CN113549122B - 靶向GLUTs的糖基化四价铂类化合物、合成方法及其应用 - Google Patents
靶向GLUTs的糖基化四价铂类化合物、合成方法及其应用 Download PDFInfo
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- CN113549122B CN113549122B CN202110745318.2A CN202110745318A CN113549122B CN 113549122 B CN113549122 B CN 113549122B CN 202110745318 A CN202110745318 A CN 202110745318A CN 113549122 B CN113549122 B CN 113549122B
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Abstract
Description
技术领域
本发明属于药物合成领域,尤其是涉及糖基化四价铂类化合物、合成方法及其应用。
背景技术
化疗可以有效控制或消除转移灶。因此,化疗在晚期恶性肿瘤和难治性癌症的治疗中起着重要作用。自1978年以来,以顺铂、卡铂、奥沙利铂为代表的铂类抗肿瘤药物已成为睾丸癌、结直肠癌、非小细胞肺癌、卵巢癌、乳腺癌、头颈癌、鼻咽癌等恶性肿瘤的首选化疗药物。
二价铂配合物具有cis-[PtL2X2]的通式,其中L为载体基团,如氨或氮,X为离去基团,如卤素离子、硫酸根和羧酸盐等。而由于相同的作用机制,大多数具有这种结构的顺铂类似物都会和顺铂产生不同程度的交叉耐药性,这种耐药性极大地影响了该类药物的研发。四价铂化合物有希望发展成为新一代铂类抗癌药物。四价铂是二价铂的氧化态化合物,是新型铂类抗肿瘤新药研究开发的热点领域,大部分二价铂配合物都可以经H2O2、Br2、Cl2等氧化剂氧化成四价铂配合物。
四价铂配合物本身没有抗肿瘤活性,进入体内后易被还原后释放二价铂配合物发挥活性,保留了传统二价铂药物广谱高效的生物活性,它们拥有许多独一无二的优势:稳定性比二价铂化合物强;容易被结构修饰,能更方便地优化药物结构;和二价铂类药物作用机制不同,对于耐药性提供了有效的克服策略;可口服,克服了传统二价铂配合物只能注射给药的缺点。拥有平面结构的二价铂配合物不仅能与DNA结合,还能与其他生物大分子也能发生强烈反应而产生毒副作用。相反,具有八面体结构的四价铂配合物基本不与其他生物大分子发生反应,有效地降低了毒副作用。
铂类药物作为抗肿瘤的重要药物,自首次发现顺铂以来便备受关注,铂类药物发展迅速,科研人员众多,研究成果硕果累累,尤其是最近引起科学家们密切关注的糖基化二价铂及糖基化四价铂药物,许多药物进入了临床试验阶段,铂类药物未来依旧会有极大的发展潜力。
因此,我们设计合成了一系列新型糖基化顺铂化合物,并对其生物活性进行了评价。设计了不同糖配体及不同碳链长度的顺铂化合物,以探索合适的糖型和铂核之间的连接物,同时,还设计了不同长度的烷烃,研究了轴向配体对糖基化铂(IV)配合物活性的影响。
发明内容
有鉴于此,本发明旨在提出一种糖基化四价铂类化合物、合成方法及其应用,以优化合成路线克服现有技术缺陷,考虑不同糖型葡萄糖转运蛋白的特性不同,我们使用葡萄糖、半乳糖、甘露糖和鼠李糖对单功能糖基化顺铂化合物进行修饰。引入不同长度的烷烃链调节化合物的脂水分配系数;糖基化配体与铂母核之间引入不通长度的连接链改变分子柔性和立体构型,从而讨论对抗肿瘤活性的影响,筛选出具有作为抗肿瘤药物潜力的化合物。
为达到上述目的,本发明的技术方案是这样实现的:
靶向GLUTs的糖基化四价铂类化合物,靶向GLUTs的糖基化四价铂类化合物的结构通式为:
其中,R1为葡萄糖、半乳糖、甘露糖和鼠李糖中的一种,R2、R3独立地为C1-C4低级烷烃。
优选的,靶向GLUTs的糖基化四价铂类化合物为A1-A10中的一种:
本发明的第二个目的提供了靶向GLUTs的糖基化四价铂类化合物的合成方法,其特征在于:包括以下步骤:
(1)将顺铂加入到酸中,再加入H2O2,室温搅拌直至反应液变为澄清状态,用油泵将酸旋干,向浓缩物中加入乙醚析出黄色沉淀,离心、干燥后,得到通式为B的黄色固体;
(2)在N2保护下,将通式为C的化合物溶于无水DMF中,加入TBTU和Et3N,室温搅拌30分钟后,分批加入通式为B的化合物,室温反应后,浓缩除掉DMF,浓缩物经柱层析纯化得到通式为D的化合物;
(3)将通式为D的化合物溶于三氟乙酸的二氯甲烷溶液中,室温下反应,TLC监测原料消耗完毕,减压浓缩将二氯甲烷除掉,浓缩物继续用油泵抽30分钟,然后向浓缩物中加入乙醚,析出大量淡黄色沉淀,离心、弃掉上清液、沉淀并经干燥后既得通式为A的四价铂类化合物;
靶向GLUTs的糖基化四价铂类化合物的合成流程如下:
其中,R4为叔丁氧羰基团保护的葡萄糖、半乳糖、甘露糖和鼠李糖中的一种。
优选的,步骤(1)中,酸为乙酸或丙酸中的一种,加入H2O2后搅拌时间为1-3小时;
步骤(2)中混合物在DMF中的搅拌时间为20-28小时,反应条件为避光;
步骤(3)中室温反应时间为1-3小时,用来析出沉淀的有机溶剂为乙醚。
优选的,通式为B的化合物、通式为C的化合物、TBTU和三乙胺的摩尔投料比为1:(1-2):(1-2):(1-2),三氟乙酸二氯甲烷的体积浓度为5%-30%。
优选的,通式为B的化合物、通式为C的化合物、TBTU和三乙胺的摩尔投料比为1:1.5:1.5:1.5,三氟乙酸二氯甲烷的体积浓度为10%。
本发明的第三个目的提供了碳苷类糖基化四价铂糖基配合物在肿瘤治疗药物中的应用,药物包含碳苷类糖基化四价铂类化合物以及药学上可接受的载体,载体为微囊、微球、纳米粒或脂质体中的一种。
本发明的第四个目的提供了碳苷类糖基化四价铂在制备抗肿瘤药物中的应用,碳苷类糖基化四价铂化合物用于制备抗宫颈癌、乳腺癌、肺癌、肝癌、前列腺癌药物。
优选的,药物给药剂型为片剂、胶囊剂、气雾剂、分散片、口服液、栓剂、滴丸剂、大输液、小针、冻干粉针、软膏或搽剂。
更优选的,药物给药剂型为大输液或小针。
相对于现有技术,本发明的有益效果为:
(1)本发明将糖基基团引入四价铂母核,设计合成了一系列新型糖基化修饰的四价铂类化合物,利用肿瘤细胞表面高表达的糖转运蛋白GLUTs,提高了药物对肿瘤细胞的靶向性,提高生物利用度,降低对正常细胞的毒副作用;改善了酯水分配系数,提高了肿瘤细胞对药物的摄入量,进一步的提高了抗癌、抗肿瘤能力;
(2)本发明通过调节四价铂轴向配体链的长度,调节其还原电位,影响了药物的活性;体内抗肿瘤活性结果显示,该系列化合物能在一定程度上抑制肿瘤生长,表现出较高的安全性,具有进一步研发的潜力。
附图说明
构成本发明的一部分的附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为本发明实施例所述的化合物A1的1H谱;图2为本发明实施例所述的化合物A1的13C谱;图3为本发明实施例所述的化合物A1的质谱;
图4为本发明实施例所述的化合物A2的1H谱;图5为本发明实施例所述的化合物A2的13C谱;图6为本发明实施例所述的化合物A2的质谱;
图7为本发明实施例所述的化合物A3的1H谱;图8为本发明实施例所述的化合物A3的13C谱;图9为本发明实施例所述的化合物A3的质谱;
图10为本发明实施例所述的化合物A4的1H谱;图11为本发明实施例所述的化合物A4的13C谱;图12为本发明实施例所述的化合物A4的质谱;
图13为本发明实施例所述的化合物A5的1H谱;图14为本发明实施例所述的化合物A5的13C谱;图15为本发明实施例所述的化合物A5的质谱;
图16为本发明实施例所述的化合物A6的1H谱;图17为本发明实施例所述的化合物A6的13C谱;图18为本发明实施例所述的化合物A6的质谱;
图19为本发明实施例所述的化合物A7的1H谱;图20为本发明实施例所述的化合物A7的13C谱;图21为本发明实施例所述的化合物A7的质谱;
图22为本发明实施例所述的化合物A8的1H谱;图23为本发明实施例所述的化合物A8的13C谱;图24为本发明实施例所述的化合物A8的质谱;
图25为本发明实施例所述的化合物A9的1H谱;图26为本发明实施例所述的化合物A9的13C谱;图27为本发明实施例所述的化合物A9的质谱;
图28为本发明实施例所述的化合物A10的1H谱;图29为本发明实施例所述的化合物A10的13C谱;图30为本发明实施例所述的化合物A10的质谱;
图31为本发明实施例所述的LO2细胞的生存率曲线;
图32为本发明实施例所述的根皮素对糖基化四价铂化合物活性的影响;
图33为本发明实施例所述的四价铂化合物A1、A5以及顺铂对MCF-7的体内抗肿瘤活性。
具体实施方式
除非另外说明,本文中所用的术语均具有本领域技术人员常规理解的含义,为了便于理解本发明,将本文中使用的一些术语进行了下述定义。
在说明书和权利要求书中使用的,单数型“一个”和“这个”包括复数参考,除非上下文另有清楚的表述。例如,术语“(一个)细胞”包括复数的细胞,包括其混合物。
所有的数字标识,例如pH、温度、时间、浓度,包括范围,都是近似值。同时也要了解,虽然不总是明确的叙述所有的数字标识之前都加上术语“约”。同时也要了解,虽然不总是明确的叙述,本文中描述的试剂仅仅是示例,其等价物是本领域已知的。
除了特别说明,本文中提及的各种试剂均来自市售满足实验要求的高纯度试剂。
实施例1:通式B所示化合物的合成
化合物B1的合成
将500mg顺铂加入到50mL乙酸中,室温搅拌。然后向反应液中滴加5mL双氧水,继续室温搅拌大约2个小时左右直至反应液变为澄清状态。用油泵将乙酸旋干,向浓缩物中加入乙醚析出黄色沉淀。离心、干燥后,得到黄色固体B1(601.8mg,96%)。
化合物B2、B3和B4的合成
化合物B2、B3和B4的合成参照化合物B1。
实施例2:通式C所示化合物的合成
3-((2R,3R,4S,5R,6R)-3,4,5-三((叔丁氧羰基)氧基)-6-((叔丁氧羰基)氧基)甲基)四氢-2H-吡喃-2-基)氧基)丙酸(化合物6)的合成
将10g D-葡萄糖溶于50mL乙酸酐中,冰浴下滴加1mL的高氯酸,撤掉冰浴后继续搅拌。当反应溶液变为澄清状态时即视为反应完毕,旋干乙酸酐,用饱和NaHCO3溶液将乙酸充分的萃取干净后,有机相用无水MgSO4干燥,用旋转蒸发仪将有机溶剂旋干后,浓缩物用油泵继续浓缩30分钟左右,得到化合物1,可直接用于下一步反应。
将全乙酰葡萄糖1(10g,25.6mmol)溶于100mL二氯甲烷中,加入DMAPA(16.1mL,128mmol)后,室温反应5小时。TLC监测原料消耗完毕后,冰浴条件下加入三氯乙腈(25.7g,256mmol),DBU(0.8mL,5.1mmol)。室温反应1小时后,加入二氯甲烷稀释反应液,用2M的盐酸溶液萃取,将DMAPA充分除去。有机相用无水MgSO4干燥,浓缩,粗产物经柱层析纯化得到白色固体化合物2(9.7g,77%)。1H NMR(400MHz,CDCl3)δ6.52(d,J=3.3Hz,1H),5.57–5.47(m,1H),5.20–5.03(m,2H),4.28–4.13(m,2H),4.13–4.05(m,1H),2.03(d,J=1.1Hz,3H),2.01(d,J=1.1Hz,3H),1.99(d,J=1.1Hz,3H),1.97(d,J=1.0Hz,3H).13C NMR(101MHz,CDCl3)δ170.56,170.01,169.86,169.52,160.79,92.95,70.06,69.91,69.76,67.84,61.43,20.69,20.61,20.46.
称取5g预活化完毕的分子筛置于100mL两口瓶中,抽真空,然后用烤瓶器烘烤分子筛5分钟左右,放置室温后再次烘烤分子筛5分钟,重复烘烤三次。放置室温后,将糖基化供体化合物2(5g,10.1mmol)溶于50mL无水二氯甲烷中,加入到上述两口瓶中。然后加入糖基化受体3-丁烯-1-醇(2.88g,40mmol),室温充分搅拌5分钟后,将反应体系冷却至-78℃后继续搅拌30分钟,然后滴加TMSOTf(1.1g,5mmol)。缓慢升至室温搅拌过夜。用硅藻土过滤除掉白色不溶物,将母液旋干后经柱层析纯化得到白色固体3(3g,74%)。1H NMR(400MHz,CDCl3)δ5.80–5.57(m,1H),5.16(t,J=9.5Hz,1H),5.09–4.84(m,4H),4.47(d,J=7.8Hz,1H),4.22(dd,J=12.1,4.3Hz,1H),4.09(d,J=12.1Hz,1H),3.88(dd,J=15.6,6.4Hz,1H),3.65(dd,J=7.7,1.9Hz,1H),3.49(dd,J=15.8,7.2Hz,1H),2.38–2.22(d,J=1.6Hz,2H),2.11–1.91(m,12H).
将化合物3(2.8g,6.96mmol)溶于适量甲醇中,加入200-300mg甲醇钠,室温反应10分钟左右,TLC监测原料消耗完毕后,用IR 120H+阳离子交换树脂调pH至中性,过滤除去树脂,旋干母液得到白色固体4。然后将4溶于120mL乙腈中,0℃下加入Boc酸酐(15.3g,70mmol),DMAP(85mg,0.7mmol)和三乙胺(7.1g,70mmol)。升至室温搅拌48小时。浓缩除去有机溶剂,粗产物经柱层析纯化得到白色固体5(3.58g,81%)。1H NMR(400MHz,CDCl3)δ5.75(m,1H),5.23–4.87(m,3H),4.76(dt,J=17.4,9.0Hz,2H),4.49(d,J=7.5Hz,1H),4.28(dd,J=11.5,5.6Hz,1H),4.11(d,J=11.7Hz,1H),3.99–3.80(m,1H),3.80–3.61(m,1H),3.51(q,J=7.4Hz,1H),2.30(d,J=6.4Hz,2H),1.51–1.35(m,36H).13C NMR(100MHz,CDCl3)δ153.11,152.71,152.43,152.37,151.97,151.91,151.44,134.49,116.69,100.70,83.21,82.68,82.47,75.46,74.10,71.74,71.54,69.45,64.90,33.90,27.74,27.69,27.66,27.62.
将化合物5(3g,4.7mmol)溶于30mL乙腈、30mL四氯化碳和42mL蒸馏水的混合溶剂中,加入高碘酸钠(10.1g,47mmol)、三氯化铑(8.4mg,0.04mmol)后室温反应4个小时。然后用二氯甲烷和饱和食盐水萃取,有机相用无水MgSO4干燥,浓缩,粗产物经柱层析纯化得到白色固体6(2.18g,71%)。1H NMR(400MHz,CDCl3)δ4.96(d,J=7.4Hz,1H),4.79(d,J=7.6Hz,1H),4.71(d,J=7.2Hz,1H),4.54(d,J=5.4Hz,1H),4.26(s,1H),4.20-4.01(m,2H),3.83(d,J=5.3Hz,1H),3.72(s,1H),2.62(s,2H),1.53(m,36H).13C NMR(100MHz,CDCl3)δ176.18,153.09,152.66,152.39,152.31,151.96,151.93,100.92,83.21,82.78,82.68,82.58,75.39,73.93,71.81,71.42,65.18,64.75,34.72,27.72,27.68,27.61,27.59,27.53.
2.化合物7-12的合成
化合物7-12的合成参照化合物6。
化合物7:白色固体:1H NMR(400MHz,CDCl3)δ5.25(d,J=3.1Hz,1H),4.92(dd,J=10.3,8.1Hz,1H),4.71(dd,J=10.3,3.3Hz,1H),4.47(d,J=8.1Hz,1H),4.25–4.04(m,3H),3.87–3.81(m,2H),2.65–2.62(m,2H),1.46–1.43(m,36H).13C NMR(101MHz,CDCl3)δ175.97,153.08,152.41,152.18,101.58,82.96,82.88,73.78,71.74,71.17,69.70,65.08,64.55,34.90,27.80,27.75.
化合物8:白色固体:1H NMR(400MHz,CDCl3)δ4.96(d,J=7.4Hz,1H),4.79(d,J=7.6Hz,1H),4.71(d,J=7.2Hz,1H),4.54(d,J=5.4Hz,1H),4.26(s,1H),4.20-4.01(m,2H),3.83(d,J=5.3Hz,1H),3.72(s,1H),2.62(s,2H),1.53(m,36H).13C NMR(100MHz,CDCl3)δ176.18,153.09,152.66,152.39,152.31,151.96,151.93,100.92,83.21,82.78,82.68,82.58,75.39,73.93,71.81,71.42,65.18,64.75,34.72,27.72,27.68,27.61,27.59,27.53.
化合物9:白色固体:1H NMR(400MHz,CDCl3)δ5.13(s,1H),4.98(d,J=9.8Hz,1H),4.83(d,J=12.3Hz,2H),4.02–3.81(m,2H),3.68(d,J=3.7Hz,1H),2.64(d,J=4.2Hz,2H),1.45(d,J=12.5Hz,27H),1.25(s,3H).13C NMR(101MHz,CDCl3)δ176.70,152.89,152.68,152.44,97.73,82.92,82.79,82.59,73.83,72.12,71.85,66.71,63.14,34.42,27.80,17.36.
化合物10:白色固体:1H NMR(400MHz,CDCl3)δ4.98(t,J=9.7Hz,1H),4.81(t,J=9.8Hz,1H),4.72(dd,J=9.7,7.8Hz,1H),4.47(d,J=7.8Hz,1H),4.27(dd,J=11.8,5.7Hz,1H),4.13–4.07(m,1H),3.90(dt,J=9.7,5.6Hz,1H),3.68(ddd,J=9.6,5.9,2.6Hz,1H),3.54(dt,J=9.6,6.1Hz,1H),2.42(t,J=7.4Hz,2H),1.91–1.80(m,2H),1.50–1.40(m,36H).13C NMR(101MHz,CDCl3)δ178.94,153.23,152.53,152.08,100.69,83.31,82.97,82.79,82.58,75.55,74.19,71.88,71.58,68.73,64.93,30.29,27.84,27.79,27.72,24.58.
化合物11:白色固体:1H NMR(400MHz,CDCl3)δ4.96(t,J=9.7Hz,1H),4.81(t,J=9.6Hz,1H),4.71(t,J=8.3Hz,1H),4.47(d,J=7.8Hz,1H),4.29(dd,J=11.6,5.9Hz,1H),4.12(dd,J=8.3,5.6Hz,1H),3.88(dd,J=9.7,5.3Hz,1H),3.74–3.68(m,1H),3.46(dd,J=9.4,5.5Hz,1H),2.32(t,J=6.4Hz,2H),1.67–1.38(m,38H).13CNMR(101MHz,CDCl3)δ179.17,153.22,152.54,152.08,152.06,100.75,83.30,82.85,82.78,82.59,75.60,74.23,71.87,71.66,69.54,65.02,33.60,28.85,27.84,27.80,27.73,21.22.
化合物12:白色固体:1H NMR(400MHz,CDCl3)δ4.98(dt,J=12.4,6.9Hz,1H),4.76(ddd,J=17.7,14.6,8.9Hz,1H),4.50(t,J=8.0Hz,1H),4.29(dd,J=11.9,5.9Hz,1H),4.12(dt,J=10.5,5.0Hz,1H),3.87(dt,J=9.4,6.2Hz,1H),3.79–3.66(m,1H),3.47(dt,J=9.6,6.5Hz,1H),2.32(t,J=7.5Hz,1H),1.67–1.52(m,6H),1.46–1.44(m,36H).13C NMR(101MHz,CDCl3)δ179.10,153.25,152.57,152.11,152.08,100.82,83.30,82.79,82.58,75.62,74.31,71.87,71.72,69.90,65.07,33.88,29.83,29.22,27.87,27.82,27.78,27.75,25.41,24.47.
实施例3:通式为A的化合物的合成
化合物A1的合成
氮气保护下,将化合物6(200mg,0.31mmol)溶于5mL无水DMF中,加入TBTU(147.6mg,0.46mmol),Et3N(46.5mg,0.46mmol)。室温搅拌30分钟后,分批加入化合物B1(174.9mg,0.47mmol)。室温避光反应24小时后,浓缩除掉DMF,浓缩物经柱层析纯化得到淡黄色固体化合物D1(213.1mg,68%)。1H NMR(400MHz,CDCl3)δ6.00–5.94(m,6H),5.04(t,J=9.2Hz,1H),4.92–4.74(m,2H),4.65(t,J=8.3Hz,1H),4.32(d,J=11.1Hz,1H),4.15(d,J=11.7Hz,1H),4.04(s,1H),3.87(s,1H),3.76(d,J=9.0Hz,1H),2.57(s,2H),2.11(s,3H),1.42(d,J=10.3Hz,36H).13C NMR(101MHz,CDCl3)δ181.40,180.70,152.74,152.56,152.02,100.90,84.26,83.40,83.17,82.99,75.29,74.81,71.65,70.64,67.34,63.91,37.71,29.69,27.77,27.74,27.70,27.63,22.97.
将化合物D1(150mg,0.15mmol)溶于10%的三氟乙酸二氯甲烷溶液中(1mL TFA:9mL DCM),室温下反应2小时后,TLC监测原料消耗完毕,减压浓缩将二氯甲烷除掉,浓缩物继续用油泵抽30分钟。然后向浓缩物中加入100mL乙醚,析出大量淡黄色沉淀,离心,弃掉上清液,沉淀经干燥后得到淡黄色固体A1(46.7mg,51%)。1H NMR(400MHz,MeOD)δ4.17(d,J=7.9Hz,1H),3.76(dt,J=10.6,5.4Hz,1H),3.60(ddd,J=13.6,8.5,3.5Hz,2H),3.39(dd,J=11.9,5.0Hz,1H),3.13(t,J=8.8Hz,1H),3.02(ddd,J=19.6,11.5,6.6Hz,4H),2.91–2.84(m,1H),2.43–2.30(m,2H),1.78(s,3H).13C NMR(101MHz,MeOD)δ181.69,181.55,104.51,77.87,77.84,75.16,71.60,67.74,64.29,62.58,37.94,22.63.HRMS:calcd forC11H24Cl2N2O10Pt(M+H)+,610.0456;found,610.0510.
化合物A2-A10的合成
化合物A2-A10的合成步骤参照化合物A1的合成步骤。
化合物A2:1H NMR(400MHz,MeOD)δ4.42(d,J=7.3Hz,1H),4.06(dt,J=10.7,5.5Hz,1H),3.94–3.82(m,2H),3.75(qd,J=11.4,6.1Hz,2H),3.53(ddd,J=25.2,14.5,7.8Hz,3H),2.64(dd,J=11.7,6.3Hz,2H),2.07(s,3H).13C NMR(101MHz,MeOD)δ181.68,181.57,105.08,76.62,74.81,72.68,70.31,67.68,64.29,62.46,38.03,22.63.HRMS:calcdfor C11H24Cl2N2O10Pt(M+H)+,610.0456;found,610.0509.
化合物A3:1H NMR(400MHz,MeOD)δ3.95(dt,J=10.0,6.3Hz,1H),3.87–3.79(m,2H),3.77–3.55(m,8H),2.65(t,J=6.2Hz,2H),2.06(s,3H).13C NMR(101MHz,MeOD)δ181.72,181.61,101.66,74.47,72.53,72.03,68.63,65.32,64.29,62.83,37.47,22.63.HRMS:calcd for C11H24Cl2N2O10Pt(M+H)+,610.0456;found,610.0510.
化合物A4:1H NMR(400MHz,MeOD)δ3.80(dt,J=10.0,6.4Hz,1H),3.71(dd,J=3.3,1.6Hz,1H),3.59–3.46(m,4H),3.30–3.23(m,3H),2.55(s,2H),1.97(s,3H),1.17(d,J=6.2Hz,3H).13C NMR(101MHz,MeOD)δ181.69,181.50,101.61,74.06,72.29,72.07,69.78,65.16,64.27,37.44,22.65,18.05.HRMS:calcd for C11H24Cl2N2O9Pt(M+H)+,594.0507;found,594.0556.
化合物A5:1H NMR(400MHz,MeOD)δ4.26(d,J=7.6Hz,1H),3.86(dd,J=21.0,9.5Hz,2H),3.68–3.59(m,2H),3.27(s,3H),3.14(t,J=8.1Hz,1H),2.45(s,2H),2.02(s,3H),1.84(s,2H).13C NMR(101MHz,MeOD)δ183.91,181.75,104.29,78.03,77.83,75.14,71.64,70.00,64.29,62.72,33.48,27.04,22.66.HRMS:calcd for C12H26Cl2N2O10Pt(M+H)+,624.0612;found,624.0644.
化合物A6:1H NMR(400MHz,MeOD)δ4.28(d,J=7.8Hz,1H),3.94–3.83(m,2H),3.67(dd,J=11.9,4.4Hz,1H),3.59–3.53(m,1H),3.36(d,J=6.9Hz,1H),3.28(d,J=5.4Hz,2H),3.17(t,J=8.4Hz,1H),2.41(s,2H),2.06(s,3H),1.68(d,J=2.5Hz,4H).13C NMR(101MHz,MeOD)δ184.26,181.74,104.24,78.05,77.87,75.13,71.66,70.44,64.30,62.75,36.62,30.05,23.53,22.64.HRMS:calcd for C13H28Cl2N2O10Pt(M+H)+,637.0769;found,637.0771.
化合物A7:1H NMR(400MHz,MeOD)δ4.26(d,J=7.8Hz,1H),3.94–3.83(m,2H),3.67(dd,J=11.9,5.0Hz,1H),3.58–3.53(m,1H),3.35(d,J=8.8Hz,1H),3.27(t,J=10.3Hz,2H),3.21–3.13(m,1H),2.37(t,J=7.3Hz,2H),2.06(s,3H),1.63(dt,J=14.3,7.0Hz,4H),1.43(dt,J=12.0,6.0Hz,2H).13C NMR(101MHz,MeOD)δ184.32,181.76,104.30,78.05,77.86,75.14,71.64,70.66,64.30,62.73,36.93,30.33,26.64,26.57,22.66.HRMS:calcdfor C14H30Cl2N2O10Pt(M+H)+,652.0925;found,652.0972.
化合物A8:1H NMR(400MHz,MeOD)δ4.17(d,J=7.9Hz,1H),3.76(dt,J=10.6,5.5Hz,1H),3.65–3.53(m,2H),3.39(dd,J=11.9,4.9Hz,1H),3.13(t,J=8.6Hz,1H),3.07–2.94(m,5H),2.87(t,J=8.5Hz,1H),2.35(dd,J=12.6,7.0Hz,2H),2.11(q,J=7.5Hz,2H),0.77(t,J=7.5Hz,3H).13C NMR(101MHz,MeOD)δ184.87,181.58,104.56,77.88,75.20,71.62,67.77,64.30,62.60,38.00,30.04,10.42.HRMS:calcd for C12H26Cl2N2O10Pt(M+H)+,624.0612;found,624.0659.
化合物A9:1H NMR(400MHz,MeOD)δ4.45(d,J=7.9Hz,1H),4.04(s,1H),3.87(d,J=12.1Hz,2H),3.67(d,J=12.5Hz,2H),3.41(t,J=8.3Hz,1H),3.22–3.10(m,2H),2.63(d,J=5.5Hz,2H),2.34(t,J=7.2Hz,2H),1.60(dd,J=14.9,7.7Hz,2H),0.94(t,J=7.4Hz,3H).13C NMR(101MHz,MeOD)δ184.26,181.62,104.57,77.90,75.21,71.64,67.78,64.31,62.61,39.02,38.02,20.34,14.09.HRMS:calcd for C13H28Cl2N2O10Pt(M+H)+,638.0769;found,638.0817.
化合物A10:1H NMR(400MHz,MeOD)δ4.45(d,J=7.4Hz,1H),4.30(s,1H),4.08(dd,J=18.2,11.3Hz,2H),3.87(d,J=11.7Hz,3H),3.67(d,J=12.1Hz,1H),3.17(d,J=8.3Hz,1H),2.63(t,J=30.2Hz,3H),2.37(t,J=7.2Hz,1H),1.71–1.47(m,2H),1.36(dd,J=14.9,6.8Hz,2H),0.92(t,J=7.0Hz,3H).13C NMR(101MHz,MeOD)δ184.43,181.64,104.58,104.44,77.90,75.22,75.04,71.65,67.78,64.31,62.75,62.61,38.03,36.80,29.15,23.34,14.16.HRMS:calcd for C14H30Cl2N2O10Pt(M+H)+,652.0925;found,652.0964.
实施例4:体外细胞毒性实验
使用MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化铵)比色法测定48小时的IC50,所有化合物均在同一批次进行实验,测定了A1-A10,10种化合物对人肺癌细胞系(A549)、人乳腺癌细胞系(MCF-7)、人肝癌细胞系(HepG-2)、人宫颈癌细胞系(Hela)、顺铂耐药人宫颈癌细胞系(Hela/DDP)、和人正常肝细胞系(LO2)的细胞毒作用。将细胞接种于96孔板中,于37℃,5%CO2及100μL完全培养基中孵育24h,然后加入含不同浓度药物的100μL新配制培养基,继续孵育48h,再加入MTT(5mg/mL,20μL)孵育4h,最后去掉培养基,加入150μL二甲基亚砜(DMSO),于570nm处测量吸光度计算IC50值。
表1为化合物A1-A10与顺铂、奥沙利铂对5种人癌细胞株的细胞毒性作用对比表,如表1所示,化合物A1-A10与药物顺铂和奥沙利铂相比,对人乳腺癌细胞MCF-7和人宫颈癌细胞Hela表现出较为明显的细胞毒性,对正常人肝细胞LO2表现出较好的安全性。其中,对于人乳腺癌细胞MCF-7,A1(IC50=1.14)、A5(IC50=1.47)和A7(IC50=2.21)的IC50值最小,为顺铂的0.15-0.30倍;对于人宫颈癌细胞Hela,A1(IC50=2.37)、A7(IC50=1.01)和A9(IC50=1.05)的IC50值最小,为顺铂的0.22-0.52倍。
新合成的糖基化顺铂化合物几乎打破了顺铂耐药Hela/DDP细胞的耐药性,特别是化合物A4和A10,它们的抗药因子分别为0.76和0.79,远高于顺铂的抗药因子6.84。对于连接了不同糖配体顺铂化合物,它们的细胞毒性没有表现出明显的变化。
对于碳链长度不同的四价铂化合物来说,A8-A10比A1的细胞毒性弱,说明轴向烷烃链的延长不利于糖基化四价铂配合物的抗肿瘤活性;铂母核与糖配体之间连接链的长度对其抗肿瘤活性影响较大,中间含有5个碳的A7的细胞毒性略强于含有2个碳的A1的细胞毒性,而含有其它碳数的铂化合物没有表现出明显增强的细胞毒性。以顺铂为母核的四价铂配合物的抗肿瘤活性比传统化疗药顺铂、奥沙利铂有所增强,且拥有对抗顺铂耐药的特性,该系列化合物有着成为广谱抗肿瘤药物开发的先导化合物的潜力。
表1:化合物A1-A10与顺铂、奥沙利铂对5种人癌细胞株的细胞毒性作用
说明:RF:抗性因子=IC50(Hela/DDP)/IC50(Hela)
SI:选择性指数=IC50(LO2)/IC50(HepG-2)。
实施例5:LO2细胞存活率的研究
如表1所示,10种糖基化顺铂化合物对正常人肝细胞LO2均表现出较高的安全性,相对于人肝癌细胞HepG-2的选择指数都高于顺铂和奥沙利铂的选择指数。其中A1、A2、A3和A10的选择指数均为顺铂和奥沙利铂5倍以上。
如图31所示,在药物浓度范围为0–100μM时,用A1、A2、A3和A10孵育时的细胞生存能力明显高于顺铂和奥沙利铂。当浓度为4.97μM时(顺铂IC50=4.97μM),使用糖基化四价铂孵育的生存能力大于80%,尤其是A2和A10的细胞生存率几乎是100%。上述实验结果说明糖基化四价铂在保持较好抗肿瘤活性的同时,对正常细胞的毒性较小,这为四价铂抗肿瘤药物的发展提供了参考。
实施例6:葡萄糖转运蛋白抑制剂对体外抗肿瘤活性的影响
由于糖基配体的引入,糖基化四价铂抗肿瘤活性表现出明显的增强。为了研究葡萄糖转运蛋白(GLUTs)对该系列糖基化四价铂化合物是否存在转运作用,采用根皮素作为GLUTs抑制剂,研究A1、A2、A3、A4、顺铂和奥沙利铂在Hela细胞中的转运机制。加入根皮素的浓度为100μM,并且我们通过实验验证此浓度对Hela细胞的生长没有产生抑制作用,加入待测试的化合物的浓度为100μM,与抑制剂混合共同作用细胞48小时。
如图32所示,当加入抑制剂根皮素后,A1-A4的IC50值出现了明显的增加,其中A1的IC50值增加了近4.7倍,而阳性药物顺铂和奥沙利铂的细胞毒性不受抑制剂的影响。说明抑制剂对糖基化四价铂细胞毒性的发挥产生了抑制作用,葡萄糖转运蛋白(GLUTs)抑制剂在抑制相关糖转运的同时,也抑制了细胞对新合成的糖基化四价铂的转运作用。
实施例7:体内抗癌活性实验
为了进一步评价糖基化四价铂化合物作为抗肿瘤药物的潜力,选择对MCF-7肿瘤细胞活性相对较好的A1和A5作为测试化合物,阳性药物顺铂作为对照组,对乳腺癌MCF-7裸鼠肿瘤模型进行了体内活性评价。如图33所示,图33A为肿瘤体积的时间变化曲线图;图33B为实验结束时肿瘤重量示意图;图33C为裸鼠体重的时间变化曲线;图33D为实验结束时摘除肿瘤的示意图。糖基化四价铂化合物A1和A5在一定程度上抑制了肿瘤的生长,抑制效果明显优于阴性对照组,抑制肿瘤生长的比例分别为29.2%和43.1%,但活性比阳性药顺铂(肿瘤抑制率63.8%)较弱。但是从小鼠的体重变化趋势来看(图33C),糖基化四价铂测试组小鼠体重没有明显变化,而顺铂测试组小鼠体重明显减轻,说明糖基化四价铂化合物在体内的毒性远低于顺铂。通过此实验可以看出,该系列糖基化四价铂化合物在体内表现出较高的安全指数和较低的毒性,对肿瘤的生长也具有一定的抑制作用,具有进一步研发的潜力。
这一系列原始创新性研究,有望获得对多种肿瘤有效的先导分子,为解决传统二价铂类药物存在的缺陷提供新的候选药物分子,也为四价铂类化合物的修饰开辟新的途径。虽然顺铂对多种肿瘤类型均有活性,然而顺铂的毒副作用、耐药性成为治疗成功的主要障碍。以顺铂为四价铂母核,并对其进行糖基化修饰克服了传统顺铂的缺点。通过实验研究发现,糖基化四价铂化合物对肿瘤细胞具有靶向性,并对正常细胞毒性较小,因此是具有开发潜力的一类四价铂化合物。此类源头上创新药物的研究,对国民经济和社会发展及人类健康均具有重要的理论价值和实际意义。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (3)
其中,R1为葡萄糖、半乳糖、甘露糖和鼠李糖中的一种,R2为C2-C4低级烷烃,R3为C1-C4低级烷烃;
所述的靶向GLUTs的糖基化四价铂类化合物的合成方法,包括以下步骤:
(1)将顺铂加入到酸中,再加入H2O2,室温搅拌直至反应液变为澄清状态,将酸旋干后加入乙醚析出沉淀,离心、干燥后得到通式为B的化合物;
(2)在N2保护下,将通式为C的化合物溶于无水DMF中,加入TBTU和Et3N,室温搅拌30分钟后,分批加入通式为B的化合物,室温反应后,浓缩除掉DMF,浓缩物经柱层析纯化得到通式为D的化合物;
(3)将通式为D的化合物溶于三氟乙酸的二氯甲烷溶液中,室温下反应,原料消耗完毕后减压浓缩将二氯甲烷除掉,然后向浓缩物中加入乙醚,离心、弃掉上清液、沉淀并经干燥后既得通式为A的四价铂类化合物;
靶向GLUTs的糖基化四价铂类化合物的合成流程如下:
其中,R4为叔丁氧羰基团保护的葡萄糖、半乳糖、甘露糖和鼠李糖中的一种;靶
向GLUTs的糖基化四价铂类化合物为A1-A10中的一种:
步骤(1)中,酸为乙酸或丙酸中的一种,加入H2O2后搅拌时间为1-3小时;
步骤(2)中混合物在DMF中的搅拌时间为20-28小时,反应条件为避光;
步骤(3)中室温反应时间为1-3小时,用来析出沉淀的有机溶剂为乙醚。
2.根据权利要求1所述的靶向GLUTs的糖基化四价铂类化合物的合成方法,其特征在于:通式为B的化合物、通式为C的化合物、TBTU和三乙胺的摩尔投料比为1:(1-2):(1-2):(1-2),三氟乙酸二氯甲烷的体积浓度为5%-30%。
3.根据权利要求1所述的靶向GLUTs的糖基化四价铂类化合物的合成方法,其特征在于:通式为B的化合物、通式为C的化合物、TBTU和三乙胺的摩尔投料比为1:1.5:1.5:1.5,三氟乙酸二氯甲烷的体积浓度为10%。
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