新型微管蛋白抑制剂先导化合物的优化及其构效关系研究

发布时间：2018-11-03 19:09

【摘要】：过去的十多年里,一类新的抗肿瘤药—肿瘤血管阻断剂(vascular disrupting agents,VDAs)引起广泛关注。与血管生成抑制剂(angiogenesis inhibitors,AIs)不同,肿瘤血管阻断剂以成熟的肿瘤血管为靶标,通过调节细胞凋亡过程引起血管坍塌而发挥抗肿瘤作用。正常组织和肿瘤的脉管系统之间的形态学差异使得肿瘤血管阻断剂优先阻断肿瘤组织的血流而不影响正常组织的供血。目前,进入临床实验的十多种肿瘤血管阻断剂中,进展最快的CA-4P(即CA-4的磷酸前体药)已经进入三期临床用来治疗未分化的甲状腺癌,对非小细胞性肺癌的治疗也已进行到二期临床。尽管目前尚不清楚其具体作用机制,但这类化合物大都有相同的药理作用,如抑制微管聚集,竞争秋水仙碱结合位点以及破坏肿瘤血管骨架等。本课题组前期抗肿瘤新药研究中发现了一系列具有高抗癌活性的新化合物,如下图所示先导物1。后续又对C环进行优化(骨架跃迁)得到了化合物2,作为新的先导物。先导物1和2具有相当强的抗癌活性,其GI50分别为1.5-1.7 n M,1.9-3.2 n M,它们对微管的聚集也有一定的抑制作用,其IC50分别为0.93μM,0.77μM,较CA-4而言其微管聚集抑制活性相当甚至更强,进一步的研究也表明其能破坏肿瘤血管。因此,此类化合物将有潜力成为新的抗肿瘤候选药。课题组前期研究显示,某些药效基团对先导物活性而言是必须的。本论文对先导物的优化集中于A/B环、C环和取代基团(R_1、R_2、R_3),设计并最终合成了相关衍生物24个。所有新化合物均进行了抑制多种人肿瘤细胞生长实验。其中,9b,11a以及11b均对多种人肿瘤细胞系有良好抑制活性(GI50=5 n M),与先导物活性相当。此外,少数化合物还进行了抑制微管聚集和秋水仙碱结合实验,确定新化合物和先导物具有相同作用机制。另一方面,经修饰C环的7a,8c活性却大大的降低(GI5010μM),暗示着C环可能对化合物活性极其重要。本论文研究得到了更为系统和明确的构效关系,为课题进一步研究奠定基础,有助于指导新一轮的结构优化。
[Abstract]:In the past decade, a new class of anti-tumor agents-tumor vascular blocker (vascular disrupting agents,VDAs) has attracted wide attention. Unlike angiogenesis inhibitors (angiogenesis inhibitors,AIs), tumor vascular blockers target mature tumor blood vessels and play an antitumor role by regulating the process of apoptosis, which results in the collapse of blood vessels. The morphological differences between the normal tissue and the vascular system of the tumor make the tumor vascular blocker block the blood flow of the tumor tissue and not affect the blood supply of the normal tissue. At present, among the more than ten kinds of tumor vascular blockers that enter clinical trials, CA-4P, the precursor of CA-4, has been used to treat undifferentiated thyroid cancer. Treatment of non-small cell lung cancer has also been carried out to the second-stage clinical. Although its specific mechanism is still unknown, most of these compounds have the same pharmacological effects, such as inhibition of microtubule aggregation, competition for colchicine binding sites and destruction of tumor vascular skeleton. A series of new compounds with high anticancer activity have been found in the preliminary study of new anti-tumor drugs, as shown in the figure below. Subsequently, the C-ring was optimized (skeleton transition) and compound 2 was obtained as a new precursor. The GI50 of lead 1 and 2 were 1.5-1.7 n MU 1.9-3.2 nMrespectively. They also inhibited the aggregation of microtubules, and their IC50 were 0.93 渭 M ~ 0.77 渭 M, respectively. The inhibitory activity of microtubule aggregation is even stronger than that of CA-4, and further studies have shown that it can destroy tumor blood vessels. Therefore, such compounds will have the potential to become new anti-tumor candidates. The previous study of our group showed that some effective groups were necessary for the activity of the lead. In this paper, the optimization of the precursors is focused on the A / B ring, C ring and substituent group (R _ 1 / R _ 2T _ 2 / R _ S _ 3), and 24 related derivatives have been designed and synthesized. All the new compounds were used to inhibit the growth of human tumor cells. Among them, 9b, 11a and 11b had good inhibitory activity on various human tumor cell lines (GI50=5 n M), and lead activity were comparable. In addition, the inhibition of microtubule aggregation and colchicine binding experiments of a few compounds have been carried out. It is concluded that the new compounds and the lead compounds have the same mechanism of action. On the other hand, the activity of modified C ring 7a ~ (8) c is greatly reduced (GI5010 渭 M), suggests that C ring may be extremely important to the activity of the compound). In this paper, a more systematic and explicit structure-activity relationship is obtained, which lays a foundation for further research and helps to guide the new round of structural optimization.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

【参考文献】