桦木酮衍生物缩氨基硫脲金属配合物的合成与表征
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摘要
以桦木醇为起始物,通过对其3号位与28号位进行修饰,合成了两种配体(桦木酮酸缩氨基硫脲和28-O-丁二酸酯桦木酮缩氨基硫脲)及其金属配合物.利用红外、氢谱、质谱、元素分析及热重分析等测试手段对金属配合物进行了表征,并对所合成配体及金属配合物进行了抗菌活性测试与Hela癌细胞毒性测试.通过抑菌活性试验发现:桦木酮酸缩氨基硫脲金属镉、银络合物对S.aureus 4220型和E.coli 1924型细菌有抑制作用,28-O-丁二酸酯桦木酮缩氨基硫脲对大多数细菌都有一定的抑制作用,28-O-丁二酸酯桦木酮对Streptococcus mutans 3289型细菌的抗菌活性与氯霉素相当.通过细胞毒性试验发现:桦木酮酸缩氨基硫脲铜配合物、28-O-丁二酸酯桦木酮缩氨基硫脲及其金属络合物具有良好的抑制Hela细胞的能力,且其抑制率随着化合物浓度的增加而增加;本文所合成的金属络合物抑制Hela细胞的能力优于其配体;在癌细胞毒性测试中的化合物IC50值为10～25μM.
Two ligands(betulonic acid thiosemicarbazone and 28-O-succinylbetulone thiosemicarbazone)and their metal complexes have been synthesized using betulin as a starting material via modification of 3-and 28-position of betulin.The complexes were characterized by infrared spectra analysis and proton nuclear magnetic resonance,elemental analysis,matrix-assisted laser desorption ionization mass spectrometry and thermogravimetric analysis.Finally,antibacterial activity test and Hela cancer cell toxicity of the synthesized ligand and metal complexes were performed.The inhibition of S.aureus 4220 and E.coli 1924 was found by antibacterial activity test.28-O-succinylbetulone thiosemicarbazone has a certain inhibitory effect on most bacteria,and 28-O-succinylbetulone has antibacterial activity comparable to chloramphenicol in Streptococcus mutans 3289.The cytotoxicity test showed that betulonic acid thiosemicarbazone copper complex,28-O-succinylbetulone thiosemicarbazone and its metal complex had the ability to inhibit Hela cells,and their inhibition rates increase with the increase of compounds concentration metal complexes synthesized and tested in this paper have better ability to inhibit Hela cells than their ligands.IC50 values of compounds in cytotoxicity tests are 10-25μM.
Two ligands(betulonic acid thiosemicarbazone and 28-O-succinylbetulone thiosemicarbazone)and their metal complexes have been synthesized using betulin as a starting material via modification of 3-and 28-position of betulin.The complexes were characterized by infrared spectra analysis and proton nuclear magnetic resonance,elemental analysis,matrix-assisted laser desorption ionization mass spectrometry and thermogravimetric analysis.Finally,antibacterial activity test and Hela cancer cell toxicity of the synthesized ligand and metal complexes were performed.The inhibition of S.aureus 4220 and E.coli 1924 was found by antibacterial activity test.28-O-succinylbetulone thiosemicarbazone has a certain inhibitory effect on most bacteria,and 28-O-succinylbetulone has antibacterial activity comparable to chloramphenicol in Streptococcus mutans 3289.The cytotoxicity test showed that betulonic acid thiosemicarbazone copper complex,28-O-succinylbetulone thiosemicarbazone and its metal complex had the ability to inhibit Hela cells,and their inhibition rates increase with the increase of compounds concentration metal complexes synthesized and tested in this paper have better ability to inhibit Hela cells than their ligands.IC50 values of compounds in cytotoxicity tests are 10-25μM.
引文
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[3]Saxena B B,Zhu L,Hao M,et al.Boc-lysinated-betulonic acid:apotent,anti-prostate cancer agent[J].Bioorg Med Chem,2006,14(18):6349-6358.
[4]Chintharlapalli S,Papineni S,Ramaiah S K,et al.Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors[J].Cancer Res,2007,67(6):2816-2823.
[5]Sun I-C,Shen J-K,Wang H-K,et al.Anti-AIDS agents.Part 32:Synthesis and anti-HIV activity of betulin derivatives[J].Bioorg Med Chem Lett,1998,8(10):1267-1272.
[6]Shah M,Patel P,Parekh H Orient.Synthesis and biological evaluation of thienopyrimidine derivatives[J].Chem,2002,18(1):159-161.
[7]Xiong J,Kashiwada Y,Chen C-H,et al.Conjugates of betulin derivatives with AZT as potent anti-HIV agents[J].Bioorg Med Chem,2010,18(17):6451-6469.
[8]Qian K,Yu D,Chen C-H,et al.Anti-AIDS agents.Part 78:Design,synthesis,metabolic stability assessment,and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus(HIV)agents[J].Med Chem,2009,52(10):3248-3258.
[9]Rajasekaran A,Murugesan S.Synthesis and antimicrobial evaluation of thiosemicarbazones[J].Indian Chem Soc,2002,79(6):544-545.
[10]El-Hawash Soad A M,Abdel Wahab Abeer E,El-Demellawy Maha A.Cyanoacetic acid hydrazones of 3-(and 4-)acetylpyridine and some derived ring systems as potential antitumor and anti-HCV agents[J].Arch Pharm,2006,339(1):14-23.
[11]Fujii N,Mallari J P,Hansell E J,et al.Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain[J].Bioorg Med Chem Lett,2005,15(1):121-123.
[12]Lebrecht D,Geist A,Ketelsen U-P,et al.The 6-maleimidocaproyl hydrazone derivative of doxorubicin(DOXO-EMCH)is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage[J].Int J Cancer,2007,120(4):927-934.
[13]Beraldo H,Gambino D.The wide pharmacological versatility of semicarbazones,thiosemicarbazones and their metal complexes[J].Mini Rev Med Chem,2004,4(1):31-39.
[14]Khan S A,Yusuf M.Synthesis,spectral studies and in vitro antibacterial activity of steroidal thiosemicarbazone and their palladium(Pd(II))complexes[J].Eur J Med Chem,2009,44(5):2270-2274.
[15]Mazoir N,Benharref A,Bailén M,et al.Bioactive triterpene derivatives from latex of two Euphorbia species[J].Phytochemistry,2008,69(6):1328-1338.
[16]Rosenberg B,Vancamp L,Trosko J E,et al.Plati-num compounds:a new class of potent antiumor agents[J].Nature,1969,222(5191):385-386.
[17]Orvig C,Abrams M J.Medicinal inorganic chemistry:introduction[J].Chem Rev,1999,99(9):2201-2203.
[18]Clarke M J,Zhu F C,Frasca D R.Non-Platinum Chemotherapeutic Metallopharmaceuticals[J].Chem Rev,1999,99(9):2511-2533.
[19]Wong E,Giandomenico C M.Current status of platinum-based antitumor drug[J].Chem Rev,1999,99(9):2451-2466.
[20]Jamieson E,Lippard S J.Stopped-flow kinetic studies of the binding of HMG-domain proteins to cisplatin-modified DNA[J].Chem Rev,1999,99(9):2467-2498.
[21]陈振锋,彭艳,谭明雄,等.基于中药活性成分的金属基抗肿瘤药物前期研究[J].化学进展,2009,21(5):929-933.
[22]Haran K P,Godden S M,Boxrud D,et al.Prevalence and characterization of staphylococcus aureus,including methicillin-resistant staphylococcus aureus,isolated from bulk tank milk from minnesota dairy farms[J].J Clin Microbiol,2012,50(3):688-695.
[23]Zhan H Y,Qi W,Ye L,et al.A novel method for banking stem cells from human exfoliated deciduous teeth:lentiviral TERT immortalization and phenotypical analysis[J].Stem Cell Res Ther,2016,7(1):50-61.
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