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吲哚衍生物 2-(5-甲氧基-2-甲基-1H-吲哚-3-基)-N'-[(E)-(3-硝基苯基)亚甲基]乙二酰肼作为顺铂诱导的器官损伤有希望的化学保护剂的分子对接、药代动力学研究和体内药理学研究。

Molecular docking, pharmacokinetic studies, and in vivo pharmacological study of indole derivative 2-(5-methoxy-2-methyl-1H-indole-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene] acetohydrazide as a promising chemoprotective agent against cisplatin induced organ damage.

机构信息

Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Khyber Pakhtunkhwa, Peshawar, Pakistan.

出版信息

Sci Rep. 2021 Mar 18;11(1):6245. doi: 10.1038/s41598-021-84748-y.

DOI:10.1038/s41598-021-84748-y
PMID:33737575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7973782/
Abstract

Cisplatin is an efficient anticancer drug against various types of cancers however, its usage involves side effects. We investigated the mechanisms of action of indole derivative, 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene] acetohydrazide (MMINA) against anticancer drug (cisplatin) induced organ damage using a rodent model. MMINA treatment reversed Cisplatin-induced NO and malondialdehyde (MDA) augmentation while boosted the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD). The animals were divided into five groups (n = 7). Group1: Control (Normal) group, Group 2: DMSO group, Group 3: cisplatin group, Group 4: cisplatin + MMINA group, Group 5: MMINA group. MMINA treatment normalized plasma levels of biochemical enzymes. We observed a significant decrease in CD4COX-2, STAT3, and TNF-α cell population in whole blood after MMINA dosage. MMINA downregulated the expression of various signal transduction pathways regulating the genes involved in inflammation i.e. NF-κB, STAT-3, IL-1, COX-2, iNOS, and TNF-α. The protein expression of these regulatory factors was also downregulated in the liver, kidney, heart, and brain. In silico docking and dynamic simulations data were in agreement with the experimental findings. The physiochemical properties of MMINA predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS and inflammation.

摘要

顺铂是一种针对多种癌症的有效抗癌药物，但其使用涉及副作用。我们使用啮齿动物模型研究了吲哚衍生物 2-(5-甲氧基-2-甲基-1H-吲哚-3-基)-N'-[(E)-(3-硝基苯基)亚甲基]乙二酰肼 (MMINA) 对抗癌药物（顺铂）诱导的器官损伤的作用机制。MMINA 治疗逆转了 Cisplatin 诱导的 NO 和丙二醛 (MDA) 增加，同时提高了谷胱甘肽过氧化物酶 (GPx) 和超氧化物歧化酶 (SOD) 的活性。动物被分为五组（n=7）。第 1 组：对照（正常）组，第 2 组：DMSO 组，第 3 组：顺铂组，第 4 组：顺铂+MMINA 组，第 5 组：MMINA 组。MMINA 治疗使生化酶的血浆水平正常化。我们观察到 MMINA 剂量后全血中 CD4COX-2、STAT3 和 TNF-α 细胞群显著减少。MMINA 下调了参与炎症的各种信号转导途径调节基因的表达，即 NF-κB、STAT-3、IL-1、COX-2、iNOS 和 TNF-α。这些调节因子的蛋白表达在肝、肾、心和脑中也下调。计算机对接和动态模拟数据与实验结果一致。MMINA 的物理化学性质预测它是一种良好的类药分子，其作用机制可通过抑制 ROS 和炎症来预测。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/0965f5fd0844/41598_2021_84748_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/5c5e6f537cd4/41598_2021_84748_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/7a7bcd9efb4a/41598_2021_84748_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/93ae2486d1fe/41598_2021_84748_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/9d5486c76d9f/41598_2021_84748_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/67c624db97cc/41598_2021_84748_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/e892a3215b7e/41598_2021_84748_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/dc3ac93a53e1/41598_2021_84748_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/73b91dbc84d1/41598_2021_84748_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/696176b92aba/41598_2021_84748_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/89cffd82aa6c/41598_2021_84748_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34de/7973782/0965f5fd0844/41598_2021_84748_Fig11_HTML.jpg

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