具有抗肿瘤活性的新型香豆素衍生物合成和活性研究
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摘要
香豆素类衍生物具有抗心律失常、抗骨质疏松、抗凝血、抗氧化、镇痛、降压、平喘、光敏以及抗HIV、抗肿瘤、抗菌等多方面的生物学活性,具有潜在的药用价值。因而,本文以香豆素为母体结构,基于活性亚结构拼接的原理,引入二硫代氨基甲酸酯、磺酰胺、硫醚、哌嗪等活性亚结构单元,设计合成了两类共计51个新型香豆素衍生物。所有目标化合物均通过1HNMR、MS和元素分析等手段进行了结构表征。
(1)含DTC与硫醚单元的香豆素芳基磺酰胺衍生物。通过将溴乙基引入7-磺酰胺基香豆素的N原子上,并进一步与DTC及巯基杂环等活性基团结合,合成出了一系列磺酰胺类香豆素结构,得到共计17个化合物,并用MTT法对肺癌A549细胞株进行了抗增殖活性的测试。结果表明：该系列目标物中大多化合物并未表现出明显的细胞毒性,仅三个化合物Y11190、Y11192、Y11199在10.0μM左右表现出一定的细胞毒性,细胞存活率分别为68.42%、53.00%、51.15%；构效关系表明,含吡咯烷或者甲基噻二唑结构单元的化合物表现出较高的细胞毒性。
(2)含DTC与哌嗪结构单元的香豆素衍生物。通过将DTC与哌嗪环引入香豆素的4-位,构建了一类DTC-哌嗪香豆素化合物库,共得到34个化合物,并用MTT法对其进行了细胞毒性的测试。结果表明：香豆素的6-位取代基对目标化合物的生物活性具有一定的影响,我们可以看到,当香豆素6-位无取代或为吸电子作用的氯、氟取代时,目标物并未表现出特别优异的抑制效果,仅有几个化合物表现出了较好的细胞毒性,如Y11208, Y12129-Y12132, IC50<10.0μM;当6-位为给电子的甲基和甲氧基取代时,化合物的细胞毒性发生显著提升,尤其是甲基取代时表现出极好的诱导凋亡的效果,具有特殊代表性的是化合物Y12123、 Y12126, IC50在0.1μM～1.0μM浓度区间内。
Coumarin derivatives that possess the activity of anti-arrhythmic, anti-clotting, antiosteoporosis, anti-oxidant, analgesic, anti-hypertensive, and asthma, photosensitive and anti-HIV, antitumor, and other biological activities, have great potential Med. value. Thus, We incorporated some different bioactive units, such as dithiocarbamate (DTC), sulfonamide, thioether, piperazine and other active substructure unit into the coumarin framework based on the connecting principle of actively biological groups. There were two types of coumarin derivatives been designed and synthesized. All the target compounds were characterized by1HNMR, MS and elemental analysis.
(1) DTC and arylsulfonamide coumarin derivatives. By modifying the N atom of7-(N-coumarin) arylsulfonamides with bromoethyl and introducing dithiocarbamate unit or heterocycle unit into the substituted coumarin ring, we got17novel compounds, which were then tested for their cytotoxic activity against A549cell line by MTT assay. The results indicated that most of the target compounds were found to be weakly cytotoxic against A549cell line, and only compounds Y11190、Y11192、Y11199exhibited some cytotoxic activity, with the cell livability being68.42%,53.00%and51.15%when the concentration increased to10.0μM, respectively. These compounds with the piperidine ring or methyl-1,3,4-thiadiazole showed a certain degree of cytotoxicity on the tumor cell.
(2) DTC and piperazine coumarin derivatives. A set of novel Aryl4-(2-oxo-2H-chromen-4-yl)piperazine-l-carbodithioate derivatives were synthesized by introducing DTC and piperazine units to benzopyran-2-one nucleus at C-4position, and we got34novel compounds. The cytotoxic activity test showed that this series of compounds highlighted the substituents on C-6positions, which had some effects on their cytotoxic activity. When the coumarin ring was without any substituents or was replaced by some electron-withdrawing groups such as chlorine or flurine on its C-6positions, these compounds showed good rather than excellent cytoxic activityies, eg. compounds Y11208, Y12129-Y12132, with their IC50、10.0μM. When the coumarin ring was replaced by some electron-donating groups such as methyl or methoxyl on its C-6positions, their cytoxic activity against A549cell line were significantly increased, the cell apoptosis induced by the derivatives was especially significant when the substituent was a methyl group, with the representive compounds Y12123and Y12126showed their IC50ranging from0.1μM to1.0μM.
(1)含DTC与硫醚单元的香豆素芳基磺酰胺衍生物。通过将溴乙基引入7-磺酰胺基香豆素的N原子上,并进一步与DTC及巯基杂环等活性基团结合,合成出了一系列磺酰胺类香豆素结构,得到共计17个化合物,并用MTT法对肺癌A549细胞株进行了抗增殖活性的测试。结果表明：该系列目标物中大多化合物并未表现出明显的细胞毒性,仅三个化合物Y11190、Y11192、Y11199在10.0μM左右表现出一定的细胞毒性,细胞存活率分别为68.42%、53.00%、51.15%；构效关系表明,含吡咯烷或者甲基噻二唑结构单元的化合物表现出较高的细胞毒性。
(2)含DTC与哌嗪结构单元的香豆素衍生物。通过将DTC与哌嗪环引入香豆素的4-位,构建了一类DTC-哌嗪香豆素化合物库,共得到34个化合物,并用MTT法对其进行了细胞毒性的测试。结果表明：香豆素的6-位取代基对目标化合物的生物活性具有一定的影响,我们可以看到,当香豆素6-位无取代或为吸电子作用的氯、氟取代时,目标物并未表现出特别优异的抑制效果,仅有几个化合物表现出了较好的细胞毒性,如Y11208, Y12129-Y12132, IC50<10.0μM;当6-位为给电子的甲基和甲氧基取代时,化合物的细胞毒性发生显著提升,尤其是甲基取代时表现出极好的诱导凋亡的效果,具有特殊代表性的是化合物Y12123、 Y12126, IC50在0.1μM～1.0μM浓度区间内。
Coumarin derivatives that possess the activity of anti-arrhythmic, anti-clotting, antiosteoporosis, anti-oxidant, analgesic, anti-hypertensive, and asthma, photosensitive and anti-HIV, antitumor, and other biological activities, have great potential Med. value. Thus, We incorporated some different bioactive units, such as dithiocarbamate (DTC), sulfonamide, thioether, piperazine and other active substructure unit into the coumarin framework based on the connecting principle of actively biological groups. There were two types of coumarin derivatives been designed and synthesized. All the target compounds were characterized by1HNMR, MS and elemental analysis.
(1) DTC and arylsulfonamide coumarin derivatives. By modifying the N atom of7-(N-coumarin) arylsulfonamides with bromoethyl and introducing dithiocarbamate unit or heterocycle unit into the substituted coumarin ring, we got17novel compounds, which were then tested for their cytotoxic activity against A549cell line by MTT assay. The results indicated that most of the target compounds were found to be weakly cytotoxic against A549cell line, and only compounds Y11190、Y11192、Y11199exhibited some cytotoxic activity, with the cell livability being68.42%,53.00%and51.15%when the concentration increased to10.0μM, respectively. These compounds with the piperidine ring or methyl-1,3,4-thiadiazole showed a certain degree of cytotoxicity on the tumor cell.
(2) DTC and piperazine coumarin derivatives. A set of novel Aryl4-(2-oxo-2H-chromen-4-yl)piperazine-l-carbodithioate derivatives were synthesized by introducing DTC and piperazine units to benzopyran-2-one nucleus at C-4position, and we got34novel compounds. The cytotoxic activity test showed that this series of compounds highlighted the substituents on C-6positions, which had some effects on their cytotoxic activity. When the coumarin ring was without any substituents or was replaced by some electron-withdrawing groups such as chlorine or flurine on its C-6positions, these compounds showed good rather than excellent cytoxic activityies, eg. compounds Y11208, Y12129-Y12132, with their IC50、10.0μM. When the coumarin ring was replaced by some electron-donating groups such as methyl or methoxyl on its C-6positions, their cytoxic activity against A549cell line were significantly increased, the cell apoptosis induced by the derivatives was especially significant when the substituent was a methyl group, with the representive compounds Y12123and Y12126showed their IC50ranging from0.1μM to1.0μM.
引文
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