几种碘代卟啉化合物的合成及其性能的评价

发布时间：2018-05-05 12:34

本文选题：卟啉 + ~(131)I　；参考：《中国工程物理研究院》2014年博士论文

【摘要】：国际癌症研究机构报道癌症在2012年造成820万人死亡,并且未来20年,估计每年癌症病例将由目前的1400万上升到2200万,严重影响了人类的生存和发展。如果早期发现,通过手术和放射治疗,大部分癌症都可以治愈。但是,临床发现的病例大多已是中晚期,无法进行手术治疗,放疗和化疗会引起厌食、脱发等较大的毒副作用,治疗过程中给病人带来了极大的痛苦,因此,需要开发新的治疗方法。近年来,光动力治疗以适用性好、毒性小和无耐药性等优势,引起了广泛关注。卟啉化合物具有良好的亲肿瘤性和光动力性质,且易与核素结合,因此,可以很好地将光动力治疗和核素治疗结合在一起,在癌症治疗领域具有广阔的应用前景。本论文合成了五种带不同取代基的卟啉化合物,考察了其作为光动力治疗光敏剂的抗菌性能和细胞毒性；选用131I对光动力性质优良的卟啉化合物进行标记,研究了制备条件对标记率的影响,得到了高放化纯度的标记物；考察了标记物的体内外性质,对其抗肿瘤性能进行了初步评价。具体内容如下： (1)设计合成了五种不同取代基(-H、-NO2、-NH2、-OH、-OCH3)的卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH和TPPOCH3,一种金属卟啉CuTPPOCH3,两种富勒烯-卟啉化合物C60-TPPOCH3和C60-TPPOH,并通过红外(IR)、核磁共振氢谱(1HNMR)、质谱(MS)和紫外-可见光谱(UV-Vis)对化合物进行表征。 (2)采用平板菌落计数法考察了卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH、 TPPOCH3和CuTPPOCH3在不同浓度和光照条件下,对大肠杆菌和金黄色葡萄球菌的细菌毒性。结果表明：化合物的暗毒性低,细菌毒性具有明显的光照和浓度依赖性,并与光照能量密度和浓度呈正相关关系；TPPOH在光照条件下具有较强的细菌毒性；当TPPOCH3的卟吩环中心络合顺磁性金属离子铜后,细菌毒性明显下降；化合物对金黄色葡萄球菌的抑制效果明显优于大肠杆菌。 (3)考察了卟啉化合物TPP、TPPNO2、TPPNH2、TPPOH和TPPOCH3对人肝癌细胞HepG2、SMMC-7721和人正常肝细胞HL-7702存活率的影响。结果表明：化合物的暗毒性低,细胞毒性具有明显的光照和浓度依赖性,并与光照能量密度和浓度呈正相关的关系；TPPOH的光毒性较高；各化合物对三种细胞的毒性差异不显著。 (4)采用密度泛函理论(B3LYP)优化了化合物TPPNH2和TPPOH及其碘标记物的分子结构,计算了Mulliken电荷分布和能量,从理论上预测了碘标记TPPNH2和TPPOH的最可几位点。 (5)以氯胺T为氧化剂,对TPPOH和TPPNH2进行131I标记,研究了制备条件对标记率的影响,得到了高放化纯度的标记物。优化条件为：a)13II-TPPOH:pH为5.5,TPPOH浓度2mg/mL,氯胺T浓度0.25mg/mL,反应温度20℃,反应时间15min,标记率98%; b)131I-TPPNH2:pH为1.5, TPPNH2浓度2mg/mL,氯胺T浓度3mg/mL,反应温度95℃,反应时间40min,标记率96%。两种标记物体内稳定性好,血液清除较快,对肝脏和肺有较高的亲和性,肝脏是主要代谢途径,肿瘤中有良好的积累和滞留性质,表明131I-TPPOH和131I-TPPNH2对肿瘤的治疗有潜在价值。 (6)初步评价了131I-TPPOH和131I-TPPNH2的抗肿瘤性能,结果表明：在131I的核素治疗和卟啉的光动力治疗双重作用下,131I-TPPOH和131I-TPPNH2都具有较好的抗肿瘤性能,但131I-TPPOH的抗肿瘤性能更优且毒性小,有望成为一种具有双重功效的肿瘤治疗药物。
[Abstract]:The International Cancer Research Institute reported that cancer killed 8 million 200 thousand people in 2012, and in the next 20 years, it is estimated that cancer cases will rise from 14 million to 22 million a year, seriously affecting human survival and development. If early detection, most cancers can be cured by surgery and radiation treatment. However, the clinical cases are large. Most of them are middle and late stage, unable to perform surgical treatment, radiotherapy and chemotherapy will cause anorexia, hair loss and other major toxic and side effects, and bring great pain to the patients during the treatment. Therefore, new treatment methods need to be developed. In recent years, photodynamic therapy has attracted wide attention, with the advantages of good applicability, small toxicity and no drug resistance. The compound has good ONCOPHILIC and photodynamic properties, and is easy to combine with nuclides. Therefore, the combination of photodynamic therapy and nuclide therapy can be well combined, and it has a broad application prospect in the field of cancer treatment.
In this paper, five porphyrin compounds with different substituents were synthesized, and the antibacterial properties and cytotoxicity of the photosensitizers were investigated. 131I was used to mark the porphyrin compounds with good photodynamic properties, and the effects of the preparation conditions on the labeling rate were studied. Its properties in vivo and in vitro were preliminarily evaluated for its anti-tumor properties.
(1) the porphyrin compounds of five different substituents (-H, -NO2, -NH2, -OH, -OCH3), TPP, TPPNO2, TPPNH2, TPPOH and TPPOCH3, a metalloporphyrin CuTPPOCH3, two kinds of fulleren-porphyrin compounds, are designed, and the compounds are entered by IR, nuclear magnetic resonance hydrogen spectrum, mass spectrometry and ultraviolet visible spectrum. Characterization.
(2) the bacterial toxicity of porphyrin compounds TPP, TPPNO2, TPPNH2, TPPOH, TPPOCH3 and CuTPPOCH3 on Escherichia coli and Staphylococcus aureus under different concentrations and illumination conditions were investigated by the plate colony counting method. The results showed that the dark toxicity of the compounds was low, the toxicity of the compounds had obvious light and concentration dependence, and the light energy was associated with the light energy. There is a positive correlation between density and concentration; TPPOH has strong bacterial toxicity under light conditions. When the porphyrin ring in TPPOCH3 is complex with paramagnetic metal ions copper, the toxicity of bacteria is obviously decreased, and the inhibitory effect of the compound on Staphylococcus aureus is obviously better than that of Escherichia coli.
(3) the effects of porphyrin compounds TPP, TPPNO2, TPPNH2, TPPOH and TPPOCH3 on the survival rate of HL-7702 in human hepatocellular carcinoma cells, HepG2, SMMC-7721 and human normal hepatocytes were investigated. The results showed that the dark toxicity of the compounds was low, the cytotoxicity had obvious light and concentration dependence, and the relationship with light energy density and concentration was positively correlated; TPPOH The toxicity of the compounds to three kinds of cells was not significant.
(4) the molecular structure of TPPNH2 and TPPOH and their iodine markers were optimized by density functional theory (B3LYP), and the charge distribution and energy of Mulliken were calculated. The most possible loci of iodine labeled TPPNH2 and TPPOH were predicted theoretically.
(5) with chloramine T as an oxidant, TPPOH and TPPNH2 were labeled with 131I, and the effect of preparation conditions on the labeling rate was studied, and the marker of high degree of purity was obtained. The optimization conditions were as follows: a) 13II-TPPOH:pH was 5.5, TPPOH concentration 2mg/mL, chloramine T concentration 0.25mg/mL, reaction temperature 20 C, reaction time 15min, labeling rate 98%, b) 1.5, The concentration of H2 is 2mg/mL, the concentration of chloramine T is 3mg/mL, the reaction temperature is 95, the reaction time is 40min, the labeling rate 96%. is stable, the blood scavenging is faster, the liver and lung have higher affinity, the liver is the main metabolic pathway, the tumor has good accumulation and retention properties, which indicates that 131I-TPPOH and 131I-TPPNH2 have potential for the treatment of tumor. In value.
(6) the anti-tumor properties of 131I-TPPOH and 131I-TPPNH2 were evaluated preliminarily. The results showed that both 131I-TPPOH and 131I-TPPNH2 had good anti-tumor performance under the dual effects of 131I and porphyrin photodynamic therapy, but 131I-TPPOH had better anti-tumor performance and less toxicity. It was expected to be a dual efficacy tumor treatment. Medications.

【学位授予单位】：中国工程物理研究院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5

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