CN106478734B - 一种具有抗癌活性的吡唑官能团化的氮杂环卡宾钌化合物及其制备方法和应用 - Google Patents
一种具有抗癌活性的吡唑官能团化的氮杂环卡宾钌化合物及其制备方法和应用 Download PDFInfo
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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Abstract
本发明公开了一种具有抗癌活性的吡唑官能团化的氮杂环卡宾钌化合物及其制备方法和应用。本发明以5‑甲基‑1‑氢‑吡唑甲酸乙酯为起始化合物,通过烷基化、还原、氯化、成盐和金属交换反应得到吡唑官能团化的氮杂环卡宾钌化合物,通式可表示为[LRu(p‑cymene)Cl](X)(L=吡唑官能团化的氮杂环卡宾配体,X为阴离子)。该种氮杂环卡宾钌化合物在乳腺癌细胞(Bcap‑37)、肠癌细胞(LoVo)、胃癌细胞(SCG7901)和耐顺铂胃癌细胞(SCG7901‑R)的细胞毒性实验中,能有效抑制癌细胞分裂繁殖。该种氮杂环卡宾钌化合物结构多变、合成方便、性能稳定、环境友好,在空气中能长期稳定存在,在制药和精细化工行业中具有广泛的应用前景。
Description
技术领域
本发明属于抗癌药物领域,具体涉及一种具有抗癌活性的吡唑官能团化的氮杂环卡宾钌化合物。
背景技术
金属化合物在抗肿瘤药物领域里具有非常大的应用价值,例如最早被批准运用于临床的顺铂类金属化合物,如今已作为化疗药物用来治疗癌症。但是顺铂类药物在使用过程会有剂量限制性毒性和使癌细胞产生耐药性。为了克服这些缺点,就需要寻找更多更新颖的金属化合物。
氮杂环卡宾金属化合物因其具有稳定的配位能力、合成方便、结构多变,在生物化学领域得到了广泛的应用。其中氮杂环卡宾金、银、铂、钌具有抗肿瘤活性,显示出了潜在的药用价值。因此,开发一类具有抗癌活性的氮杂环卡宾钌化合物在抗癌药物研发方面具有重要意义。
发明内容
本发明的目的是提供一种新的具有抗癌活性的吡唑官能团化的氮杂环卡宾钌化合物及其制备方法和应用。
一种吡唑官能团化的氮杂环卡宾钌化合物,结构通式为[LRu(p-cymene)Cl]+(X)-,其中阳离子[LRu(p-cymene)Cl]+的结构式如下:
其中,R1和R2独立地选自C1~C5烷基、取代或者未取代的苄基、取代或者未取代的苯基;
所述的苄基或苯基上的取代基选自一个或多个C1~C5烷基、卤素、三氟甲基。
该类化合物以吡唑官能团化的氮杂环卡宾化合物为配体,其中心原子为二价钌金属离子,分别与一个吡唑碳原子、一个卡宾碳原子,一个氯离子和一个p-cymene基团配位。
其中吡唑官能团化的氮杂环卡宾配体的结构如下:
作为优选,所述的R1和R2独立地选自甲基、乙基、异丙基、苄基、2,4,6-三甲基苯基、2,6-二异丙基苯基、4-叔丁基苄基、4-三氟甲基苄基、2,3,4,5,6-五甲基苄基或2,3,4,5,6-五氟苄基。
作为优选,所述的氮杂环卡宾钌化合物的阴离子X-为六氟磷酸根离子,四氟硼酸根离子或卤素离子。
本发明还提供了一种所述的氮杂环卡宾钌化合物的制备方法,包括:
(1)以乙腈为溶剂,加入吡唑官能化的咪唑盐配体和氧化银,避光反应4-6小时,得到中间反应液;
其中,咪唑盐配体的结构如下:
(2)向步骤(1)得到的中间反应液中加入[Ru(p-cymene)Cl2]2,继续反应2-4小时,经过后处理得到所述的氮杂环卡宾钌化合物。
步骤(1)中,咪唑盐配体和氧化银的摩尔比为2:1,反应温度为40~60℃。
其中,原料咪唑盐配体采用如下方法制备得到:以5-甲基-1-氢-吡唑甲酸乙酯为起始化合物,通过烷基化、还原、氯化、与取代咪唑反应得到吡唑官能化的咪唑盐配体。
步骤(2)中,咪唑盐配体与[Ru(p-cymene)Cl2]2的摩尔比为2:1,反应温度为室温。
所述的后处理包括:对反应液进行过滤,滤液浓缩,加入乙醚,重结晶得到吡唑官能化的氮杂环卡宾钌化合物。
本发明还提供了一种所述的氮杂环卡宾钌化合物在制备抗癌药物中的应用。
作为优选,所述的抗癌药物用于预防或/和抑制乳腺癌细胞(Bcap-37)、肠癌细胞(LoVo)、胃癌细胞(SCG7901)和耐顺铂胃癌细胞(SCG7901-R)
本发明合成的新型吡唑官能化的氮杂环卡宾钌化合物,其中吡唑环上的取代基和咪唑环上的取代基容易改变、易于合成、性能稳定、环境友好,在空气中能长期稳定存在。在乳腺癌细胞(Bcap-37)、肠癌细胞(LoVo)、胃癌细胞(SCG7901)和耐顺铂胃癌细胞(SCG7901-R)的细胞毒性实验中,表现出非常理想的生物活性,能有效抑制癌细胞分裂繁殖。
具体实施方式
通过下述实施例将有助于理解本发明,但不限制本发明的内容。
实施例1
5-甲基-1-氢-吡唑甲酸乙酯(30.8g,200mmol)溶于200mL干燥四氢呋喃溶液中,在冰浴条件下缓慢加入去油氢化钠(4.8g,200mmol),完全加入氢化钠后升温至50℃搅拌1小时,冷却至室温。然后将碘甲烷(28.2g,200mmol)溶于100mL四氢呋喃中,缓慢滴加到反应中,滴加完毕,加热至50℃继续搅拌2小时。反应完全后,冷却至室温,减压除去四氢呋喃,然后加入100mL水,用乙酸乙酯萃取(100mL×3),合并有机层,干燥,减压除去乙酸乙酯得到5-甲基-1-甲基-吡唑甲酸乙酯26.6g,85%。在干燥的三颈烧瓶中加入氢化铝锂(3.8g,100mmol),200mL干燥的四氢呋喃,然后将5-甲基-1-甲基-吡唑甲酸乙酯(16.8g,100mmol)溶于100mL干燥的四氢呋喃中,缓慢滴加到三颈烧瓶中,滴加完毕继续搅拌4小时。还原完毕,滴加无水乙醇除去剩余的四氢铝锂,减压除去四氢呋喃后加入500mL甲醇,调节pH至中性,加热回流6小时,抽滤,滤液浓缩后溶于100mL二氯甲烷,过滤,并用50mL饱和氯化钠水溶液洗涤两次,有机层干燥后浓缩得到5-甲基-1-甲基-吡唑甲醇8.8g,70%。将5-甲基-1-甲基-吡唑甲醇(6.3g,50mmol)溶于20mL二氯甲烷溶液中,缓慢滴加二氯亚砜(6g,50mmol),滴加完毕继续搅拌2小时,反应完全后缓慢加入饱和碳酸氢钠水溶液调节pH至中性,然后加入200mL二氯甲烷萃取,有机层合并、干燥、浓缩、后得到3-氯甲基-1-甲基-5-甲基吡唑6.5g,90%。在50mL圆底烧瓶中加入3-氯甲基-1-甲基-5-甲基吡唑(1.44g,10mmol)和N-(2,4,6-三甲基苯基)咪唑(1.86g,10mmol),乙腈20mL,加热回流6小时,冷却至室温,减压蒸除溶剂,将得到的固体溶于水,过滤,滤液中滴加饱和六氟磷酸铵水溶液,析出固体,干燥后得到3.8g咪唑盐配体(HL1PF6),产率88%。
在50℃温度下,将配体HL1PF6,440mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到355mg氮杂环卡宾配体配位的钌化合物1,产率50%。1H NMR(CD3CN):7.51(s,1H),7.20(s,1H),7.16(s,1H),7.00(s,1H),6.34(s,1H),5.88,5.76,5.41,5.32(both d,4H),5.30,4.96(both d,2H),3.82(s,3H),2.50(s,3H),2.38(s,3H),2.24(s,3H),2.00(s,3H),1.99-1.97(m,1H),1.62(s,3H),1.12,0.60(both d,6H).13C NMR(CD3CN):175.8(Ru-C),145.8,144.3,144.1,140.2,138.8,137.5,136.8,130.0,128.6,125.2,121.2,108.4,90.5,88.5,48.8,46.2,31.6,24.0,21.0,19.8,19.6,17.8,15.4,11.1ppm。
实施例2
配体HL2PF6参照实施例1方法合成,溴乙烷代替碘甲烷。在50℃温度下,加入配体HL2PF6,454mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到333mg氮杂环卡宾配体配位的钌化合物2,产率46%。1H NMR(400MHz,CD3CN):7.54(s,1H),7.16(s,1H),7.14(s,1H),6.99(s,1H),6.36(s,1H),5.86,5.78,5.43,5.34(both d,4H),5.31,4.96(both d,2H),4.86-4.69(m,2H),2.48(s,3H),2.36(s,3H),2.25(s,3H),2.02(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.40(t,3H),1.14,0.58(both d,6H)ppm。13C NMR(CD3CN):173.8(Ru-C),146.8,146.3,146.1,140.1,138.7,136.5,136.4,129.9,128.8,126.2,124.2,107.4,89.5,87.5,47.8,46.1,31.5,23.9,20.7,19.7,19.6,18.0,17.9,15.4,12.2ppm。
实施例3
配体HL3PF6参照实施例1方法合成,异丙基溴代替碘甲烷。在50℃温度下,加入配体HL3PF6,468mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到353mg氮杂环卡宾配体配位的钌化合物3,产率53%。1H NMR(CD3CN):7.50(s,1H),7.22(s,1H),7.18(s,1H),6.80(s,1H),6.30(s,1H),5.82,5.72,5.41,5.30(both d,4H),5.26,4.86(both d,CH2,2H),4.04(m,1H),2.42(s,CH3,3H),2.34(s,3H),2.26(s,3H),2.12(s,3H),1.98-1.92(m,1H),1.62(s,3H),1.56(d,6H),1.16,0.60(both d,6H)ppm。13C NMR(CD3CN):171.8(Ru-C),145.8,145.3,144.1,141.1,139.7,136.5,136.4,128.9,128.0,125.2,123.2,108.4,90.5,88.5,48.8,46.1,32.5,24.1,21.7,19.0,18.8,18.0,15.9,13.4,11.2ppm。
实施例4
配体HL4PF6参照实施例1方法合成,苄基溴代替碘甲烷。在50℃温度下,加入配体HL4PF6,516mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到472mg氮杂环卡宾配体配位的钌化合物4,产率60%。1H NMR(CD3CN):7.54(s,1H),7.16(s,1H),7.16(s,1H),7.14-7.12(m,3H),7.06(s,2H),7.07(s,1H),6.99(s,1H),6.36(s,1H),5.86,5.78,5.43,5.34(both d,4H),5.31(d,2H),4.69(d,2H),2.48(s,3H),2.36(s,3H),2.25(s,3H),2.02(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.14,0.58(both d,6H)ppm。13C NMR(CD3CN):177.0(Ru-C),147.1,146.8,146.6,142.1,140.7,138.5,138.4,138.3,129.9,129.1,128.8,128.7,126.2,125.6,124.0,110.4,88.5,86.5,48.8,47.1,32.5,25.9,22.7,19.8,19.2,18.2,18.0,13.2ppm。
实施例5
配体HL5PF6参照实施例1方法合成,(2,4,6-三甲基)苄氯代替碘甲烷。在50℃温度下,加入配体HL5PF6,558mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到356mg氮杂环卡宾配体配位的钌化合物5,产率43%。1H NMR(CD3CN):7.50(s,CH,1H),7.10(s,CH,1H),7.14-6.90(m,4H),6.36(s,1H),5.60-5.43,(m,4H),5.31,4.99(both d,2H),4.90(s,2H),2.47(s,3H),2.38(s,3H),2.35(s,6H),2.30(s,3H),2.28(s,3H),2.02(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.10-0.80(m,6H)ppm。13C NMR(CD3CN):169.8(Ru-C),148.8,147.3,145.1,141.1,139.7,137.5,137.4,135.2,136.7,129.5,128.6,126.0,124.0,107.2,89.3,87.2,47.5,46.0,31.3,24.7,23.5,20.2,19.7,19.6,18.4,18.0,17.9,12.8ppm。
实施例6
配体HL6PF6参照实施例1方法合成,(4-叔丁基)苄氯代替碘甲烷。在50℃温度下,加入配体HL6PF6,572mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到354mg氮杂环卡宾配体配位的钌化合物6,产率42%。1H NMR(CD3CN):7.45(s,1H),7.34(d,2H)7.20(s,1H),7.15(d,2H),7.14(s,1H),6.99(s,1H),6.35(s,1H),5.66,5.40(both d,4H),5.30,4.95(both d,CH2,2H),4.84(m,2H),2.48(s,3H),2.36(s,3H),2.26(s,3H),2.04(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.40(s,9H),1.14,0.60(both d,6H)ppm。13C NMR(CD3CN):170.0(Ru-C),148.6,146.4,146.2,146.0,140.2,138.5,136.4,136.3,136.2,129.9,128.9,126.9,126.0,124.8,124.0,107.2,89.6,87.4,47.5,46.0,34.0,31.1,31.0,23.9,20.5,19.8,19.5,18.0,17.6,12.0ppm。
实施例7
配体HL7PF6参照实施例1方法合成,(4-三氟甲基)苄氯代替碘甲烷。在50℃温度下,加入配体HL7PF6,584mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到461mg氮杂环卡宾配体配位的钌化合物7,产率54%。1H NMR(CD3CN):7.54-7.50(m,3H),7.16-7.15(m,3H),7.00-6.99(m,2H),6.06(s,1H),5.80,5.38(both d,4H),5.30,4.98(both d,2H),4.60(m,2H),2.50(s,3H),2.39(s,3H),2.28(s,3H),2.07(s,3H),1.99-1.96(m,1H),1.66(s,3H),1.10,0.66(both d,6H)ppm。13C NMR(CD3CN):168.8(Ru-C),146.6,146.6,146.0,140.2,138.5,136.3,136.6,129.8,128.4,126.7,125.7,127.5,124.2,107.7,89.5,87.2,47.5,46.4,31.6,23.8,20.7,19.5,19.4,18.8,17.4,11.1ppm。
实施例8
配体HL8PF6参照实施例1方法合成,(五氟甲基)苄氯代替碘甲烷。在50℃温度下,加入配体HL8PF6,606mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到534mg氮杂环卡宾配体配位的钌化合物8,产率61%。1H NMR(CD3CN):7.51(s,1H),7.12(s,1H),7.10(s,1H),6.98(s,1H),6.35(s,1H),5.84,5.76,5.41,5.32(both d,4H),5.31,4.96(both d,2H),4.82(s,2H),2.46(s,3H),2.35(s,3H),2.26(s,3H),2.03(s,3H),1.99-1.96(m,1H),1.61(s,3H),1.15,0.60(both d,6H)ppm。13C NMR(CD3CN):168.3(Ru-C),146.4,146.3,146.3,144.5,140.3,140.3,138.5,138.3,136.5,136.4,129.9,128.8,126.2,124.2,110.5,107.4,89.5,87.5,47.8,46.1,31.5,23.9,20.6,19.7,19.5,18.0,17.1,15.0,12.2ppm。
实施例9
配体HL9PF6参照实施例1方法合成,N-(苄基)咪唑代替N-(2,4,6-三甲基)咪唑。在反应温度为50℃条件下,加入配体HL9PF6,426mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,结晶得到299mg氮杂环卡宾配体配位的钌化合物9,产率43%。1HNMR(CD3CN):7.51(s,1H),7.33(s,2H),7.26(s,1H),7.23(s,2H),7.11(s,1H),6.35(s,1H),5.88,5.74,5.41,5.35(s,4H),5.31,4.98(s,CH2,2H),4.84(s,2H),4.67(s,2H),2.12(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.40(s,3H),1.00,0.88(s,6H)ppm。13C NMR(CD3CN):170.8(Ru-C),149.3,145.4,140.7,138.7,136.5,135.6,128.7,128.5,126.9,126.7,126.0,117.8,106.6,54.2,53.0.48.5,33.2,23.3,21.3,15.6,11.1ppm。
实施例10
配体HL10PF6参照实施例1方法合成,N-((2,4,6-三甲基)苄基)咪唑代替N-(2,4,6-三甲基)咪唑。在50℃温度下,加入配体HL10PF6,468mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到339mg氮杂环卡宾配体配位的钌化合物10,产率46%。1HNMR(CD3CN):7.48(s,1H),7.26(s,1H),6.79(s,1H),6.16(s,1H),5.18,5.15(both d,4H),4.67,4.57(both d,2H),3.86(m,2H),2.87(m,1H),2.48(s,3H),2.41(s,3H),2.34(s,6H),2.32(s,3H),1.29(3,H)1.20(s,6H)ppm。13C NMR(CD3CN):170.8(Ru-C),149.3,146.1,145,4,140.8,140.7,136.2,135.6,134.5,128.7,127.7,126.0,53.7,49.2,48.5,33.2,23.3,21.9,21.3,19.4,15.8,11.3ppm。
实施例11
配体HL11PF6参照实施例1方法合成,N-(对叔丁基苄基)咪唑代替N-(2,4,6-三甲基)咪唑。在50℃温度下,加入配体HL11PF6,482mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到310mg氮杂环卡宾配体配位的钌化合物11,产率42%。1HNMR(CD3CN):7.49(s,1H),7.38(s,2H),7.22(s,1H),7.20(s,2H),6.05(s,1H),5.86,5.44,(s,4H),5.30,4.78(s,CH2,2H),4.83(s,2H),4.66(s,2H),2.10(s,3H),1.99-1.95(m,1H),1.62(s,3H),1.39(s,3H),1.33(s,9H),1.00,0.90(s,6H)ppm。13C NMR(CD3CN):169.0(Ru-C),149.8,145.0,140.9,138.6,136.8,135.6,128.8,128.7,126.6,126.8,126.3,118.8,106.7,54.1,53.2.48.6,34.3,33.4,31.5,23.7,21.5,16.4,11.0ppm。
实施例12
配体HL12PF6参照实施例1方法合成,N-(对三氟甲基苄基)咪唑代替N-(2,4,6-三甲基)咪唑。在50℃温度下,加入配体HL12PF6,494mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到330mg氮杂环卡宾配体配位的钌化合物12,产率44%。1HNMR(CD3CN):7.51(s,1H),7.33(s,2H),7.26(s,1H),7.23(s,2H),6.35(s,1H),5.88,5.74,5.41,5.35(s,4H),5.31,4.98(s,CH2,2H),4.84(s,2H),4.67(s,2H),2.12(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.40(s,3H),1.00,0.88(s,6H)ppm。13C NMR(CD3CN):171.1(Ru-C),149.3,145.4,140.7,138.7,136.5,135.6,128.7,128.5,126.9,126.7,126.0,117.8,106.6,54.2,53.0.48.5,34.2,33.2,23.3,21.3,15.6,11.1ppm。
实施例13
配体HL13PF6参照实施例1方法合成,N-(五氟甲基苄基)咪唑代替N-(2,4,6-三甲基)咪唑。在50℃温度下,加入配体HL13PF6,516mg(1mmol),乙腈10mL,氧化银116mg(0.5mmol),反应4小时,然后加入[Ru(p-cymene)Cl2]2 306mg(0.5mmol)室温继续反应2小时,离心过滤,滤液浓缩至2mL,加入乙醚析出黄色固体,将黄色固体用乙醚洗涤2次,再用乙腈溶解,缓慢加入乙醚,重结晶得到409mg氮杂环卡宾配体配位的钌化合物13,产率52%。1HNMR(CD3CN):7.51(s,1H),7.26(s,1H),6.35(s,1H),5.88,5.74,5.41,5.35(s,4H),5.31,4.98(s,CH2,2H),4.84(s,2H),4.67(s,2H),2.12(s,3H),1.98-1.96(m,1H),1.60(s,3H),1.40(s,3H),1.00,0.88(s,6H)ppm。13C NMR(CD3CN):168.8(Ru-C),149.3,145.4,144.8,141.3,140.7,136.2,135.6,128.7,126.0,117.8,115.2,106.6,54.2,53.0.48.5,40.6,33.2,23.3,21.3,15.6,11.1ppm
实施例14
将实施例1-13得到的吡唑官能团化的氮杂环卡宾钌化合物通过体外细胞毒性实验阐明本发明所述氮杂环卡宾钌化合物的抗癌生物活性:
取生长期癌细胞(Bcap-37、LoVo、SCG7901、SCG7901-R),胰酶消化后,种板(96孔板,5×103个细胞/孔),37℃孵育24h使细胞贴壁,加入不同浓度的实施例1-13中制备的吡唑官能团化的氮杂环卡宾钌化合物(100μL/孔),培养48h后,每孔加入30μL噻唑蓝(MTT,5mg/mL),继续培养4h后去除上清,每孔加入100μL二甲基亚砜(DMSO),振荡,使结晶产物充分溶解,492nm处于酶标仪上检测各孔吸光度,绘制出细胞存活曲线,并计算各组纳米粒对细胞的半抑制浓度(IC50)值。抗肿瘤药物脂质体对各种肿瘤细胞的体外毒性结果见表1。
表1:实施例1-13中氮杂环卡宾钌化合物对癌细胞的IC50(μM)
IC50 | Bcap-37 | LoVo | SCG7901 | SCG7901-R |
1 | 12.6±0.2 | 6.0±0.6 | 7.2±0.6 | 8.7±0.9 |
2 | 11.2±0.8 | 9.2±0.5 | 2.9±0.5 | 5.8±0.4 |
3 | 3.8±0.2 | 7.1±0.8 | 7.4±0.6 | 7.0±0.2 |
4 | 5.7±0.5 | 6.4±0.3 | 6.1±0.1 | 10.2±0.8 |
5 | 9.2±2.4 | 5.4±1.9 | 9.2±0.4 | 12±1 |
6 | 9.6±0.8 | 4.3±0.5 | 8.7±0.7 | 16±5 |
7 | 4.3±0.5 | 4.1±1 | 2.9±0.6 | 9.2±2.4 |
8 | 5.0±0.3 | 3.4±0.1 | 1.3±0.1 | 7.4±1.7 |
9 | 8.5±0.2 | 5.3±0.9 | 8.8±1.3 | 11.1±1.7 |
10 | 7.8±1.6 | 6.2±0.4 | 9.2±1.4 | 10.9±0.9 |
11 | 8.8±1.2 | 7.7±1.5 | 10.4±1.4 | 8.2±1 |
12 | 4.5±0.2 | 6.3±0.6 | 1.5±0.9 | 4.9±0.9 |
13 | 3.9±0.9 | 6.1±0.3 | 2.4±0.3 | 5.1±1 |
顺铂 | 8.5±0.9 | 4.1±0.2 | 10.5±0.6 | 83.1±14.5 |
Claims (8)
1.一种吡唑官能团化的氮杂环卡宾钌化合物,其特征在于,结构通式为[LRu(p-cymene)Cl]+X-,其中阳离子[LRu(p-cymene)Cl]+的结构式如下:
其中,R1和R2独立地选自C1~C5烷基、取代或者未取代的苄基、取代或者未取代的苯基;
所述的苄基或苯基上的取代基选自一个或多个C1~C5烷基、卤素、三氟甲基。
2.根据权利要求1所述的氮杂环卡宾钌化合物,其特征在于,所述的氮杂环卡宾钌化合物的阴离子X-为六氟磷酸根离子,四氟硼酸根离子或卤素离子。
3.一种如权利要求1~2任一项所述的氮杂环卡宾钌化合物的制备方法,其特征在于,包括:
(1)以乙腈为溶剂,加入吡唑官能化的咪唑盐配体和氧化银,避光反应4-6小时,得到中间反应液;
其中,咪唑盐配体的结构如下:
(2)向步骤(1)得到的中间反应液中加入[Ru(p-cymene)Cl2]2,继续反应2-4小时,经过后处理得到所述的氮杂环卡宾钌化合物。
4.根据权利要求3所述的氮杂环卡宾钌化合物的制备方法,其特征在于,步骤(1)中,咪唑盐配体和氧化银的摩尔比为2:1,反应温度为40~60℃。
5.根据权利要求3所述的氮杂环卡宾钌化合物的制备方法,其特征在于,步骤(2)中,咪唑盐配体与[Ru(p-cymene)Cl2]2的摩尔比为2:1,反应温度为室温。
6.一种如权利要求1~2任一项所述的氮杂环卡宾钌化合物在制备抗癌药物中的应用。
7.根据权利要求6所述的氮杂环卡宾钌化合物在制备抗癌药物中的应用,其特征在于,所述的抗癌药物用于预防或/和抑制乳腺癌细胞、肠癌细胞和胃癌细胞。
8.根据权利要求7所述的氮杂环卡宾钌化合物在制备抗癌药物中的应用,其特征在于,所述的胃癌细胞为耐顺铂胃癌细胞。
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