L-苯丙氨酸二肽衍生物的合成及其抗肿瘤活性研究
|
摘要
目的:探讨L-苯丙氨酸二肽衍生物的合成及其抗肿瘤活性。方法:以L-酪氨酸或L-苯丙氨酸为原料,依次酰化反应、缩合反应、亲核取代及烷基化等反应合成得到苯丙氨酸二肽衍生物,并用噻唑蓝(MTT)法测定其对人前列腺癌细胞(PC3)、人慢性髓原白血病细胞(K562)、人红白细胞白血病细胞(HEL)3类肿瘤细胞株的抗肿瘤活性。结果:共合成了3a~3h共8个未见文献报道的苯丙氨酸二肽衍生物,MTT结果显示,部分衍生物对K562细胞株具有一定抑制作用,衍生物3b,3e,3f对PC3和K562有较好的抑制作用。结论:合成了8个新的苯丙氨酸二肽衍生物,其对K562及PC3肿瘤细胞株具有一定的抑制作用。
Objective: To synthesize L-phenylalanine dipeptide derivatives and study their inhibitory effects on tumor cells. Methods: Starting from L-tyrosine or L-phenylalanine,L-phenylalanine dipeptide derivatives were synthesized via acetylation,condensation,nucleophilic substitution and/or alkylation. The cell proliferation inhibiting activities of the derivatives were evaluated by thiazolyl blue tetrazolium bromide( MTT) method. Results: A total of 8 3 a ~ 3 h phenylalanine dipeptide derivatives were synthesized. Some of the target compounds showed certain inhibitory effect against leukemia cell lines K562 and HEL in vitro. Furthermore,the derivatives 3 b,3 e and 3 f had preferably inhibitory effect on prostate cancer cell line PC3 and K562 cells in vitro. Conclusions: Phenylalanine dipeptide derivatives possess good inhibitory effects on the leukemia and prostate cancer cells and are worth of further research.
Objective: To synthesize L-phenylalanine dipeptide derivatives and study their inhibitory effects on tumor cells. Methods: Starting from L-tyrosine or L-phenylalanine,L-phenylalanine dipeptide derivatives were synthesized via acetylation,condensation,nucleophilic substitution and/or alkylation. The cell proliferation inhibiting activities of the derivatives were evaluated by thiazolyl blue tetrazolium bromide( MTT) method. Results: A total of 8 3 a ~ 3 h phenylalanine dipeptide derivatives were synthesized. Some of the target compounds showed certain inhibitory effect against leukemia cell lines K562 and HEL in vitro. Furthermore,the derivatives 3 b,3 e and 3 f had preferably inhibitory effect on prostate cancer cell line PC3 and K562 cells in vitro. Conclusions: Phenylalanine dipeptide derivatives possess good inhibitory effects on the leukemia and prostate cancer cells and are worth of further research.
引文
[1]吴菲,林国桢,张晋昕.我国恶性肿瘤发病现状及趋势[J].中国肿瘤,2012,21(2):81-85.
[2]EDIRIWICKREMA A,SALTZMAN W M,Nanotherapy for cancer:targeting and multifunctionality in the future of cancer therapies[J].Acs Biomater Sci Eng,2015,1(2):64-78.
[3]CHEN W,ZHENG R,ZENG H,et al.Annual report on status of cancer in China,2011[J].Chin J Cancer Res,2015,27(1):2-12.
[4]段纪俊,陈万青,张思维.中国恶性肿瘤死亡率的国际比较[J].中国社会医学杂志,2009,26(6):377-378.
[5]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].Ca-Cancer J Clin,2016,66(2):115.
[6]SHEWACH D S,KUCHTA R D.Introduction to cancer chemotherapeutics[J].Chem Rev,2009,109(7):2859-2861.
[7]RIEDL S,LEBER R,RINNER B,et al.Human lactoferricin derived dipeptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine[J].BBA-Biomembranes,2015,1848(11):2918-2931.
[8]BERGEL F,STOCK J A.Cytoactive amino-acid and peptide derivatives.Part I.Substituted phenylalanines[J].J Chem Soc,1954,2:2409-2417.
[9]SURESHBABU A R,DHAMODHARAN V,RAGHUNATHAN R.Cytotoxic N-(fluorenyl-9-methoxycarbonyl)(Fmoc)-dipeptides:structure-activity relationships and synergistic studies[J].Eur J Med Chem,2010,45(6):2494-2502.
[10]XU B X,WANG N,PAN W D,et al.Synthesis and anti-tumor activity evaluation of Matijin-Su derivatives[J].Bioorg Chem,2014,56(5):34-40.
[11]胡磊,陈小敏,童洋,等.L-苯丙氨酸二肽衍生物的合成及其抗肿瘤活性研究[J].中国药学杂志,2016,25(21):1831-1838.
[12]李惠斌,蔡景龙,潘博,等.成纤维细胞体外培养、冻存及复苏的实验研究[J].中国美容医学杂志,2005,14(4):394-396.
[13]张春燕,刘晏杰.体外培养人肺腺癌细胞液氮冻存及复苏培养[J].实用肿瘤学杂志,1992(2):27-28.
[14]李衍忠,赵萍,詹晓平,等.新型吡咯类氨基酸缀合物的合成与抗肿瘤活性测定[J].有机化学,2015,35(1):167-174.
[15]SASHIDHARA K V,ROSAIAH J N,TYAGI E,et al.Rare dipeptide and urea derivatives from roots of Moringa oleifera,as potential anti-inflammatory and antinociceptive agents[J].Eur J Med Chem,2009,44(1):432-436.
[16]VALE N,NOGUEIRA F,DO ROSáRIO V E,et al.Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs[J].Eur J Med Chem,2009,44(6):2506-2516.
[17]ZHAO M,BI L,BI W,et al.Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity[J].Bioorg Med Chem,2006,14(14):4761-4774.
[18]曲莉莎,曾万玲,梁光义.马蹄金的解热利胆作用及其对免疫功能的影响[J].辽宁中医杂志,2003,30(2):146-147.
[19]曲莉莎,曾万玲,谢达莎,等.马蹄金提取物镇痛、抗炎及抑菌作用的实验研究[J].中国中药杂志,2003,28(4):374-377.
[20]杨秀虾,梁光义,徐必学,等.马蹄金素衍生物体外抗肿瘤实验研究[J].亚太传统医药,2014,10(5):16-18.
[2]EDIRIWICKREMA A,SALTZMAN W M,Nanotherapy for cancer:targeting and multifunctionality in the future of cancer therapies[J].Acs Biomater Sci Eng,2015,1(2):64-78.
[3]CHEN W,ZHENG R,ZENG H,et al.Annual report on status of cancer in China,2011[J].Chin J Cancer Res,2015,27(1):2-12.
[4]段纪俊,陈万青,张思维.中国恶性肿瘤死亡率的国际比较[J].中国社会医学杂志,2009,26(6):377-378.
[5]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].Ca-Cancer J Clin,2016,66(2):115.
[6]SHEWACH D S,KUCHTA R D.Introduction to cancer chemotherapeutics[J].Chem Rev,2009,109(7):2859-2861.
[7]RIEDL S,LEBER R,RINNER B,et al.Human lactoferricin derived dipeptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine[J].BBA-Biomembranes,2015,1848(11):2918-2931.
[8]BERGEL F,STOCK J A.Cytoactive amino-acid and peptide derivatives.Part I.Substituted phenylalanines[J].J Chem Soc,1954,2:2409-2417.
[9]SURESHBABU A R,DHAMODHARAN V,RAGHUNATHAN R.Cytotoxic N-(fluorenyl-9-methoxycarbonyl)(Fmoc)-dipeptides:structure-activity relationships and synergistic studies[J].Eur J Med Chem,2010,45(6):2494-2502.
[10]XU B X,WANG N,PAN W D,et al.Synthesis and anti-tumor activity evaluation of Matijin-Su derivatives[J].Bioorg Chem,2014,56(5):34-40.
[11]胡磊,陈小敏,童洋,等.L-苯丙氨酸二肽衍生物的合成及其抗肿瘤活性研究[J].中国药学杂志,2016,25(21):1831-1838.
[12]李惠斌,蔡景龙,潘博,等.成纤维细胞体外培养、冻存及复苏的实验研究[J].中国美容医学杂志,2005,14(4):394-396.
[13]张春燕,刘晏杰.体外培养人肺腺癌细胞液氮冻存及复苏培养[J].实用肿瘤学杂志,1992(2):27-28.
[14]李衍忠,赵萍,詹晓平,等.新型吡咯类氨基酸缀合物的合成与抗肿瘤活性测定[J].有机化学,2015,35(1):167-174.
[15]SASHIDHARA K V,ROSAIAH J N,TYAGI E,et al.Rare dipeptide and urea derivatives from roots of Moringa oleifera,as potential anti-inflammatory and antinociceptive agents[J].Eur J Med Chem,2009,44(1):432-436.
[16]VALE N,NOGUEIRA F,DO ROSáRIO V E,et al.Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs[J].Eur J Med Chem,2009,44(6):2506-2516.
[17]ZHAO M,BI L,BI W,et al.Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity[J].Bioorg Med Chem,2006,14(14):4761-4774.
[18]曲莉莎,曾万玲,梁光义.马蹄金的解热利胆作用及其对免疫功能的影响[J].辽宁中医杂志,2003,30(2):146-147.
[19]曲莉莎,曾万玲,谢达莎,等.马蹄金提取物镇痛、抗炎及抑菌作用的实验研究[J].中国中药杂志,2003,28(4):374-377.
[20]杨秀虾,梁光义,徐必学,等.马蹄金素衍生物体外抗肿瘤实验研究[J].亚太传统医药,2014,10(5):16-18.