摘要
5-氟尿嘧啶(5-Fu)是一种在临床上已为人们熟知的一类抗瘤谱广、有效率高的抗代谢药物。它的结构与肿瘤细胞所必需的代谢结构尿嘧啶相类似,在同一系统酶中互相竞争,阻断代谢环节,阻碍DNA的合成,从而抑制肿瘤细胞的增殖。作为一种抗癌药物,它对多种肿瘤有抑制作用。但它的一大缺点是服药有效剂量与中毒量相近,在杀死癌细胞的同时正常细胞损伤也较严重。5-Fu半衰期短,仅10-20min,临床上为了维持长时间的稳态浓度,往往采取持续静脉滴注的给药方式;5-Fu口服吸收不完全,生物利用度低。这些缺点限制了它在临床上的广泛应用。因此,有必要开发新型5-FU缓释制剂,延长药物的半衰期,提高生物利用度。近些年来,许多化学家们对它们进行化学修饰,期望得到高效低毒的抗肿瘤前药。
在生物医学上,总是希望药物有高效的选择性,即对靶细胞有一定的识别能力,这样就可以最大限度地避免药物的副作用。光动力学治疗(photodynamic therapy,PDT)是20世纪新兴的一种肿瘤治疗方式,它是利用卟啉及其金属络合物对癌细胞有特殊的亲和性,能够在肿瘤细胞中有选择性的滞留,而且,卟啉化合物在有氧存在的情况下,经一定波长的光照后可吸收能量并激发出单线态氧而杀死癌细胞。利用它的这种特性,当卟啉化合物聚集在癌变部位时,用某种波段的光或激光照射病灶便可杀死癌细胞,从而达到治疗的目的。因此,作为癌定位剂和诊疗药物,卟啉化合物正受到化学界、医学界及生物学界的广泛关注。
为了减小5-氟尿嘧啶的毒副作用,我们将不同取代的苯基卟啉与5-氟尿嘧啶-1-基乙酸乙酯以不同形式化学键相连接,合成了六种“卟啉-5-氟尿嘧啶-1-基乙酸乙酯化合物”,期望卟啉起到生物导弹的作用,将5-氟尿嘧啶直接运至癌组织,杀伤癌细胞,提高药物的疗效,降低毒性。在激光能达到的部位,还可以配合激光技术进行治疗,以达更佳疗效。
本文设计合成了六种“卟啉-5-氟尿嘧啶-1-基乙酸乙酯”化合物,并且确证了它们的结构。具体内容如下:
1.通过红外光谱,紫外光谱,核磁共振谱及质谱确证了六种“卟啉-5-氟尿嘧啶-1-基乙酸乙酯化合物”的结构。
2.对以上各化合物的合成、分离和纯化条件进行了摸索和改进,得到了较好的结果。
5-Fluorouracil is a kind of popular antimetabolic drug used in clinic.It has the similar structure with uracil which is necessary to the cancer cell.It contents with uracil in the same enzyme system,blocks the metabolic link,impeds the synthesis of DNA,and then prohibits the propagation of the cancer cells.As a kind of antitumor drug,5-Fluorouracil has inhibition effect on many kinds of cancer,but it also seriously hurts the normal cells while it kills the cancer cells. The half life time of 5-FU in vivo is only10-20minutes and its bioavailbility is very low.Continuous infusion was commonly used to maintain long-time steady concentration. Its these shortcomings limit its application of clinic. In recent years,many chemists have modified their chemical structures and hope to develop a better drug to overecome its shortcomings.
In order to improve the target activity of anticancer medicine and reduce their untowa- rd effects,the effective drug is expected with high selectivity,which means it can distinguish target cell from normal cell properly. Phtodynamic therapy(PDT) is newly developed treatment for tumor since the 20th century.Porphyrin and metalloporphyrins have special affinity with cancer cell because their distinctive structure.They can be taken up and retained by tumor tissue selectively.With the appropriate light,they can produce fluorescence and kill the cancer cell.So the research on the use of porphyrin and metalloporphyrins for tumor localization and therapy have caused great interests of chemists,medicals and biologists.
In order to improve the lipophilicity and half life time of 5-FU,we synthesize 5-Fluo- rouracil-1-acetic ether .As the same time in order to decrease the toxicity of 5-Fluorouracil,we synthesized a series of porphyrin-5-Fluorouracil-1-acetic ether compounds.We expected these compounds can reach tumor tissue directly and kill cancer cell,so as to improve the curative effect.Furthermore, they cure cancer coordinating laser technology at the position of the body which the laser can reach for better curative effect.
In this paper,we synthesized and charactered six porphyrin-5-Fluorouracil-1-acetic ether compounds. The results are as follows:
In the first part, six porphyrin-5-Fluorouracil -1-acetic ether compounds have been prepared.That is,Phenylporphyrin substituted by different organs and 5-Fluorouracil-1-acetic ether were linked up by different bonds.The structures of six porphyrin-5-Fluorouracil- 1-acetic ether compounds have been characterized by UV, IR, 1HNMR and MS.
In the second part ,optimum reaction and separaion conditions have been reaserched and improved
引文
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