1. Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production.
- Author
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Youssif BGM, Abdelrahman MH, Abdelazeem AH, Abdelgawad MA, Ibrahim HM, Salem OIA, Mohamed MFA, Treambleau L, and Bukhari SNA
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antioxidants chemical synthesis, Antioxidants chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Humans, Indoles chemical synthesis, Indoles chemistry, Male, Mice, Models, Molecular, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Polymerization drug effects, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Pyrazines chemical synthesis, Pyrazines chemistry, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Structure-Activity Relationship, Tubulin metabolism, Antineoplastic Agents pharmacology, Antioxidants pharmacology, Drug Design, Indoles pharmacology, Pyrazines pharmacology, Reactive Oxygen Species metabolism, Small Molecule Libraries pharmacology
- Abstract
A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a-g) and their reaction intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS generation during the metabolic phase of phagocytosis in a dose-dependent manner where compounds 5d and 5e were the most potent samples with higher inhibitory activities (IC
50 values 3.3 and 1.4 μM, respectively) than that of the reference acetylsalicylic acid (IC50 = 9.7 μM). Results for the determination of potential antioxidant properties of the synthesized compounds showed that compounds 5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even comparable to Trolox. Compounds 3d-f and 5d-f with the least IC50 values in MTT assay were tested against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical study were performed to determine the consequence of exposure to chronic low dose of chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by co-treatment with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies were performed to explore the binding mode of the most active compounds against EGFR and BRAF kinases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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