新型含苯并噁/噻唑啉酮环的噁二唑和咪唑并噻二唑衍生物的合成、表征及生物活性研究
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摘要
1.以邻氨基苯酚(硫酚)和尿素为起始原料,经一系列反应,合成出了30个新型含苯并噁/噻唑啉酮环的2,5-二取代-1,3,4-噁二唑衍生物(TM-I-6a~6o')和18个新型的含苯并噁/噻唑啉酮环的2,6-二取代-咪唑[2,1-b]-1,3,4-噻二唑衍生物(TM-II-5a~5i')。此外,还合成了4个新的中间体,即5-(苯并噁/噻唑啉酮-3-亚甲基)-2-巯基-1,3,4-噁二唑和2-氨基-5-(苯并噁/噻唑啉酮-3-甲基)-1,3,4-噻二唑。利用IR、1D NMR、2D NMR及元素分析确定了中间体及目标产物的结构。
2.对所合成的两类新目标化合物进行了抗癌、抗炎、抗病毒活性测试。对目标化合物TM-I-6a~6o'的测试结果表明:部分目标化合物对SHP1具有弱的抑制活性,其中TM-I-6o在浓度为20μg/mL时,抑制率最高,为36.51±1.67 %,这说明此类目标化合物具有弱的抑制前列腺癌的活性;大部分目标化合物对肝癌、肺癌和肠癌均具有弱的抑制活性,但对肝癌和肺癌的抑制活性较肠癌好,其中TM-I-6o对肝癌的抑制率最高,为21.65 %,TM-I-6o'对肺癌的抑制率最高,为33.06 %,TM-I-6d对肠癌的抑制率最高,为17.11 %;部分目标化合物对T/B淋巴细胞转化具有弱的抑制活性,其中TM-I-6e'对T淋巴细胞转化的抑制活性最高,为17.75 %,TM-I-6l'对B淋巴细胞转化的抑制活性最高,为38.35 %;目标化合物对Cdc25B磷酸酯酶和TNF-α无抑制活性。
对目标化合物TM-II-5a~5i'的测试结果表明:部分目标化合物对β2-AR的拮抗效果较好, TM-II-5c'的拮抗效果最好,反应率为70 %;大部分目标化合物对肝癌、肺癌和肠癌均具有弱的抑制活性,但对肝癌的抑制活性较肺癌和肠癌好,其中TM-II-5h对肝癌的抑制率最高,为33.43 %,TM-II-5a对肺癌的抑制率最高,为16.60 %,TM-II-5g对肠癌的抑制率最高,为23.73 %;目标化合物对T/B淋巴细胞转化具有弱的抑制活性,其中TM-II-5i'对T淋巴细胞转化的抑制活性最高,为16.04 %,TM-II-5a'对B淋巴细胞转化的抑制活性最高,为12.46 %;部分目标化合物对TNF-α具有弱的抑制活性,其中TM-II-5h'的抑制率最高,为18.85 %;目标化合物对趋化因子受体(CCR2)和流感病毒神经氨酸酶无抑制活性。
3.总之,生物活性实验结果表明,两类目标化合物(TM-I-6a~6o'和TM-II-5a~5i')中部分化合物具有弱的抗癌及抗炎活性。这些初步的实验结果表明这些化合物在抗癌(前列腺癌、肺腺癌、肝癌、肺癌和肠癌)及抗炎方面具有潜在的应用价值。
1. Thirty novel target compounds TM-I-6a~6o' and eighteen novel target compounds TM-II-5a~5i', 2,5-disubstituted-1,3,4-oxadiazoles and 2,6-disubstituted -imidazo[2,1-b]-1,3,4-thiadiazoles containing benzoxazolinon/benzothiazolinon moiety, were synthesized by 2-aminophenol or 2-aminothiophenol and urea as starting materials via a series of reactions. Moreover, four novel related intermediate compounds, 5-[(benzoxazolinon/benzothiazolinon-3-yl)methyl]-2-mercapto-1,3,4-oxadiazoles and 2-amino-5-[(benzoxazolinon/benzothiazolinon-3-yl)methyl]-1,3,4-thiadiazoles, were also synthesized. The structures of the intermediates and target compounds were characterized by IR, 1D NMR, 2D NMR and elemental analysis.
2. All the newly synthesized target compounds (TM-I-6a~6o' and TM-II-5a~5i') were screened for their anticancer, antiinflammatory and antivirus activity. The assay results of compounds TM-I-6a~6o' showed that some of target compounds possessed weak inhibitory activity to SHP1, and the inhibitory rate of TM-I-6o was higher than others with 36.51±1.67 % at 20μg/mL. This indicated that compounds TM-I-6a~6o' had weak inhibitory activity to prostate cancer. Most compounds displayed weak inhibitory activities to liver cancer, lung cancer and intestinal cancer, and TM-I-6o exhibited higher inhibitory activity to liver cancer (21.65 %), TM-I-6o' exhibited higher inhibitory activity to lung cancer (33.06 %), TM-I-6d showed higher inhibitory activity to intestinal cancer (17.11 %). Some of target compounds also showed weak inhibitory activity to T/B lymphocyte transformation, the inhibitory rate of TM-I-6e' was higher to T lymphocyte transformation(17.75 %), and TM-I-6l' was higher to B lymphocyte transformation (38.35 %). But all the newly synthesized target compounds TM-I-6a~6o' have no inhibitory activity to Cdc25B phosphatase and TNF-α.
The assay results of compounds TM-II-5a~5i' showed good effect againstβ2-adrenergic receptor (β2-AR), and the antagonistic effect of TM-II-5c' was higher (70 %). Most compounds displayed weak activities against liver cancer, lung cancer and intestinal cancer, and TM-II-5h exhibited higher inhibitory activity to liver cancer (33.43 %), TM-II-5a exhibited higher inhibitory activity to lung cancer (16.60 %), TM-II-5g showed higher inhibitory activity to intestinal cancer (23.73 %). The target compounds also showed weak inhibitory activity to T/B lymphocyte transformation, the inhibitory rate of TM-II-5i' was higher to T lymphocyte transformation(16.04 %), and TM-II-5a' was higher to B lymphocyte transformation (12.46 %). Some of target compounds also showed weak activity against TNF-α, and TM-II-5h' was higher (18.85 %). But all the newly synthesized target compounds TM-II-5a~5i' have no inhibitory activity to C-C chemokine receptor 2 (CCR2) and influenza virus neuraminidase.
3. In conclusion, the assay results of biological activity show that some target compounds in TM-I-6a~6o' and TM-II-5a~5i' have weak anticancer and antiinflammatory activities. These preliminary results are promising and some of these compounds may be potential candidates for new anticancer (prostate cancer, lung cancer, liver cancer, lung cancer, intestinal cancer) and antiinflammatory agents.
2.对所合成的两类新目标化合物进行了抗癌、抗炎、抗病毒活性测试。对目标化合物TM-I-6a~6o'的测试结果表明:部分目标化合物对SHP1具有弱的抑制活性,其中TM-I-6o在浓度为20μg/mL时,抑制率最高,为36.51±1.67 %,这说明此类目标化合物具有弱的抑制前列腺癌的活性;大部分目标化合物对肝癌、肺癌和肠癌均具有弱的抑制活性,但对肝癌和肺癌的抑制活性较肠癌好,其中TM-I-6o对肝癌的抑制率最高,为21.65 %,TM-I-6o'对肺癌的抑制率最高,为33.06 %,TM-I-6d对肠癌的抑制率最高,为17.11 %;部分目标化合物对T/B淋巴细胞转化具有弱的抑制活性,其中TM-I-6e'对T淋巴细胞转化的抑制活性最高,为17.75 %,TM-I-6l'对B淋巴细胞转化的抑制活性最高,为38.35 %;目标化合物对Cdc25B磷酸酯酶和TNF-α无抑制活性。
对目标化合物TM-II-5a~5i'的测试结果表明:部分目标化合物对β2-AR的拮抗效果较好, TM-II-5c'的拮抗效果最好,反应率为70 %;大部分目标化合物对肝癌、肺癌和肠癌均具有弱的抑制活性,但对肝癌的抑制活性较肺癌和肠癌好,其中TM-II-5h对肝癌的抑制率最高,为33.43 %,TM-II-5a对肺癌的抑制率最高,为16.60 %,TM-II-5g对肠癌的抑制率最高,为23.73 %;目标化合物对T/B淋巴细胞转化具有弱的抑制活性,其中TM-II-5i'对T淋巴细胞转化的抑制活性最高,为16.04 %,TM-II-5a'对B淋巴细胞转化的抑制活性最高,为12.46 %;部分目标化合物对TNF-α具有弱的抑制活性,其中TM-II-5h'的抑制率最高,为18.85 %;目标化合物对趋化因子受体(CCR2)和流感病毒神经氨酸酶无抑制活性。
3.总之,生物活性实验结果表明,两类目标化合物(TM-I-6a~6o'和TM-II-5a~5i')中部分化合物具有弱的抗癌及抗炎活性。这些初步的实验结果表明这些化合物在抗癌(前列腺癌、肺腺癌、肝癌、肺癌和肠癌)及抗炎方面具有潜在的应用价值。
1. Thirty novel target compounds TM-I-6a~6o' and eighteen novel target compounds TM-II-5a~5i', 2,5-disubstituted-1,3,4-oxadiazoles and 2,6-disubstituted -imidazo[2,1-b]-1,3,4-thiadiazoles containing benzoxazolinon/benzothiazolinon moiety, were synthesized by 2-aminophenol or 2-aminothiophenol and urea as starting materials via a series of reactions. Moreover, four novel related intermediate compounds, 5-[(benzoxazolinon/benzothiazolinon-3-yl)methyl]-2-mercapto-1,3,4-oxadiazoles and 2-amino-5-[(benzoxazolinon/benzothiazolinon-3-yl)methyl]-1,3,4-thiadiazoles, were also synthesized. The structures of the intermediates and target compounds were characterized by IR, 1D NMR, 2D NMR and elemental analysis.
2. All the newly synthesized target compounds (TM-I-6a~6o' and TM-II-5a~5i') were screened for their anticancer, antiinflammatory and antivirus activity. The assay results of compounds TM-I-6a~6o' showed that some of target compounds possessed weak inhibitory activity to SHP1, and the inhibitory rate of TM-I-6o was higher than others with 36.51±1.67 % at 20μg/mL. This indicated that compounds TM-I-6a~6o' had weak inhibitory activity to prostate cancer. Most compounds displayed weak inhibitory activities to liver cancer, lung cancer and intestinal cancer, and TM-I-6o exhibited higher inhibitory activity to liver cancer (21.65 %), TM-I-6o' exhibited higher inhibitory activity to lung cancer (33.06 %), TM-I-6d showed higher inhibitory activity to intestinal cancer (17.11 %). Some of target compounds also showed weak inhibitory activity to T/B lymphocyte transformation, the inhibitory rate of TM-I-6e' was higher to T lymphocyte transformation(17.75 %), and TM-I-6l' was higher to B lymphocyte transformation (38.35 %). But all the newly synthesized target compounds TM-I-6a~6o' have no inhibitory activity to Cdc25B phosphatase and TNF-α.
The assay results of compounds TM-II-5a~5i' showed good effect againstβ2-adrenergic receptor (β2-AR), and the antagonistic effect of TM-II-5c' was higher (70 %). Most compounds displayed weak activities against liver cancer, lung cancer and intestinal cancer, and TM-II-5h exhibited higher inhibitory activity to liver cancer (33.43 %), TM-II-5a exhibited higher inhibitory activity to lung cancer (16.60 %), TM-II-5g showed higher inhibitory activity to intestinal cancer (23.73 %). The target compounds also showed weak inhibitory activity to T/B lymphocyte transformation, the inhibitory rate of TM-II-5i' was higher to T lymphocyte transformation(16.04 %), and TM-II-5a' was higher to B lymphocyte transformation (12.46 %). Some of target compounds also showed weak activity against TNF-α, and TM-II-5h' was higher (18.85 %). But all the newly synthesized target compounds TM-II-5a~5i' have no inhibitory activity to C-C chemokine receptor 2 (CCR2) and influenza virus neuraminidase.
3. In conclusion, the assay results of biological activity show that some target compounds in TM-I-6a~6o' and TM-II-5a~5i' have weak anticancer and antiinflammatory activities. These preliminary results are promising and some of these compounds may be potential candidates for new anticancer (prostate cancer, lung cancer, liver cancer, lung cancer, intestinal cancer) and antiinflammatory agents.
引文
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