Identification of new modulator of DNA repairing pathways based on natural product (±)-peharmaline A

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI:10.1016/j.bmc.2023.117365

Akshay S. Kulkarni , Anshurekha Dash , Rahul D. Shingare , Jagdish Chand , Diksha Manhas , Aman Singh , Utpal Nandi , Anindya Goswami , D. Srinivasa Reddy

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Abstract

The complex heterogenic environment of tumour mass often leads to drug resistance and facilitate chemo insensitivity triggering more malignant phenotypes among cancer patients. Major DNA-damaging cancer drugs have been consistently proven unsuccessful in terms of elevating chemo-resistance. (±)-peharmaline A, a hybrid natural product isolated from seeds of Peganum harmala L. possesses significant cytotoxic activities. Herein, we have described the design, and synthesis of a novel library of close and simplified analogues around the anticancer natural product (±)-peharmaline A and investigated their cytotoxic activities, which led to the identification of three structurally simplified lead compounds exhibiting better potency than parent natural product. Among them, demethoxy analogue of peharmaline A was further investigated for its anticancer potential eliciting demethoxy analogue as potent DNA-damage inducing agent attenuating the expression of the proteins responsible for the DNA damage repair. Therefore, this demethoxy analogue warrants detailed investigations for the confirmations of the molecular mechanism-based studies responsible for its anticancer activity.

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基于天然产物(±)-peharmaline A的DNA修复途径新调节剂的鉴定

肿瘤团块复杂的异质环境往往导致耐药和促进化疗不敏感，从而在癌症患者中引发更多的恶性表型。主要的破坏dna的抗癌药物在提高化疗耐药性方面一直被证明是不成功的。(±)-peharmaline A(±)-peharmaline A是一种从Peganum harmala L.种子中分离得到的杂种天然产物，具有显著的细胞毒活性。在此，我们设计和合成了一个新的抗癌天然产物(±)-peharmaline a的接近和简化的类似物库，并研究了它们的细胞毒活性，从而鉴定了三个结构简化的先导化合物，其效力优于母体天然产物。其中，peharmaline A的去甲氧基类似物被进一步研究，因为它的抗癌潜力引发去甲氧基类似物作为有效的DNA损伤诱导剂，可以减弱DNA损伤修复蛋白的表达。因此,该demethoxy模拟权证详细调查确认的分子机理研究负责其抗癌活性 .______________________________________________________________________________

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.