Pingaew Ratchanok, Mandi Prasit, Nantasenamat Chanin, Prachayasittikul Supaluk, Ruchirawat Somsak, Prachayasittikul Virapong
Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand.
Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Eur J Med Chem. 2014 Jun 23;81:192-203. doi: 10.1016/j.ejmech.2014.05.019. Epub 2014 May 6.
A novel series of N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinolines (14-33) containing triazole moiety were designed and synthesized through rational cycloadditions using the modified Pictet-Spengler reaction and the Click chemistry. Antiproliferative activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) revealed that many substituted triazole analogs of benzoates (20, 29) and benzaldehydes (30, 32) exhibited anticancer activity against all of the tested cancer cell lines in which the ester analog 20 was shown to be the most potent compound against HuCCA-1 (IC50 = 0.63 μM) and A549 (IC50 = 0.57 μM) cell lines. Triazoles bearing phenyl (15, 24), tolyl (26, 27), acetophenone (19), benzoate (20, 29), benzaldehyde (21, 30) and naphthalenyl (25) substituents showed stronger anticancer activity against HepG2 cells than that of the etoposide. Interestingly, the p-tolyl analog (27) displayed the most potent inhibitory activity (IC50 = 0.56 μM) against HepG2 cells without affecting normal cells. Of the investigated tetrahydroisoquinoline-triazoles, the promising compounds 20 and 27 were selected for molecular docking against AKR1C3, which was identified to be a plausible target site.
通过使用改良的Pictet-Spengler反应和点击化学进行合理的环加成反应，设计并合成了一系列含三唑部分的新型N-苯磺酰基-1,2,3,4-四氢异喹啉（14 - 33）。对四种癌细胞系（如HuCCA - 1、HepG2、A549和MOLT - 3）的抗增殖活性研究表明，许多苯甲酸酯（20, 29）和苯甲醛（30, 32）的取代三唑类似物对所有测试的癌细胞系均表现出抗癌活性，其中酯类似物20被证明是对HuCCA - 1（IC50 = 0.63 μM）和A549（IC50 = 0.57 μM）细胞系最有效的化合物。带有苯基（15, 24）、甲苯基（26, 27）、苯乙酮（19）、苯甲酸酯（20, 29）、苯甲醛（21, 30）和萘基（25）取代基的三唑对HepG2细胞显示出比依托泊苷更强的抗癌活性。有趣的是，对甲苯基类似物（27）对HepG2细胞表现出最有效的抑制活性（IC50 = 0.56 μM），且不影响正常细胞。在研究的四氢异喹啉 - 三唑中选择了有前景的化合物20和27对AKR1C3进行分子对接，AKR1C3被确定为一个合理的靶点。
