被发现以来,喜树碱的许多衍生物被开发为Topo I的有效抑制剂。喜树碱的两种此类衍生物,即拓扑替康和伊立替康,通常被用作美国食品药品监督管理局(FDA)批准了针对Topo I的药物。同样,第一个Topo II抑制剂(依托泊苷,鬼臼毒素的类似物)于1966年开发,并于1983年获得FDA批准作为抗癌药。还开发了Topo II的其他几种抑制剂,例如阿霉素,米托蒽醌和替尼泊苷。据报道,这些药物会引起细胞毒性不可逆DNA双链断裂(可裂解复合物)的积累。因此,本综述描述了植物来源的次生代谢物的抗癌潜力,所述次生代谢物属于针对拓扑异构酶的生物碱,类黄酮和萜类。此外,鉴于计算机辅助药物设计领域的最新进展,本综述还讨论了使用诸如ADMET,分子对接,分子动力学模拟和QSAR等计算方法来评估和预测安全性,功效,效力的方法。和鉴定这些有效的抗癌治疗分子。针对拓扑异构酶的类黄酮和类萜。此外,鉴于计算机辅助药物设计领域的最新进展,本综述还讨论了使用诸如ADMET,分子对接,分子动力学模拟和QSAR等计算方法来评估和预测安全性,功效,效力的方法。和鉴定这些有效的抗癌治疗分子。针对拓扑异构酶的类黄酮和类萜。此外,鉴于计算机辅助药物设计领域的最新进展,本综述还讨论了使用诸如ADMET,分子对接,分子动力学模拟和QSAR等计算方法来评估和预测安全性,功效,效力的方法。和鉴定这些有效的抗癌治疗分子。
更新日期:2020-09-18
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