新型微管蛋白抑制劑先導(dǎo)化合物的優(yōu)化及其構(gòu)效關(guān)系研究
發(fā)布時間：2018-11-03 19:09
【摘要】：過去的十多年里,一類新的抗腫瘤藥—腫瘤血管阻斷劑(vascular disrupting agents,VDAs)引起廣泛關(guān)注。與血管生成抑制劑(angiogenesis inhibitors,AIs)不同,腫瘤血管阻斷劑以成熟的腫瘤血管為靶標(biāo),通過調(diào)節(jié)細(xì)胞凋亡過程引起血管坍塌而發(fā)揮抗腫瘤作用。正常組織和腫瘤的脈管系統(tǒng)之間的形態(tài)學(xué)差異使得腫瘤血管阻斷劑優(yōu)先阻斷腫瘤組織的血流而不影響正常組織的供血。目前,進(jìn)入臨床實驗的十多種腫瘤血管阻斷劑中,進(jìn)展最快的CA-4P(即CA-4的磷酸前體藥)已經(jīng)進(jìn)入三期臨床用來治療未分化的甲狀腺癌,對非小細(xì)胞性肺癌的治療也已進(jìn)行到二期臨床。盡管目前尚不清楚其具體作用機(jī)制,但這類化合物大都有相同的藥理作用,如抑制微管聚集,競爭秋水仙堿結(jié)合位點(diǎn)以及破壞腫瘤血管骨架等。本課題組前期抗腫瘤新藥研究中發(fā)現(xiàn)了一系列具有高抗癌活性的新化合物,如下圖所示先導(dǎo)物1。后續(xù)又對C環(huán)進(jìn)行優(yōu)化(骨架躍遷)得到了化合物2,作為新的先導(dǎo)物。先導(dǎo)物1和2具有相當(dāng)強(qiáng)的抗癌活性,其GI50分別為1.5-1.7 n M,1.9-3.2 n M,它們對微管的聚集也有一定的抑制作用,其IC50分別為0.93μM,0.77μM,較CA-4而言其微管聚集抑制活性相當(dāng)甚至更強(qiáng),進(jìn)一步的研究也表明其能破壞腫瘤血管。因此,此類化合物將有潛力成為新的抗腫瘤候選藥。課題組前期研究顯示,某些藥效基團(tuán)對先導(dǎo)物活性而言是必須的。本論文對先導(dǎo)物的優(yōu)化集中于A/B環(huán)、C環(huán)和取代基團(tuán)(R_1、R_2、R_3),設(shè)計并最終合成了相關(guān)衍生物24個。所有新化合物均進(jìn)行了抑制多種人腫瘤細(xì)胞生長實驗。其中,9b,11a以及11b均對多種人腫瘤細(xì)胞系有良好抑制活性(GI50=5 n M),與先導(dǎo)物活性相當(dāng)。此外,少數(shù)化合物還進(jìn)行了抑制微管聚集和秋水仙堿結(jié)合實驗,確定新化合物和先導(dǎo)物具有相同作用機(jī)制。另一方面,經(jīng)修飾C環(huán)的7a,8c活性卻大大的降低(GI5010μM),暗示著C環(huán)可能對化合物活性極其重要。本論文研究得到了更為系統(tǒng)和明確的構(gòu)效關(guān)系,為課題進(jìn)一步研究奠定基礎(chǔ),有助于指導(dǎo)新一輪的結(jié)構(gòu)優(yōu)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.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914
本文編號：2308704
[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.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 陳萬青;鄭榮壽;張思維;曾紅梅;左婷婷;賈漫漫;夏昌發(fā);鄒小農(nóng);赫捷;;2012年中國惡性腫瘤發(fā)病和死亡分析[J];中國腫瘤;2016年01期
，本文編號：2308704
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