水杨酸-α-氨基膦酸酯衍生物的合成及抗肿瘤活性
|
摘要
采用微波辅助法,以α-氨基膦酸酯和水杨酸为原料,以CDI/DMAP为催化剂,合成了10个结构新颖的水杨酸-α-氨基膦酸酯衍生物,所有目标化合物的结构均经IR,~1H-NMR,~(13)C-NMR和HRMS确认.优化反应条件:微波功率700 W、反应3 h.利用MTT法测定了目标化合物的抗肿瘤活性,结果显示,目标化合物对用于测试的三种肿瘤细胞:人急性髓系白血病细胞(KGla)、人肝癌细胞(HepG2)、宫颈癌细胞(Hela)均有一定的抑制作用,其中2E、2F对Hela抑制作用较好.
In this paper,ten novel salicylic acid-α-aminophosphonate derivatives were synthesized through the microwaved-assisted method,usingα-aminophosphate derivatives and o-hydroxybenzaldehydes in DCC/DMAP.All of the target compounds were characterized by IR,1H-NMR,~(13)C NMR and HRMS.The optimum conditions were as following:microwaved reaction at 700 W for 3 h.The antitumor activity of the target compounds was determined by MTT method.The results showed that the target compounds had inhibitory effects against three kinds of tumor cells:human acute myeloid leukemia cells(KGla),human hepatoma cells(HepG2),cervical cancer cells(Hela).Among the ten compounds,2E,2F showed a good inhibitory activity against cells Hela.
In this paper,ten novel salicylic acid-α-aminophosphonate derivatives were synthesized through the microwaved-assisted method,usingα-aminophosphate derivatives and o-hydroxybenzaldehydes in DCC/DMAP.All of the target compounds were characterized by IR,1H-NMR,~(13)C NMR and HRMS.The optimum conditions were as following:microwaved reaction at 700 W for 3 h.The antitumor activity of the target compounds was determined by MTT method.The results showed that the target compounds had inhibitory effects against three kinds of tumor cells:human acute myeloid leukemia cells(KGla),human hepatoma cells(HepG2),cervical cancer cells(Hela).Among the ten compounds,2E,2F showed a good inhibitory activity against cells Hela.
引文
[1]HUSSAIN S,SHARMA J,AMIR M.Synthesis and antimicrobial activities of 1,2,4-triazole and 1,3,4-thiadiazole derivatives of5-amino-2-hydroxybenzoic acid[J].Journal of Chemistry,2008,5(4):963-968.
[2]KHIATI Z,OTHMAN A A,GUESSAS B.Synthesis and antibacterial activity of 1,3,4-oxadiazole and 1,2,4-triazole derivatives of salicylic acid and its synthetic intermediates[J].South African Journal of Chemistry,2015,60(1):20-24.
[3]GUO Z H,YIN Y,WANG C,et al.Design,synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents[J].Bioorganic&Medicinal Chemistry,2015,23(18):6148-6156.
[4]FIORUCCI S,SANTUCCI L,GRESELE P,et al.Gastrointestinal safety of NO-aspirin(NCX-4016)in healthy human volunteers:A proof of concept endoscopic study[J].Gastroenterology,2003,124(3):600-607.
[5]LAZZARATO L,DONNOLA M,ROLANDO B,et al.Searching for new NO-donor aspirin-like molecules:a new class of nitrooxyacyl derivatives of salicylic acid[J].Journal of Medicinal Chemistry,2008,51(6):1894-1903.
[6]BAILON E,COMALADA M J,MICHELENA P,et al.UR-1505,a salicylate able to selectively block T-cell activation,shows intestinal anti-inflammatory activity in the chronic phase of the DSS model of rat colitis[J].Inflammatory Bowel Diseases,2008,14(7):888-897.
[7]王杰,邬皓,李家明,等.水杨酰芳胺类化合物的设计、合成及体外抗肿瘤活性研究[J].有机化学,2013,33(5):1026-1034.
[8]PICKENS L B,KIM W,WANG P,et al.Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575[J].Journal of the American Chemical Society,2009,131(48):17677-17689.
[9]YANG Y,SHI L,ZHOU Y,et al.Design,synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2010,20(22):6653-6656.
[10]杨家强,马俊,车万莉,等.水杨酰氧基膦酸酯衍生物的微波辅助合成及抗肿瘤活性研究[J].有机化学,2014(12):2566-2571.
[11]YAMAGUCHI T,MATSUMURA Y,ISHII T,et al.Synthesis of nicotinamide derivatives having a hydroxy-substituted benzene ring and the influence of their structures on the apoptosis-inducing activity against leukemia cells[J].Drug Development Research,2011,72(3):289-297.
[12]杨家强,谷晴,胡月维,等.超声辐射下O,O′-二烷基-α-取代苯基-α-苯磺酰氧基甲基膦酸酯的合成与生物活性[J].有机化学,2013,33(10):2226-2231.
[13]杨家强,刘思兰,车万莉,等.新型E-2,3-二芳基丙烯酰氧基膦酸酯衍生物的设计、合成与抗肿瘤活性[J].药学学报,2015(4):464-468.
[14]NING L,WANG W,LIANG Y,et al.Synthesis and cytotoxicity of O,O′-dialkyl{[2-(substitutedphenoxy)acetamido](substitutedphenyl)methylphosphonates[J].European Journal of Medicinal Chemistry,2012,48:379-384.
[15]郭深深,代本才,陈8),等.胆酸酰氧基膦酸酯衍生物的合成及抗肿瘤活性[J].化学研究,2016,27(2):183-188.
[16]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用[J].化学试剂,2009,31(10):795-797.
[17]孙伟婷.以酰胺为底物构建c-p键的方法学研究[D].厦门:厦门大学,2016.
[18]TASHRIFI Z.Al(OTf)as an efficient catalyst for one-pot synthesis of primary diethyl 1-aminophosphonates under solvent-free conditions[J].Synthetic Communications,2008,39(1):120-131.
[19]SOBHANI S,TASHRIFI Z.One-pot synthesis of primary 1-aminophosphonates:Coupling reaction of carbonyl compounds,hexamethyldisilazane,and diethyl phosphite catalyzed by Al(OTf)3[J].Cheminform,2009,20(2):109-115.
[20]SARA SOBHANI,ELHAM SAFAEI,MOZAFFAR ASADI,et al.Efficient synthesis of secondary and primarydialkylα-aminophosphonates catalyzed by tetramethyl-tetra-3,4-pyridinoporphyrazinato copper(II)methyl sulfate under solvent-free conditions[J].Journal of Porphyrins&Phthalocyanines,2008,12(7):849-856.
[2]KHIATI Z,OTHMAN A A,GUESSAS B.Synthesis and antibacterial activity of 1,3,4-oxadiazole and 1,2,4-triazole derivatives of salicylic acid and its synthetic intermediates[J].South African Journal of Chemistry,2015,60(1):20-24.
[3]GUO Z H,YIN Y,WANG C,et al.Design,synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents[J].Bioorganic&Medicinal Chemistry,2015,23(18):6148-6156.
[4]FIORUCCI S,SANTUCCI L,GRESELE P,et al.Gastrointestinal safety of NO-aspirin(NCX-4016)in healthy human volunteers:A proof of concept endoscopic study[J].Gastroenterology,2003,124(3):600-607.
[5]LAZZARATO L,DONNOLA M,ROLANDO B,et al.Searching for new NO-donor aspirin-like molecules:a new class of nitrooxyacyl derivatives of salicylic acid[J].Journal of Medicinal Chemistry,2008,51(6):1894-1903.
[6]BAILON E,COMALADA M J,MICHELENA P,et al.UR-1505,a salicylate able to selectively block T-cell activation,shows intestinal anti-inflammatory activity in the chronic phase of the DSS model of rat colitis[J].Inflammatory Bowel Diseases,2008,14(7):888-897.
[7]王杰,邬皓,李家明,等.水杨酰芳胺类化合物的设计、合成及体外抗肿瘤活性研究[J].有机化学,2013,33(5):1026-1034.
[8]PICKENS L B,KIM W,WANG P,et al.Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575[J].Journal of the American Chemical Society,2009,131(48):17677-17689.
[9]YANG Y,SHI L,ZHOU Y,et al.Design,synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2010,20(22):6653-6656.
[10]杨家强,马俊,车万莉,等.水杨酰氧基膦酸酯衍生物的微波辅助合成及抗肿瘤活性研究[J].有机化学,2014(12):2566-2571.
[11]YAMAGUCHI T,MATSUMURA Y,ISHII T,et al.Synthesis of nicotinamide derivatives having a hydroxy-substituted benzene ring and the influence of their structures on the apoptosis-inducing activity against leukemia cells[J].Drug Development Research,2011,72(3):289-297.
[12]杨家强,谷晴,胡月维,等.超声辐射下O,O′-二烷基-α-取代苯基-α-苯磺酰氧基甲基膦酸酯的合成与生物活性[J].有机化学,2013,33(10):2226-2231.
[13]杨家强,刘思兰,车万莉,等.新型E-2,3-二芳基丙烯酰氧基膦酸酯衍生物的设计、合成与抗肿瘤活性[J].药学学报,2015(4):464-468.
[14]NING L,WANG W,LIANG Y,et al.Synthesis and cytotoxicity of O,O′-dialkyl{[2-(substitutedphenoxy)acetamido](substitutedphenyl)methylphosphonates[J].European Journal of Medicinal Chemistry,2012,48:379-384.
[15]郭深深,代本才,陈8),等.胆酸酰氧基膦酸酯衍生物的合成及抗肿瘤活性[J].化学研究,2016,27(2):183-188.
[16]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用[J].化学试剂,2009,31(10):795-797.
[17]孙伟婷.以酰胺为底物构建c-p键的方法学研究[D].厦门:厦门大学,2016.
[18]TASHRIFI Z.Al(OTf)as an efficient catalyst for one-pot synthesis of primary diethyl 1-aminophosphonates under solvent-free conditions[J].Synthetic Communications,2008,39(1):120-131.
[19]SOBHANI S,TASHRIFI Z.One-pot synthesis of primary 1-aminophosphonates:Coupling reaction of carbonyl compounds,hexamethyldisilazane,and diethyl phosphite catalyzed by Al(OTf)3[J].Cheminform,2009,20(2):109-115.
[20]SARA SOBHANI,ELHAM SAFAEI,MOZAFFAR ASADI,et al.Efficient synthesis of secondary and primarydialkylα-aminophosphonates catalyzed by tetramethyl-tetra-3,4-pyridinoporphyrazinato copper(II)methyl sulfate under solvent-free conditions[J].Journal of Porphyrins&Phthalocyanines,2008,12(7):849-856.