双靶点抗肿瘤化合物GI-06合成工艺研究

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摘要现在我国有上百万肿瘤患者，因此研发抗肿瘤药物是刻不容缓的任务。如今，恶性肿瘤的治疗方法主要有三种，分别为放疗、化疗和外科手术。恶性肿瘤首要的治疗方法是外科手术，但是对于较为晚期的恶性肿瘤尤其是伴随转移灶的肿瘤，外科手术往往无法根治。此时，化疗成为供选择的主要治疗方法。传统的化疗的最大缺点就是给药时的无选择性。由于大部分的常用抗肿瘤药物分子量都不大，因此当这些药物进入人体后，就很容易向各个部分扩散。况且这些药物对病理组织缺少特异亲和性，不能够选择性地富集在病理器官和组织上，所以就不能达到理想的治疗效果。此外，药物在体内扩散的过程中，尚未到达病理区域时，药物需要通过许多生物屏障并部分停留屏障中，例如其他健康的细胞、组织和器官。在这些部位上，药物不仅不能充分发挥药效，甚至还会对这些器官产生副作用。而对于病理部位，药物则因不能达到规定的浓度无法起到所需的治疗效果。而传统细胞毒药物具有较差的选择性、容易产生耐药性、较强的毒副作用等问题，而为了能够有效针对正常细胞和肿瘤细胞之间的区别产生的靶点特异性抗肿瘤药物则达到了毒性低、选择性高等治疗效果。随着蛋白酪氨酸激酶抑制剂Gleevec等新药的不断涌现，抗肿瘤药物研发迎来了一个新的时代——靶向治疗。由于单靶点的药物并不能彻底杀死肿瘤细胞，因此多种药物联用成为癌症临床治疗的主要策略。虽然该方法在一定程度上能提高治疗效果，但由于多种药物彼此间容易发生拮抗，如对药物的吸收和代谢产生影响；而且，这些药物通常也不能以它们单独应用时的剂量联用。本文在借鉴多种药物联合用药的基础上，采用“药效团拼合”的方法，将两种或两种以上的药效团拼成一个分子，使这个分子本身或其代谢产物作用于两个或更多的靶点，从而产生协同作用以提高疗效。49357

毕业论文关键词：多靶点；抗肿瘤；靶向治疗；结合位点

Abstract

Today, there are 2.2 million cancer patients in china,and the task of developing anti-tumor drugs is arduous and lengthy. At present, there are several methods for the treatment of malignant tumors, including: radiotherapy, chemotherapy and surgery, etc.. Surgery is the primary treatment for malignant tumors, but it is often unable for the more advanced malignant tumors, especially with the metastasis of the tumor.At this time,chemotherapy is become the main treatment measure in most cases.. The biggest disadvantage of chemotherapy is that there is no selective to the medicine. Since most of the commonly used anti tumor drug molecules are small, so when these drugs into the human body system, it is easy to spread to all parts of the. However, the lack of specific affinity of these drugs will not be able to selectively enriched in pathological organs and tissues, so it can not achieve the desired therapeutic effect. In addition, in the process of diffusion of the drug in the body, the drug can only pass through numberous of biological barriers and part of the barrier, such as other healthy cells, tissues and organs in the absence of pathological regions. In these parts, drugs not only failed to give full play of the efficacy, but also have the side effects of these organs. For the pathological parts, the drug can not reach the required concentration so can not play an ideal therapeutic effect for us. Traditional cytotoxic drugs have poor selectivity, strong side effects, easy to produce drug resistance and other characteristics and target anti-tumor drugs can effectively for the difference between normal and tumor cells, to achieve the therapeutic effect of low toxicity, high selectivity. As the protein tyrosine kinase inhibitor named Gleevec was constantly emerging, research and development of anti tumor access in a new stage - Targeted Therapy. As a target of the drug didn't kill tumor cells thoroughly, therefore, a variety of drugs combined with drug treatment become the main strategy for cancer treatment. Although this method can achieve the desired therapeutic effects in a certain extent can achieve the desired therapeutic effect, but due to multiple drugs each other easy interaction, such as the absorption and metabolism of drugs impact, even in the absence of interaction These drugs are usually unable to be applied to dose combination, inpidually. Hence, we can refer to the principle of multiple drugs and using method of "pharmacophore split" in this paper, two or more than two kinds of pharmacophore will knock together in a molecule, the molecule itself or its metabolites have effect on two or more targets, to creat synergistic in order to enhance the curative effect.