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Synthesis and antitumour evaluation of indole-2-carboxamides against paediatric brain cancer cells
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-23 , DOI: 10.1039/d1md00065a Shahinda S R Alsayed 1 , Amreena Suri 2 , Anders W Bailey 2 , Samuel Lane 3 , Eryn L Werry 3, 4 , Chiang-Ching Huang 5 , Li-Fang Yu 6 , Michael Kassiou 3 , Simone Treiger Sredni 2, 7 , Hendra Gunosewoyo 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-23 , DOI: 10.1039/d1md00065a Shahinda S R Alsayed 1 , Amreena Suri 2 , Anders W Bailey 2 , Samuel Lane 3 , Eryn L Werry 3, 4 , Chiang-Ching Huang 5 , Li-Fang Yu 6 , Michael Kassiou 3 , Simone Treiger Sredni 2, 7 , Hendra Gunosewoyo 1
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Paediatric glioblastomas are rapidly growing, devastating brain neoplasms with an invasive phenotype. Radiotherapy and chemotherapy, which are the current therapeutic adjuvant to surgical resection, are still associated with various toxicity profiles and only marginally improve the course of the disease and life expectancy. A considerable body of evidence supports the antitumour and apoptotic effects of certain cannabinoids, such as WIN55,212-2, against a wide spectrum of cancer cells, including gliomas. In fact, we previously highlighted the potent cytotoxic activity of the cannabinoid ligand 5 against glioblastoma KNS42 cells. Taken together, in this study, we designed, synthesised, and evaluated several indoles and indole bioisosteres for their antitumour activities. Compounds 8a, 8c, 8f, 12c, and 24d demonstrated significant inhibitory activities against the viability (IC50 = 2.34–9.06 μM) and proliferation (IC50 = 2.88–9.85 μM) of paediatric glioblastoma KNS42 cells. All five compounds further retained their antitumour activities against two atypical teratoid/rhabdoid tumour (AT/RT) cell lines. When tested against a medulloblastoma DAOY cell line, only 8c, 8f, 12c, and 24d maintained their viability inhibitory activities. The viability assay against non-neoplastic human fibroblast HFF1 cells suggested that compounds 8a, 8c, 8f, and 12c act selectively towards the panel of paediatric brain tumour cells. In contrast, compound 24d and WIN55,212-2 were highly toxic toward HFF1 cells. Due to their structural resemblance to known cannabimimetics, the most potent compounds were tested in cannabinoid 1 and 2 receptor (CB1R and CB2R) functional assays. Compounds 8a, 8c, and 12c failed to activate or antagonise both CB1R and CB2R, whereas compounds 8f and 24d antagonised CB1R and CB2R, respectively. We also performed a transcriptional analysis on KNS42 cells treated with our prototype compound 8a and highlighted a set of seven genes that were significantly downregulated. The expression levels of these genes were previously shown to be positively correlated with tumour growth and progression, indicating their implication in the antitumour activity of 8a. Overall, the drug-like and selective antitumour profiles of indole-2-carboxamides 8a, 8c, 8f, and 12c substantiate the versatility of the indole scaffold in cancer drug discovery.
中文翻译：
2-吲哚甲酰胺的合成及其对小儿脑癌细胞的抗肿瘤作用评价
儿童胶质母细胞瘤生长迅速，是一种具有侵袭性表型的破坏性脑肿瘤。放疗和化疗是目前手术切除的辅助治疗方法，但仍然与各种毒性有关，并且只能略微改善病程和预期寿命。大量证据支持某些大麻素（例如 WIN55,212-2）对包括神经胶质瘤在内的多种癌细胞具有抗肿瘤和细胞凋亡作用。事实上，我们之前强调了大麻素配体5对胶质母细胞瘤 KNS42 细胞的有效细胞毒活性。综上所述，在这项研究中，我们设计、合成并评估了几种吲哚和吲哚生物等排体的抗肿瘤活性。化合物8a 、 8c 、 8f 、 12c和24d对儿童胶质母细胞瘤 KNS42 细胞的活力 (IC 50 = 2.34–9.06 μM) 和增殖 (IC 50 = 2.88–9.85 μM) 具有显着的抑制活性。所有五种化合物进一步保留了针对两种非典型畸胎瘤/横纹肌样瘤 (AT/RT) 细胞系的抗肿瘤活性。当针对髓母细胞瘤 DAOY 细胞系进行测试时，仅8c 、 8f 、 12c和24d保持其活力抑制活性。 针对非肿瘤性人成纤维细胞 HFF1 细胞的活力测定表明，化合物8a 、 8c 、 8f和12c选择性地作用于儿童脑肿瘤细胞组。相反，化合物24d和WIN55,212-2对HFF1细胞具有高毒性。由于其结构与已知的大麻模拟物相似，最有效的化合物在大麻素 1 和 2 受体（CB 1 R 和 CB 2 R）功能测定中进行了测试。化合物8a 、 8c和12c未能激活或拮抗CB 1 R和CB 2 R，而化合物8f和24d分别拮抗CB 1 R和CB 2 R。我们还对用我们的原型化合物8a处理的 KNS42 细胞进行了转录分析，并突出显示了一组显着下调的七个基因。先前显示这些基因的表达水平与肿瘤生长和进展呈正相关，表明它们与8a的抗肿瘤活性有关。总体而言，吲哚-2-甲酰胺8a 、 8c 、 8f和12c的类药物和选择性抗肿瘤特性证实了吲哚支架在癌症药物发现中的多功能性。
更新日期：2021-09-15
中文翻译：
2-吲哚甲酰胺的合成及其对小儿脑癌细胞的抗肿瘤作用评价
儿童胶质母细胞瘤生长迅速，是一种具有侵袭性表型的破坏性脑肿瘤。放疗和化疗是目前手术切除的辅助治疗方法，但仍然与各种毒性有关，并且只能略微改善病程和预期寿命。大量证据支持某些大麻素（例如 WIN55,212-2）对包括神经胶质瘤在内的多种癌细胞具有抗肿瘤和细胞凋亡作用。事实上，我们之前强调了大麻素配体5对胶质母细胞瘤 KNS42 细胞的有效细胞毒活性。综上所述，在这项研究中，我们设计、合成并评估了几种吲哚和吲哚生物等排体的抗肿瘤活性。化合物8a 、 8c 、 8f 、 12c和24d对儿童胶质母细胞瘤 KNS42 细胞的活力 (IC 50 = 2.34–9.06 μM) 和增殖 (IC 50 = 2.88–9.85 μM) 具有显着的抑制活性。所有五种化合物进一步保留了针对两种非典型畸胎瘤/横纹肌样瘤 (AT/RT) 细胞系的抗肿瘤活性。当针对髓母细胞瘤 DAOY 细胞系进行测试时，仅8c 、 8f 、 12c和24d保持其活力抑制活性。 针对非肿瘤性人成纤维细胞 HFF1 细胞的活力测定表明，化合物8a 、 8c 、 8f和12c选择性地作用于儿童脑肿瘤细胞组。相反，化合物24d和WIN55,212-2对HFF1细胞具有高毒性。由于其结构与已知的大麻模拟物相似，最有效的化合物在大麻素 1 和 2 受体（CB 1 R 和 CB 2 R）功能测定中进行了测试。化合物8a 、 8c和12c未能激活或拮抗CB 1 R和CB 2 R，而化合物8f和24d分别拮抗CB 1 R和CB 2 R。我们还对用我们的原型化合物8a处理的 KNS42 细胞进行了转录分析，并突出显示了一组显着下调的七个基因。先前显示这些基因的表达水平与肿瘤生长和进展呈正相关，表明它们与8a的抗肿瘤活性有关。总体而言，吲哚-2-甲酰胺8a 、 8c 、 8f和12c的类药物和选择性抗肿瘤特性证实了吲哚支架在癌症药物发现中的多功能性。
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