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Abstract：
Lung cancer (LC) ranks second most prevalent cancer in females after breast cancer and second in males after prostate cancer. Based on the GLOBOCAN 2020 report, India represented 5.9% of LC cases and 8.1% of deaths caused by the disease. Several clinical studies have shown that LC occurs because of biological and morphological abnormalities and the involvement of altered level of antioxidants, cytokines, and apoptotic markers. In the present study, we explored the antiproliferative activity of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues against LC using in-vitro, in-silico, and in-vivo models. In-vitro screening against A549 cells revealed compounds 9B (8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) and 12B (5-(4-chlorophenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) as potential pyrimidine analogues against LC. Compounds 9B and 12B were docked with different molecular targets IL-6, Cyt-C, Caspase9, and Caspase3 using AutoDock Vina 4.1 to evaluate the binding affinity. Subsequently, in-vivo studies were conducted in albino Wistar rats through ethyl-carbamate (EC)- induced LC. 9B and 12B imparted significant effects on physiological (weight variation), and biochemical (anti-oxidant [TBAR\'s, SOD, ProC, and GSH), lipid (TC, TG, LDL, VLDL, and HDL)], and cytokine (IL-2, IL-6, IL-10, and IL-1β) markers in EC-induced LC in albino Wistar rats. Morphological examination (SEM and H&E) and western blotting (IL-6, STAT3, Cyt-C, BAX, Bcl-2, Caspase3, and caspase9) showed that compounds 9B and 12B had antiproliferative effects. Accordingly, from the in-vitro, in-silico, and in-vivo experimental findings, we concluded that 9B and 12B have significant antiproliferative potential and are potential candidates for further evaluation to meet the requirements of investigation of new drug application.
摘要：
肺癌（LC）在女性中排名第二，仅次于乳腺癌，在男性中排名第二。根据GLOBOCAN2020报告，印度占LC病例的5.9％和由该疾病引起的死亡的8.1％。一些临床研究表明，LC的发生是由于生物学和形态学异常以及抗氧化剂水平改变的参与，细胞因子,和凋亡标志物。在本研究中,我们探索了茚并[1,2-d]噻唑并[3,2-a]嘧啶类似物在体外对LC的抗增殖活性，在硅，和体内模型。针对A549细胞的体外筛选揭示了化合物9B(8-甲氧基-5-(3,4,5-三甲氧基苯基)-5,6-二氢茚并[1,2-d]噻唑并[3,2-a]嘧啶)和12B(5-(4-氯苯基)-5,6-二氢茚并[1,2-d]噻唑并[3,2-a]嘧啶类似物)作为潜在的LC化合物9B和12B与不同的分子靶标IL-6，Cyt-C，使用AutoDockVina4.1评估结合亲和力的Caspase9和Caspase3。随后，通过氨基甲酸乙酯（EC）诱导的LC在白化病Wistar大鼠中进行体内研究。图9B和12B对生理(体重变化)产生显著影响，和生物化学(抗氧化剂[TBAR，SOD,ProC,和GSH），脂质（TC，TG,LDL,VLDL,andHDL)],和细胞因子（IL-2，IL-6，IL-10和IL-1β）标志物在白化Wistar大鼠EC诱导的LC中。形态学检查（SEM和H&E）和蛋白质印迹（IL-6，STAT3，Cyt-C，巴克斯，Bcl-2，Caspase3和caspase9）表明化合物9B和12B具有抗增殖作用。因此，从体外，在硅，和体内实验结果，我们的结论是,9B和12B具有显著的抗增殖潜力,是进一步评估的潜在候选药物,以满足新药申请的研究要求.
