CN110357899B - 一类可示踪抗肿瘤鬼臼毒素衍生物及其制备和应用 - Google Patents
一类可示踪抗肿瘤鬼臼毒素衍生物及其制备和应用 Download PDFInfo
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- CN110357899B CN110357899B CN201910659179.4A CN201910659179A CN110357899B CN 110357899 B CN110357899 B CN 110357899B CN 201910659179 A CN201910659179 A CN 201910659179A CN 110357899 B CN110357899 B CN 110357899B
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Abstract
本发明公开了一类可示踪的抗结肠癌鬼臼毒素衍生物,是由鬼臼毒素类抗肿瘤活性分子和半花菁类近红外荧光试剂通过偶氮键连接,在结肠特有菌群分泌的偶氮还原酶作用下偶氮键发生断裂,同时释放抗肿瘤活性分子和半花菁类近红外荧光探针试剂,实现抗肿瘤活性分子结肠组织中靶向释放,并利用与抗肿瘤活性分子同时释放的荧光探针试剂的荧光成像分析可实现释放过程的同步示踪。其化学结构式如下:
Description
技术领域
本发明涉及一种抗肿瘤鬼臼毒素衍生物,尤其涉及一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,本发明同时还涉及该抗肿瘤鬼臼毒素衍生物在制备抗结肠癌药物中的应用,以及作为荧光成像检测试剂的应用,属于生物医药领域。
技术背景
鬼臼毒素(podophyllotoxin)是从小蘖科鬼臼属植物盾叶鬼臼Podophyllumpeltatum的根茎中分离得到的一种木脂素类化合物,具有较强的抗肿瘤活性。研究表明,鬼臼毒素及其衍生物具有多种抗肿瘤作用机制,主要有抑制微管蛋白聚合、抑制拓扑异构酶Ⅱ活性、自由基机制等。鬼臼毒素为先导衍生合成的多个活性化合物,如依托泊苷、替尼泊苷、NK-611、GL-331和NPE等已被FDA批准上市或处于临床研究阶段,主要用于结肠癌、非小细胞肺癌、卵巢癌等的治疗。但由于鬼臼毒素类药物靶向性差、病灶部位有效浓度低,导致其在临床用药时出现较强全身毒副作用。因此,开发鬼臼毒素类衍生物以增加其在病灶部位靶向性,对开发新型鬼臼毒素类抗肿瘤药物具有重要意义(Guerram M., etal. Chin. J. Nat. Med., 2012, 1, 161-169; 张仕金等,药学进展,2012, 36, 494-500)。
结肠癌是常见的消化系统恶性肿瘤之一,其发病率和死亡率逐年上升。据统计,2016年,我国结肠癌的发病率已上升至恶性肿瘤发病率的第五位,且有50%以上的结肠癌患者出现转移和复发,寻求新的治疗方法以实现对结肠癌靶向、高效和低毒治疗迫在眉睫。人体消化道系统中存在大量的微生物和细菌,但只有结肠中的厌氧菌的代谢过程中可产生偶氮还原酶。通过结肠内细菌产生的偶氮还原酶,设计制备含有偶氮键的化合物,可实现药物在结肠中靶向释放。近年来,国内外研究者对结肠靶向药物进行了系统深入的研究,目前已有多种偶氮还原酶触发型前药应用于临床结肠靶向治疗,例如,柳氮磺胺吡啶可在结肠中偶氮还原酶作用下,特异性的释放活性药物5-氨基水杨酸和磺胺,实现溃疡性结肠炎的靶向治疗;奥沙拉秦可在偶氮还原酶作用下分解为2分子的5-氨基水杨酸并用于结肠炎症的治疗等(朱文兵等,临床药物治疗杂志,2014, 12, 9-14;Ryan A., Brit. J. Pharmacol.,2017, 174, 2161-2173)。
设计合成可被结肠特有的偶氮还原酶降解的鬼臼毒素衍生物,可实现鬼臼毒素类药物的结肠靶向释放,增加在结肠病灶部位的有效药物浓度。利用偶氮还原酶为触发实现鬼臼毒素类药物的结肠靶向,存在关键问题在于结肠靶向释放鬼臼毒素衍生物的构筑和该衍生物在结肠中释药行为的实时监控。目前用于结肠中药物制剂的体内实时监测方法有γ-闪烁扫描法、硫酸钡造影X-射线检测、多层螺旋CT扫描技术和13C和15N2双向同位素标记技术等,但这些技术未能实现偶氮类前药在结肠中的代谢与活性药物释放过程的监控,且上述方法需要放射性标记,对人体有一定伤害,对于设备要求较高。半菁类荧光探针试剂吸收和发射光谱均处于近红外区(650~1000nm),在该范围内生物分子自身荧光较弱,可避免背景干扰而获得较高的分析灵敏度。并且近红外荧光具有较强的穿透性,通过近红外荧光成像能够观测到机体组织深部的信息。在药物分子上链接近红外荧光染料,有利于实现活体内药物吸收、分布和代谢信号的实时、在位、无损检测 (王少静等,中国新药杂志,2014,23, 1398-1401; AmidonSeth., et al. Aaps Pharmscitech, 2015, 16, 731-741; YuanL., et al. J. Am. Chem. Soc., 2012, 134, 13510-13523) 。
发明内容
本发明的目的在于提供一类可示踪抗肿瘤鬼臼毒素衍生物;
本发明的另一目的是提供一种上述可一类示踪抗肿瘤鬼臼毒素衍生物的制备方法;
本发明还有一个目的,就是提供上述一类可示踪的抗肿瘤鬼臼毒素衍生物的具体应用。
一、可示踪抗肿瘤鬼臼毒素衍生物
本发明的可示踪抗肿瘤鬼臼毒素衍生物,具有结构式(I)所示的化学结构:
其中,n选自1,2,3,4,5,6,7,8,9,10;
取代基R1选自H、甲基;R2选自氢、甲基、羧基、磺酸基、羟基、卤素、氨基;X-选自碘离子、溴离子、氯离子。
所述可示踪的抗结肠癌鬼臼毒素衍生物的制备方法,包括以下步骤:
(1)化合物2的合成:将化合物1溶解到干燥的二氯甲烷溶液中,0~4℃条件下加入还原剂氢化铝锂(以四氢呋喃溶液的形式加入),室温搅拌0.5~8h后;结束反应并用水淬灭、萃取、干燥,减压浓缩,柱层析分离,得化合物2。还原剂氢化铝锂与化合物1的摩尔比为1:0.4~1:2。
化合物1的制备方法参见文献方法(Tsai Y. H., et al. Nature Chemistry,2015, 7, 554-561),其结构式如下:
所得化合物2所对应的结构式如下:
(2)化合物3的合成:将化合物2溶解于干燥二氯甲烷中,加入缚酸剂三乙胺搅拌均匀;冷却至0~4℃,加入氯化剂二氯亚砜,室温搅拌反应0.5~8h;反应结束后经萃取、干燥,减压浓缩,柱层析分离,得化合物3;化合物3的结构式如下:
缚酸剂三乙胺与化合物2的摩尔比为 1:1~1:5;氯化剂二氯亚砜与化合物2的摩尔比为1:0.4~1:4;
(3)化合物5的制备:在有机溶剂中,碱存在下,化合物3和化合物4以1.5:1的摩尔比在60~200℃反应1~48小时;反应结束后经萃取、浓缩、纯化,得化合物5。
化合物4的制备方法参见文献方法(Yuan L., et al. J. Am. Chem. Soc. 2012,134, 13510-13523)。化合物4的机构式如下:
所得化合物5的结构式如下:
其中,n选自1,2,3,4,5,6,7,8,9,10;R2选自氢、甲基、羧基、磺酸基、羟基、卤素、氨基;X-选自碘离子、溴离子、氯离子。
(4)目标产物的合成:在有机溶剂中,碱存在下,化合物5和化合物6以1:0.1~1:100的摩尔比,在60~200℃反应1~48小时;反应结束后经萃取、浓缩、纯化,得目标化合物-—类可示踪的抗结肠癌鬼臼毒素衍生物。
其中,化合物6的制备方法参见文献方法(Lee K. H., et al. J. Med. Chem.,1990,33, 1364-1368)。其结构式如下:
其中,取代基R1选自H、甲基。
步骤(3)、(4)中,所述有机溶剂为四氢呋喃、乙腈、二氯甲烷、苯、甲苯、二甲苯、氯苯、三氯甲烷、甲醇、乙醇、石油醚、N,N-二甲基甲酰胺和二甲基亚砜中至少一种,优选乙腈。所述碱为有机碱、无机碱;其中有机碱为三乙胺、N, N-二异丙基乙胺,吡啶和4-二甲氨基吡啶;无机碱为碳酸钠、碳酸钾、氢氧化钠、碳酸铯、碳酸氢钠、碳酸氢钾、碳酸钡和氢氧化锂,优选碳酸钾。
可示踪的抗结肠癌鬼臼毒素衍生物的反应式如下:
二、可示踪抗肿瘤鬼臼毒素衍生物的抗结肠癌活性
以本发明实施例1制备的化合物Ib为例,通过体外抗肿瘤实验说明本发明可示踪抗肿瘤鬼臼毒素衍生物的体外抗结肠癌活性。
体外抗肿瘤实验采用MTT比色法,以鬼臼毒素临床在研药物GL-331作为阳性对照。收集处于指数生长期的结肠癌HCT 116细胞,1000 rpm离心5 分钟,弃上清,加入2 mL培养基重悬细胞,吸取10 μL细胞悬液至血细胞计数板,在倒置显微镜下计数。调整细胞密度至1×104/ mL,以1×104 /孔密度接种于细胞96孔培养板,每孔100 μL,37℃,5% CO2饱和湿度培养4小时。加入不同浓度的药物溶液,每个药物考察点设6~8个复孔,37℃,5% CO2饱和湿度培养48小时。每孔加入20 μL浓度为5 mg/mL的MTT溶液,37℃,5% CO2饱和湿度条件下反应4小时。终止反应:小心地吸取96孔板每孔的反应液,加入100 μL浓度为10%的SDS溶液,37℃,5% CO2饱和湿度条件下过夜。利用酶标仪测定每个反应孔在490 nm处的光密度OD值,从而计算药物对HCT 116细胞的抑制率。样品Ib的体外抗肿瘤活性如附图1所示。由图1可以看出,鬼臼毒素类临床二期药物GL-331表现抗HCT 116增殖活性,而本申请所提供的化合物Ib在不同浓度下均体现出对结肠癌HCT 116细胞较强的抑制活性。
体外抗肿瘤实验还表明,本发明合成的其他化合物在不同浓度下均体现出对结肠癌HCT 116细胞较强的抑制活性。因此可用于制备抗结肠癌药物。
三、可示踪抗肿瘤鬼臼毒素衍生物的荧光成像性能
以本发明实施例1制备的化合物Ib为例,对本发明合成的抗肿瘤鬼臼毒素衍生物的荧光成像进行分析。
本申请的可示踪抗结肠癌鬼臼毒素衍生物,在结肠菌群分泌的偶氮还原酶作用下偶氮键断裂,释放出的半花菁类近红外荧光试剂具有近红外波长的激发和发射,近红外穿透性强的优势有利于实现荧光的体内成像,因此该我们研究了化合物Ib在昆明种小鼠的体内的检测和成像。通过分别给两只小鼠灌胃注射0.5 mL生理盐水和0.5 mL浓度为100μM的化合物Ib,记为空白对照组小鼠和给药组小鼠,将上述小鼠培养12h后,使用小动物活体荧光成像仪进行荧光成像,结果如附图2所示。图中1号小鼠为空白对照组小鼠,2号小鼠为给药组小鼠。由图2可以看出,给药组小鼠腹部的荧光信号显著高于空白对照组小鼠,这是由于化合物Ib经灌胃后,在体内偶氮还原酶作用下偶氮键断裂,释放出荧光试剂,从而产生荧光信号。
实验表明,本发明合成的其他化合物给小鼠经灌胃后,均能在体内偶氮还原酶作用下偶氮键断裂,释放出荧光试剂,从而产生荧光信号。因此,可以用于药物在结肠释放过程的荧光成像分析。
综上所述,本发明制备的可示踪的抗结肠癌鬼臼毒素衍生物,具有靶向性高、抗肿瘤活性强和成像性能好等优点,可实现鬼臼毒素类化合物的靶向释放与释放过程的荧光成像分析一体化,对于推动肿瘤的精准、个性化治疗具有重要意义,在靶向药物的传递释放与可视化检测领域有潜在的应用价值。
附图说明
图1是化合物1b和GL-331对结肠癌细胞HCT-116的细胞毒活性图。
图2是生理盐水和化合物1b在昆明种小鼠的活体荧光成像图。
图3是化合物2的核磁共振氢谱图。
图4是化合物3的核磁共振氢谱图。
图5是化合物5a的核磁共振氢谱图。
图6是化合物Ia的核磁共振氢谱图。
图7是化合物Ib的核磁共振氢谱图。
具体实施方式
下面通过具体实施例对本发明可示踪抗肿瘤鬼臼毒素衍生物的合成方法做详细说明。
实施例1、样品Ia的制备
(1)化合物2的制备:在50 mL的圆底烧瓶中,将化合物1(269 mg,1 mmol)溶解于10mL的干燥二氯甲烷中,冰浴冷却至0 °C,逐滴加入氢化铝锂(40 mg,1 mmol)的四氢呋喃溶液(5 mL),0 °C搅拌30 分钟后室温搅拌4h。向上述反应液中缓慢加入2 mL水淬灭反应,将上述反应液用饱和碳酸氢钠溶液萃取三遍,有机相用无水硫酸钠干燥后,减压浓缩,柱层析分离,得到所述化合物,记为样品2(210 mg)。1H NMR (400 MHz, CDCl3): δ 7.78-7.85 (m,4H), 7.47 (d, J=8.0 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 4.76 (d, J=5.6 Hz, 2H),4.05 (s, 2H)。其结构式如下:
(2)化合物3的制备:在50 mL的圆底烧瓶中,将化合物2(227 mg,1 mmol)溶解于20mL的干燥二氯甲烷中,加入三乙胺(303 mg,3 mmol),室温搅拌3 分钟后冰浴冷却至0 °C,随后逐滴加入二氯亚砜(119 mg,1 mmol),室温搅拌4 h。将上述反应液用饱和碳酸氢钠溶液萃取三遍,有机相用无水硫酸钠干燥后,减压浓缩,柱层析分离,得到所述化合物,记为样品3(200 mg)。1H NMR (400 MHz, CDCl3): δ 7.80-7.84 (m, 4H), 7.49 (d, J=8.0 Hz,2H), 6.74 (d, J=8.8 Hz, 2H), 4.64 (s, 2H), 4.07 (brs, 2H)。其结构式如下:
(3)化合物5样品5a的制备:取化合物4a(511 mg,1mmol)于干燥的圆底烧瓶中,加入干燥的乙腈(5 mL)将其溶解,加入无水碳酸钾(276 mg,2 mmol)搅拌5 分钟后,加入化合物3(368 mg,1.5 mmol),室温搅拌10 分钟后加热回流反应4小时。将上述反应液过滤,减压浓缩,柱层析分离得到所述化合物,记为样品5a(327 mg)。1H NMR (400 MHz, DMSO): δ8.52 (d, J=14.8 Hz, 1H), 7.78-7.80 (m, 2H), 7.71-7.73 (m, 2H), 7.61-7.44 (m,4H), 7.51-7.54 (m, 2H), 7.42-7.46 (m, 2H), 7.15-7.16 (m, 1H), 7.06-7.09 (m,1H), 6.65 (d, J=8.8 Hz, 2H), 6.52 (d, J=14.8 Hz, 1H), 6.13 (s, 2H), 5.33 (s,2H), 3.86 (s, 3H), 2.64-2.69 (m, 4H), 1.80 (m 2H), 1.73 (s, 6H)。其结构式如下:
(4)目标产物样品Ia的制备:取化合物5a(360 mg,0.5mmol)于干燥的圆底烧瓶中,加入干燥的乙腈(5 mL),加入无水碳酸钾(138 mg,1mmol)搅拌5 分钟后,加入化合物6a(476 mg,1mmol),室温搅拌10 分钟后加热回流反应4小时。将上述反应液过滤,减压浓缩,柱层析分离得到所述化合物,记为样品Ia(289 mg)。1H NMR (400 MHz, CDCl3): δ 8.61(d, J=14.8 Hz, 1H), 7.86-7.91 (m, 4H), 7.61 (d, J=8.4 Hz, 2H), 7.47-7.50 (m,2H), 7.41 (d, J=8.4 Hz, 2H), 7.37-7.39 (m, 1H), 7.30 (s, 1H), 6.98-7.01 (m,1H), 6.96 (s, 1H), 6.81(s, 1H), 6.75 (d, J=8.8 Hz, 2H), 6.55 (s, 1H), 6.49(d, J=15.2 Hz, 1H), 6.36 (s, 2H), 5.98 (d, J=9.2 Hz, 2H), 5.32 (s, 2H), 4.89-4.91 (m, 1H), 4.82-4.83 (m, 1H), 4.64 (d, J=4.8 Hz, 1H), 4.44 (t, J=7.6 Hz,1H ), 4.01 (s, 3H), 3.96-3.98 (m, 1H), 3.83 (s, 3H), 3.79 (s, 6H), 3.28-3.33(m. 1H), 3.08-3.12 (m, 1H), 2.72-2.78 (m, 4H), 1.93 (t, J=6.0 Hz, 2H ), 1.79(s, 6H).
实施例2、样品Ib的制备
(1)化合物2的制备:同实施例1;
(2)化合物3的制备:同实施例1;
(3)化合物5a的制备:同实施例1;
(4)样品Ib的制备:取化合物5a(360 mg,0.5 mmol)于干燥的圆底烧瓶中,加入干燥的乙腈(5 mL),加入无水碳酸钾(138 mg,1 mmol)搅拌5 分钟后,加入化合物6b(476 mg,1 mmol),室温搅拌10 分钟后加热回流反应4小时。将上述反应液过滤,减压浓缩,柱层析分离得到所述化合物,记为样品Ib(212 mg)。1H NMR (400 MHz, DMSO): δ 8.56 (d, J=14.8Hz, 1H), 8.33 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.74-7.77 (m, 3H), 7.66-7.68(m, 2H), 7.52-7.57 (m, 2H), 7.46-7.48 (m, 2H), 7.20 (s, 1H), 7.11 (d, J=8.4Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.84(s, 1H), 6.54-5.59 (m, 2H), 6.28 (s,2H), 6.01 (d, J=12.8 Hz, 2H), 5.38 (s, 2H), 5.06-5.08 (m, 1H), 4.55 (d, J=4.8Hz, 1H), 4.41 (t, J=8.0 Hz, 1H ), 3.89 (s, 3H), 3.69 (m, 1H), 3.66 (s, 6H),3.17-3.18 (m. 1H), 3.06-3.12 (m, 1H), 2.67-2.73 (m, 4H), 1.83 (m, 2H ), 1.75(s, 6H)。样品Ib的结构式如下:
Claims (9)
2.如权利要求1所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,包括如下步骤:
(1)化合物2的合成:将化合物1溶解到干燥的二氯甲烷溶液中,0~4℃条件下加入还原剂氢化铝锂,搅拌反应0.5~8h后常温反应;反应结束后加水淬灭、萃取、干燥,减压浓缩,柱层析分离,得化合物2;
化合物1的结构式如下:
所得化合物2的结构式如下:
(2)化合物3的合成:将化合物2溶解于干燥二氯甲烷中,加入缚酸剂三乙胺搅拌均匀;冷却至0~4℃,加入氯化剂二氯亚砜,室温搅拌反应0.5~8h;反应结束后经萃取、干燥,减压浓缩,柱层析分离,得化合物3;
化合物3的结构式如下:
(3)化合物5的制备:在有机溶剂中,碱存在下,化合物3和化合物4以1.5:1的摩尔比在60~200℃反应1~48小时;反应结束后经萃取、浓缩、纯化,得化合物5;
化合物4的结构式如下:
所得化合物5的结构式如下:
其中,n选自1,2,3,4,5,6,7,8,9,10;R2选自氢、甲基、羧基、磺酸基、羟基、卤素、氨基;X-选自碘离子、溴离子、氯离子;
(4)目标产物的合成:在有机溶剂中,碱存在下,化合物5和化合物6以1:0.1~1:100的摩尔比,在60~200℃反应1~48小时;反应结束后经萃取、浓缩、纯化,得目标化合物——可示踪抗肿瘤鬼臼毒素衍生物;
化合物6的结构式如下:
其中,取代基R1选自H、甲基。
3.如权利要求2所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,其特征在于:步骤(1)中,还原剂氢化铝锂与化合物1的摩尔比为 1:0.4~1:2。
4.如权利要求2所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,其特征在于:步骤(2)中,三乙胺与化合物2的摩尔比为 1:1~1:5。
5.如权利要求2所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,其特征在于:步骤(2)中,氯化剂二氯亚砜与化合物2的摩尔比为1:0.4~1:4。
6.如权利要求2所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,其特征在于:步骤(3)、(4)中,所述有机溶剂为四氢呋喃、乙腈、二氯甲烷、苯、甲苯、二甲苯、氯苯、三氯甲烷、甲醇、乙醇、石油醚、N,N-二甲基甲酰胺和二甲基亚砜中至少一种。
7.如权利要求2所述一类可示踪抗肿瘤鬼臼毒素衍生物的制备方法,其特征在于:步骤(3)、(4)中,所述碱为三乙胺、N, N-二异丙基乙胺、吡啶、4-二甲氨基吡啶、碳酸钠、碳酸钾、氢氧化钠、碳酸铯、碳酸氢钠、碳酸氢钾、碳酸钡、氢氧化锂。
8.如权利要求1所述一类可示踪抗肿瘤鬼臼毒素衍生物在制备抗结肠癌药物中的应用。
9.如权利要求1所述一类可示踪抗肿瘤鬼臼毒素衍生物在制备荧光成像检测试剂中的应用。
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