稳定氮氧自由基自旋标记的鬼臼类化合物的合成及抗癌、抗氧化活性研究
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摘要
鬼臼毒素,是一种天然存在的木脂素类化合物。鬼臼及其衍生物具有广泛的生物活性,如抗肿瘤活性、抗病毒活性、抗风湿、杀虫等。其中,抗肿瘤活性最引人关注,常常作为研究开发抗癌药物的先导化合物。而稳定的氮氧自由基在生物体内具有广泛的生物活性。有研究表明,将稳定氮氧自由基引入抗癌药物中可以降低药物毒性,提高活性。稳定氮氧自由基还具有超氧化物歧化酶(SOD)类似的活性,可以防止各种生物系统的氧化损伤。
为了寻找高效低毒的抗肿瘤药物,本论文设计合成了两类稳定氮氧自由基自旋标记的鬼臼衍生物,并进行了抗肿瘤、抗氧化活性研究和脂水分配系数的测定。
1、以具有显著抗肿瘤活性的4β-氨基-4＇去甲表鬼臼为原料,考虑到L-氨基酸在人体内具有广泛的生理作用,以氨基酸作连结基,合成了五个氨基酸连结的吡咯啉类稳定氮氧自由基自旋标记的鬼臼衍生物。结果发现绝大部分该类化合物对人肺癌细胞(A-549)、白血病细胞(HL-60)、骨髓瘤细胞(RPMI-8226)的活性优于VP-16；但对白血病细胞(K562)活性优于母体化合物但小于VP-16；对肝癌细胞HepG2活性不如VP-16和母体化合物。该类化合物的脂水分配系数有所改善；而且抗氧化活性显著优于母体化合物和VP-16。
2、以具有显著抗肿瘤活性的4β-氨基-4＇去甲表鬼臼为原料,合成了七个氨基酸连结的哌啶类稳定氮氧自由基自旋标记的鬼臼衍生物。结果发现大部分化合物对人肺癌细胞(A-549)、白血病细胞(HL-60)和骨髓瘤细胞(RPMI-8226)好于VP-16的活性；但对白血病细胞(K562)活性优于母体化合物但小于VP-16；对肝癌细胞HepG2活性不如VP-16和母体化合物。该类化合物的脂水分配系数有一定的改善；与母体化合物和VP-16相比,其抗氧化能力明显增强。
Podophyllotoxin, is a naturally occurring cyclolignan compound. A number of biological activities such as cytotoxicity, antiviral, antirheumatic, insecticidal, etc., have been reported for podophyllotoxin and several related compounds and derivatives. Among them, the antitumor activity is the most attractive, making it as a lead compound for anticancer drug design and development. The stable nitroxides have a wide range of activities in biological tissues. Some studies have shown that the introduction of a nitroxyl moiety can lower general toxicity and improved the antitumor activity of the drug. Nitroxides possess superoxide dismutase (SOD) mimetic activity and have been shown to prevent oxidative damage in various biological systems.
In order to obtain the effective therapeutic agents with high activities and less toxic to normal cells, two kinds of stable nitroxyl radicals spin-labeled podophyllotoxin derivatives were designed, synthesized and evaluated for their antitumor activity, antioxidant activity and lipid-water partition coefficient in this thesis.
1. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, take into account the L-amino acids with better biological activity in human body, five spin labeled derivatives of podophyllotoxin compounds were synthesized though associated 4β-NH2-4'-demethylepipodo phyllotoxin and pyrroline stable nitroxyl radicals with natural L-amino acid as linker. As the results, most target compounds showed more effective superior or comparable cytotoxicities than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. At the same time, the lipid-water partition coefficient of the compounds to be improved; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16.
2. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, seven spin labeled podophyllotoxin derivatives compounds were synthesized though associated 4β-NH2-4'-demethylepipodophyllotoxin and piperidine stable nitroxyl radicals with natural L-amino acid as linker. We found most of target compounds showed more effective superior or comparable antitumor activity than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. The lipid-water partition coefficient of the compounds to be improved a certain extent; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16 too.
为了寻找高效低毒的抗肿瘤药物,本论文设计合成了两类稳定氮氧自由基自旋标记的鬼臼衍生物,并进行了抗肿瘤、抗氧化活性研究和脂水分配系数的测定。
1、以具有显著抗肿瘤活性的4β-氨基-4＇去甲表鬼臼为原料,考虑到L-氨基酸在人体内具有广泛的生理作用,以氨基酸作连结基,合成了五个氨基酸连结的吡咯啉类稳定氮氧自由基自旋标记的鬼臼衍生物。结果发现绝大部分该类化合物对人肺癌细胞(A-549)、白血病细胞(HL-60)、骨髓瘤细胞(RPMI-8226)的活性优于VP-16；但对白血病细胞(K562)活性优于母体化合物但小于VP-16；对肝癌细胞HepG2活性不如VP-16和母体化合物。该类化合物的脂水分配系数有所改善；而且抗氧化活性显著优于母体化合物和VP-16。
2、以具有显著抗肿瘤活性的4β-氨基-4＇去甲表鬼臼为原料,合成了七个氨基酸连结的哌啶类稳定氮氧自由基自旋标记的鬼臼衍生物。结果发现大部分化合物对人肺癌细胞(A-549)、白血病细胞(HL-60)和骨髓瘤细胞(RPMI-8226)好于VP-16的活性；但对白血病细胞(K562)活性优于母体化合物但小于VP-16；对肝癌细胞HepG2活性不如VP-16和母体化合物。该类化合物的脂水分配系数有一定的改善；与母体化合物和VP-16相比,其抗氧化能力明显增强。
Podophyllotoxin, is a naturally occurring cyclolignan compound. A number of biological activities such as cytotoxicity, antiviral, antirheumatic, insecticidal, etc., have been reported for podophyllotoxin and several related compounds and derivatives. Among them, the antitumor activity is the most attractive, making it as a lead compound for anticancer drug design and development. The stable nitroxides have a wide range of activities in biological tissues. Some studies have shown that the introduction of a nitroxyl moiety can lower general toxicity and improved the antitumor activity of the drug. Nitroxides possess superoxide dismutase (SOD) mimetic activity and have been shown to prevent oxidative damage in various biological systems.
In order to obtain the effective therapeutic agents with high activities and less toxic to normal cells, two kinds of stable nitroxyl radicals spin-labeled podophyllotoxin derivatives were designed, synthesized and evaluated for their antitumor activity, antioxidant activity and lipid-water partition coefficient in this thesis.
1. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, take into account the L-amino acids with better biological activity in human body, five spin labeled derivatives of podophyllotoxin compounds were synthesized though associated 4β-NH2-4'-demethylepipodo phyllotoxin and pyrroline stable nitroxyl radicals with natural L-amino acid as linker. As the results, most target compounds showed more effective superior or comparable cytotoxicities than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. At the same time, the lipid-water partition coefficient of the compounds to be improved; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16.
2. Based on 4β-NH2-4'-demethylepipodophyllotoxin as materials, seven spin labeled podophyllotoxin derivatives compounds were synthesized though associated 4β-NH2-4'-demethylepipodophyllotoxin and piperidine stable nitroxyl radicals with natural L-amino acid as linker. We found most of target compounds showed more effective superior or comparable antitumor activity than VP-16, against human lung carcinoma (A-549), human leukemic (HL-60) and myeloma cells (RPMI-8226) in vitro. But against leukemia cells (K562) activity more than the parent compound but less than VP-16; and less antitumor avtivity on hepatocarcinoma (HepG2) than VP-16 and parent compounds. The lipid-water partition coefficient of the compounds to be improved a certain extent; all the compounds showed significantly antioxidant activity better than the parent compound and VP-16 too.
引文
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