CAS OpenIR  > 中科院上海应用物理研究所2004-2010年
β-榄香烯-[M(CO)3(H2O)3]+ (M=188Re,99mTc)型配合物的合成及初步生物学评价
Alternative TitleSynthesis and preliminary biological evaluation of β-elemene-[M(CO)3(H2O)3]+(M=188Re, 99mTc) Complexes
任云峰
Subtype硕士
Thesis Advisor沈玉梅
2008-05-19
Degree Grantor中国科学院上海应用物理研究所
Place of Conferral上海应用物理研究所
KeywordΒ-榄香烯 Fac-[m(Co)3(H2o)3]+ 188re 99mtc 抗癌活性 水溶性 Micro-spect
Abstractβ-榄香烯是从中草药温莪术中提取的一种抗癌活性成分,是只含C,H两种元素的倍半萜烯。它不仅对乳腺癌细胞,宫颈癌细胞等实体瘤细胞疗效显著,而且不良反应小,对肝、肾功能无损害,无骨髓抑制,还能提高机体免疫功能。 但是榄香烯分子极性较小,难溶于水,临床上制成乳剂用于瘤体局部注射,大大限制了其应用。因此以β-榄香烯为先导物,对其结构进行改造,寻找水溶性好、抗癌活性高的β-榄香烯衍生物成为研究的重点。 Fac-[M(CO)3(H2O)3]+ (M=188Re,99mTc)是一种标记生物分子的较理想试剂,有较好的水溶性,可以与含有NH2,COOH,硫醚或膦等基团的单齿或多齿配体反应,形成稳定且具有高比活度的配合物。188Re和99mTc发射的γ射线能对标记前体进行示踪和SPECT显像,188Re发射的β射线还可以用于治疗。本文采用188Re和99mTc对β-榄香烯进行标记,一方面借助放射性核素研究榄香烯衍生物的水溶性及体内分布代谢情况,另一方面探讨以β-榄香烯为标记前体发展放射性药物的可行性。 首先以己二胺和三乙二醇两种分子出发合成了两种双功能螯合剂,并与氯代β-榄香烯反应得到β-榄香烯三齿配合物前体,然后与三羰基铼配位得到相应的金属配合物。所有反应中间体及最终化合物分别用IR,1H-NMR,HRMS,HPLC或元素分析进行了表征。 另外我们制备了fac-[188Re(CO)3(H2O)3]+和fac-[99mTc(CO)3(H2O)3]+两种放射性中间体,并分别对β-榄香烯-6-[二(2-吡啶甲基)-胺基]-己胺和N-β-榄香烯-N-[1-二(2-吡啶甲基)-胺基]-二甲基氨乙基乙二醇)两种配体进行放射性三羰基铼和三羰基锝的标记,得到四种新的标记化合物。经测定,相应化合物的放化产率和放化纯度均在92%以上。 在此基础上,我们初步研究了稳定同位素的β-榄香烯三羰基铼配合物对Hela和LLC细胞株的体外抗癌活性,结果表明其抗癌活性比β-榄香烯原药明显提高。通过对β-榄香烯-[99mTc(CO)3(H2O)3]+型配合物进行脂水分布系数测定发现,新合成的配合物水溶性较β-榄香烯本体分别提高了15倍以上。 最后研究了β-榄香烯-[99mTc(CO)3(H2O)3]+型配合物在荷瘤鼠体内分布情况,并进行了micro-SPECT显像观察,结果发现该类型化合物水溶性改善后,在血液中的滞留时间延长,生物利用度明显提高,在肿瘤部位有一定的浓集。
Other Abstractβ-Elemene, a natural sesquiterpene extracted from the Traditional Chinese Herb Medicinal Curcuma wenyujin,is the main effective monomer of elemene emulsion. β-Elemene exhibits anticancer effects in human and murine tumor cells in vitro and in vivo and has substantial clinical activity against various tumors without severe side effects. No bone marrow suppression and drug resistance have been observed in the clinical studies; on the contrary patient immunity was improved during the therapy with β-elemene. However β-elemene suffers the disadvantage of poor water solubility due to its property of olefin. So the searching for a new kind of β-elemene derivatives which has good aqueous solubility and high antitumor potency is very important. Fac-[M(CO)3(H2O)3]+ (M=188Re,99mTc) may be an ideal candidate agent for labeling biomolecules. It has good aqueous solubility and can reacts with some bifunctional chelator agents such as NH2 or COOH. Starting from 1, 6-Diaminohexanea and Triethylene glycol, two kind of tridentate ligands were synthesized.Two new β-elemene tricarbonyl rhenium complexes were prepared via halogenation and nucleophilic substitution reactions, followed by reaction with tricarbonyl rhenium. All the compounds were characterized by IR, 1H-NMR, HRMS, HPLC or elemental analysis. Under the similar reaction conditions, four radioactive β-elemene tricarbonyl rhenium and technetium complexes were synthesized successfully with both of their radiochemical yield and radiochemical purity is more than 92%. The antiproliferative effect of non-radioactive β-elemene-Re(CO)3 derivatives in mice lewis lung cancer cells(LLC) and human HeLa cervix carcinoma cells were evaluated by WST-1 method. Compared with that of β-elemene,their antiproliferative activities were improved significantly .The oil-water partition coefficients of β-elemene-[99mTc (CO)3(H2O)3]+ complexes were improved more than 20 times. Biodistribution and micro-SPECT imaging studies in mice bearing LLC showed a long retained time and they metabolized through renal-urnary pathway mainly.
Language中文
Document Type学位论文
Identifierhttp://ir.sinap.ac.cn/handle/331007/7285
Collection中科院上海应用物理研究所2004-2010年
Recommended Citation
GB/T 7714
任云峰. β-榄香烯-[M(CO)3(H2O)3]+ (M=188Re,99mTc)型配合物的合成及初步生物学评价[D]. 上海应用物理研究所. 中国科学院上海应用物理研究所,2008.
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