CN114835759A - 一种褪黑素-铂(iv)-碳氮长链配合物、制备方法及其在肿瘤药物中的应用 - Google Patents
一种褪黑素-铂(iv)-碳氮长链配合物、制备方法及其在肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开一种褪黑素‑铂(IV)‑碳氮长链配合物、制备方法及其在肿瘤药物中的应用;在Pt(IV)配位中心的轴向位点一侧引入褪黑素,另一侧引入碳氮长链,从而提高配合物的亲脂性;本体系中药物与未改造的铂药相比具有更好的肿瘤杀伤能力,细胞毒与顺铂相比提高了数十倍,尤其是对性激素相关的肿瘤,如卵巢癌、***、乳腺癌细胞的杀伤效果更加明显;同时褪黑素除了潜在的抗肿瘤效应,降低顺铂耐药性,与单纯褪黑素‑铂(IV)配合物比较,其缓释作用效果更佳。本药物合成工艺简单,成本低,大大提高了联合用药的疗效,与传统二价铂及同类四价铂药物相比,具有疗效好、副作用小等优势,为四价铂的修饰提供了新的思路。
Description
技术领域
本发明属于抗癌化学药物技术领域,尤其是涉及一种褪黑素-铂(IV)-碳氮长链配合物、制备方法及其在肿瘤药物中的应用。
背景技术
癌症目前已成为人类健康的极大威胁。临床上现有的癌症治疗手段以手术、放疗、化疗为主。手术切除只能针对肿瘤组织的大部分集中区域,无法实现癌细胞的彻底根除。放疗在癌症治疗中具有极大的局部性,其主要适于原发病灶切除过程中残留癌细胞部位、转移病灶集中或者术后预防的情况,适用范围小且无法实现全身控制;同时放疗对皮肤具有一定损伤,易出现放射性肺炎等。因此,化疗仍然是目前乳腺癌综合治疗的重要策略,开发新型的高效低毒且具有肿瘤多重靶向的化疗药物是我们主要研究的重点。
常用的抗肿瘤药物包括:生物烷化剂类药物(氮芥类);抗代谢类药物,如 DNA合成酶抑制剂(吉西他滨)、胸苷酸合成酶抑制剂(五氟尿嘧啶);金属类药物(顺铂、奥沙利铂、卡铂);抗生素类药物(博来霉素、多柔比星);植物类用药(紫杉醇)等。其中,顺铂以其独特的DNA靶向功能,在癌症化疗领域所向披靡,以至于长期占领一线位置,并一度被称为抗癌药里的“青霉素”。遗憾的是,在长期的化疗过程中,由于药物本身缺乏肿瘤细胞的选择性,且溶解度较差等问题的存在,使患者逐渐出现肝肾毒性、耳毒性、神经毒性、骨髓抑制作用、常见的胃肠道反应、高尿酸血症、低镁/钙血症、过敏样反应等;同时机体固有或获得的耐药性问题更加重了毒副作用的发生。因此,寻找铂类药物的新的发展方向成为研究的重点。
近年来在不断发展的铂药研究中,四价铂Pt(IV)结构凭借其独特的稳定性和超强的可塑性在众多研究中脱颖而出。Pt(IV)化合物具有稳定性更高的d6八面体构型,减少了铂处于二价状态时与体内亲核试剂如谷胱甘肽、含硫蛋白等生物分子的反应,改善了药物非靶点失活的情况。另一方面,Pt(IV)在保留原始Pt(II) 的赤道位置配位点的同时,增加两个轴向位置为后续的化学修饰提供巨大的开发空间,对于调节药物的溶解度、改善细胞摄取途径、提高药物靶向性、发挥协同作用、克服耐药、降低毒副作用等具有突出效果。此外,利用轴向配体将前药连接到肿瘤靶向活性小分子、纳米递送***、示踪***、光/声动力等结构上,避免了由于药物动力学差异造成的传统形式的联合给药的缺陷,提高生物利用度并增强靶向性、特异性等。
褪黑素(Melatonin,MT)是普遍存在于从藻类到人类等生物体内中的一种荷尔蒙,早在1993年就已经以保健品的方式投入市场,并一时风靡全球。MT 是一种来自松果体,主要是用以调节时间节律响应黑暗的激素分泌物,近年来越来越多的数据表明,MT具有抗肿瘤和肿瘤预防作用,对乳腺癌、***癌等多种癌症都有很好的治疗作用,尤其是在与其它抗肿瘤药(如顺铂,5-FU等)联用的时候能发挥更好的抗肿瘤作用。在Pt(IV)的轴向位置引入褪黑素分子及碳氮长链分子具有以下优势,1)研究发现褪黑素具有潜在的抗肿瘤作用,褪黑素受体在多癌种均具有高表达的特性,同时褪黑素可以抑制在肿瘤部位高表达的HIF-1α和Stat3,褪黑素的引入可以使铂药具有多靶向性,极大地提高了肿瘤药物的疗效;2)因为碳链分子的引入增加了铂药的稳定性,同时增强了Pt(IV)分子的脂溶性及跨膜能力,促进铂药的吸收,使其在提高抗肿瘤活性的同时,还具有药物减毒、缓释的功效;3)作为FDA批准的用于改善睡眠的一种内源性药物,不会对人体造成伤害,在体内半衰期短,能很快的代谢掉,引入Pt(IV)中显著降低了药物毒性。
本发明人在先申请的专利号为2018115158228中公开了一种铂(IV)配位一侧或对向的两侧分别连接褪黑素分子的结构,并证明其相对于单纯顺铂的抗肿瘤作用有了明显的提高,但是其作用效果时长较为集中。
发明内容
为解决上述技术问题,本发明提供一种褪黑素-铂(IV)-碳氮长链配合物、制备方法及其在肿瘤药物中的应用。基于顺铂(Cisplatin,CDDP)与褪黑素 (Melatonin,MT)的联合用药,设计合成了一系列与褪黑素相关的四价铂前药分子,同时为了提高Pt(IV)的摄取以及稳定性,在铂的另一轴向羟基引入不同长度的脂肪链。新型褪黑素-铂(IV)-碳氮长链前药的设计旨在降低铂药的毒副作用的同时达到协同增敏的作用。
本发明采用的技术方案是:一种褪黑素-铂(IV)-碳氮长链配合物,铂(IV)配位中心轴向一侧连接有褪黑素分子,另一侧连接有碳氮长链基团。
优选地,由式1所示:
其中,
R1为-CnH2n-,n为整数且1≤n≤6,优选地,-CnH2n-为直链基团,
R2为-NH-CmH2m+1或-CmH2mNO且1≤m≤20,优选地,-NH-CmH2m+1为直链基团。
优选地,n≤2,-CnH2n-为直链基团。
优选地,m≤17,优选的,2≤m≤17,-NH-CmH2m+1为直链基团。
优选地,由式2-17中任一结构式表示:
制备褪黑素-铂(IV)-碳氮长链配合物的方法:
将式21化合物与式22化合物在第一缩合剂与第一缚酸剂存在的条件下发生酯化反应,得到式20中间体化合物;
将式20化合物与式23化合物发生酯化反应,得到所述褪黑素-铂(IV)-碳氮长链配合物;
其中,
R1为-CnH2n-,n为整数且1≤n≤6,优选地,-CnH2n-为直链基团,
R2为-NH-CmH2m+1或-CmH2mNO且1≤m≤20,优选地,-NH-CmH2m+1为直链基团。
优选地,式21化合物的制备方法包括:
将如式24的褪黑素与式25化合物(丁二酸酐或戊二酸酐)在第二缩合剂与第二缚酸剂存在的条件下发生酰化反应得到式21化合物;
优选地,所述第二缩合剂为DMAP;所述第二缚酸剂为三乙胺。
优选地,所述第一缩合剂为TBTU;所述第一缚酸剂为三乙胺;反应中原料比为:式21化合物:式22化合物:第一缩合剂:第一缚酸剂为1-1.2:1:1.2-2: 1.2-2;
优选地,反应在避光且惰性气体保护的条件下进行。
褪黑素-铂(IV)-碳氮长链配合物在制备抗肿瘤药物中的应用。
优选地,用于制备抗卵巢癌、***、乳腺癌、肺癌、肝癌、肠胃癌药物。
本发明具有的优点和积极效果是:褪黑素-铂(IV)-碳氮长链配合物用于治疗癌症,其细胞毒IC50值低于顺铂数十倍,表现出对癌症细胞具有良好的抗增殖能力,尤其是对乳腺癌、***、卵巢癌细胞的杀伤力更加明显;褪黑素为FDA 批准的用于改善睡眠的一种内源性药物,不会对人体造成伤害,在体内半衰期短,能很快的代谢掉;褪黑素除了潜在的抗肿瘤效应,还具有调节生物节律,提高机体免疫力,延缓衰老,改善睡眠等功效,可以缓解顺铂引起的***毒性,降低顺铂耐药性;
将褪黑素通过酰胺化反应在仲胺位置引入羧基,随后将碳氮长链通过简单的缩合与氧化反应引入四价铂中间体;新型褪黑素-铂(IV)-碳氮长链前药的设计旨在降低铂药的毒副作用的同时达到协同增敏的作用;前药合成工艺简单,成本低,大大提高了联合用药的疗效,与传统二价铂及同类四价铂药物相比,具有疗效好、副作用小等优势,为四价铂的修饰提供了新的思路。
附图说明
图1是实施例九中化合物7的胞内释放情况;
图2是实施例十中不同给药组的小鼠体重变化;
图3是实施例十中不同给药组的小鼠肿瘤体积变化;
图4是实施例十中最终小鼠肿瘤重量;
图5是实施例十中不同给药组的小鼠存活率;
图6是实施例十中最终Pt在各组织的分布情况;
图7是实施例十中肿瘤的最终图片;
图8小鼠肾脏和肿瘤组织的H&E染色结果。
具体实施方式
下面结合附图对本发明的实施例做出说明。
本发明公开一种褪黑素-铂(IV)-碳氮长链配合物,铂(IV)配位中心轴向一侧连接有褪黑素分子,另一侧连接有碳氮长链基团,构成双取代四价铂配合物;碳氮长链基团能够与HSA结合。在Pt(IV)配位中心的轴向位点一侧引入褪黑素,旨在使铂药具有多靶向性,提高抗肿瘤疗效,降低药物毒性;另一侧引入可以与HSA结合的碳氮脂肪链,旨在提高铂药摄取的同时,增加药物稳定性达到减毒、缓释效果。
设计合成的新型抗肿瘤褪黑素-铂(IV)-碳氮长链前药与未改造的铂药相比具有更好的肿瘤杀伤能力,细胞毒性IC50值与顺铂相比提高了数十倍,尤其是对性激素相关的肿瘤卵巢癌、***、乳腺癌细胞的杀伤效果更加明显。同时褪黑素除了潜在的抗肿瘤效应,还具有调节生物节律,提高机体免疫力,延缓衰老,改善睡眠等功效,可以缓解顺铂引起的***毒性,降低顺铂耐药性。在本发明中,我们将褪黑素通过酰胺化反应在仲胺位置引入羧基,通过简单的缩合反应将碳氮长链引入四价铂中间体,得到新型抗肿瘤褪黑素-铂(IV)-碳氮长链前药。本新型药物,合成工艺简单,成本低,大大提高了联合用药的疗效,与传统二价铂及同类四价铂药物相比,具有疗效好、毒副作用小等优势,为四价铂的修饰提供了新的思路。
褪黑素-铂(IV)-碳氮长链配合物由式1所示:
其中,
其中,RR1为-CnH2n-,n为整数且n≥1,优选地,n≤6,更优选的,n≤2,-CnH2n- 为直链基团时效果更佳;R2为-NH-CmH2m+1或-CmH2mO且m≥1,优选地,m≤20,更优选的m≤17,进一步优选的,2≤m≤17,-NH-CmH2m+1为直链基团是效果更佳。在本发明某些实施例中,可由式2-9中任一结构式表示:
褪黑素-铂(IV)配合物可为中间体,由下式20表示:
其中,
其中,R1为-CnH2n--,n为整数且n≥1,优选的,n≤6,更优选的,n≤2;-CnH2n- 为直链基团。
制备上述褪黑素-铂(IV)-碳氮长链配合物的方法,具体步骤如下:
将式21化合物与式22化合物在第一缩合剂与第一缚酸剂存在的条件下发生酯化反应,得到式20中间体化合物;
将式20化合物与式23化合物发生酯化反应,得到所述褪黑素-铂(IV)-碳氮长链配合物;
其中,
R1为-CnH2n-,n为整数且n≥1,优选的,-CnH2n-为直链基团;R2为-NH-CmH2m+1或-CmH2mO,m为整数且m≥1,优选的-NH-CmH2m+1为直链基团。
其中,第一缩合剂为TBTU,第一缚酸剂为三乙胺,反应中原料比为:式 21化合物:式22化合物:第一缩合剂:第一缚酸剂为1-1.2:1:1.2-2:1.2-2;反应在避光且惰性气体保护的条件下进行。
其中,式21化合物的制备方法包括:
将如式24的褪黑素与式25化合物(丁二酸酐或戊二酸酐)在第二缩合剂与第二缚酸剂存在的条件下发生酰化反应得到式11化合物;
其中,第二缩合剂为DMAP;第二缚酸剂为三乙胺。
上述褪黑素-铂(IV)-碳氮长链配合物能够用于制备抗肿瘤药物,例如可用于制备抗卵巢癌、***、乳腺癌、肺癌、肝癌、肠胃癌药物;尤其适合与性激素相关的肿瘤卵巢癌、***、乳腺癌药物。
下面结合具体实施例对本发明方案做出说明,其中,未具体说明操作步骤的实验方法,均按照相应商品说明书进行,实施例中所用到的仪器、试剂、耗材如无特殊说明,均可从商业公司购买得到。
实施例一
本实施例的褪黑素-铂(IV)-碳氮长链配合物a结构式如下式:
本实施例所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法合成路线如下:
步骤1,将顺铂(Cisplatin)在双氧水的条件下氧化6h,结束后在0-4℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Oxoplatin (c,c,t-[Pt(NH3)2Cl2(OH)2]),a1。
步骤2,将褪黑素(MT)与丁二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀a2。
步骤3,将步骤2中的产物a2与干燥的二甲基亚砜(DMSO)混合,加入 o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物a1(Oxoplatin),常温反应24h,加乙醇,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀a3。
步骤4,将步骤3中的产物a3溶于干燥DMF中,加入异氰酸己酯,常温搅拌5h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱, DCM和MA的比例为10:1作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物a。
1H NMR(400MHz,DMSO-d6):δ8.21(d,J=9.0Hz,1H),8.06(t,J=5.6Hz, 1H),7.69(s,1H),7.14(d,J=2.5Hz,1H),6.92(dd,J=9.0,2.5Hz,1H),6.63(s,6H), 6.57(m,1H),3.81(s,3H),3.38(d,J=7.2Hz,2H),3.11(t,J=6.5Hz,2H),2.88(dd, J=12.6,6.3Hz,2H),2.78(t,J=7.1Hz,2H),2.72(t,J=6.2Hz,2H),1.81(s,3H), 1.34(d,J=8.2Hz,2H),1.26(s,6H),0.85(t,J=6.8Hz,3H).13C NMR(101MHz, DMSO-d6):δ179.48,170.43,169.20,163.85,155.80,131.39,129.82,123.56,119.07, 116.77,112.86,101.82,55.32,40.95,38.17,31.10,30.74,29.78,26.09,24.79,22.67, 22.09,13.94.HR-MS calcd forC24H39Cl2N5O7Pt(M+H)+,775.5880;found: 776.1926.
实施例二
本实施例的褪黑素-铂(IV)-碳氮长链配合物b结构式如下式:
成路线如下:
步骤1,将顺铂(Cisplatin)在双氧水的条件下氧化6h,结束后在0-4℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Oxoplatin (c,c,t-[Pt(NH3)2Cl2(OH)2]),a1。
步骤2,将褪黑素(MT)与戊二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀b2。
步骤3,将步骤2中的产物b2与干燥的二甲基亚砜(DMSO)混合,加入 o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物a1(Oxoplatin),常温反应24h,加乙醇,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀b3。
步骤4,将步骤3中的产物b3溶于干燥DMF中,加入异氰酸己酯,常温搅拌5h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱, DCM和MA的比例为10:1作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物b。
1H NMR(400MHz,DMSO-d6):δ8.22(d,J=8.9Hz,1H),8.04(t,J=5.2Hz, 1H),7.69(s,1H),7.14(d,J=1.9Hz,1H),6.92(dd,J=8.9,2.0Hz,1H),6.67(s,6H), 6.53(s,1H),3.81(s,3H),3.39(s,2H),3.02(t,J=7.1Hz,2H),2.89(d,J=5.1Hz, 2H),2.78(t,J=7.0Hz,2H),2.37(t,J=6.6Hz,2H),1.92–1.83(m,2H),1.82(s, 3H),1.35(d,J=5.9Hz,2H),1.23(s,6H),0.86(t,J=6.6Hz,3H).13C NMR(101 MHz,DMSO-d6):δ179.99,171.21,169.23,163.99,155.79,131.39,129.74,123.84, 118.91,116.71,112.86,101.83,55.32,40.95,38.25,34.53,33.99,31.10,29.78,26.09, 24.81,22.69,22.09,20.74,13.95.HR-MS calcd for C25H41Cl2N5O7Pt(M+H)+, 790.6150;found:790.2081.
实施例三
本实施例的褪黑素-铂(IV)-碳氮长链配合物c结构式如下式:
本实施例所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法合成路线如下:
步骤1,将奥沙利铂(Oxaliplatin)在双氧水的条件下氧化6h,结束后在0-4 ℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Pt(DACH)(OH)2, c1。
步骤2,将褪黑素(MT)与丁二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀c2。
步骤3,将步骤2中的产物c2与干燥的二甲基亚砜(DMSO)混合,加入 o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物c1(Pt(DACH)(OH)2),50℃加热反应24h,加三氯甲烷,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀c3。
步骤4,将步骤3中的产物c3溶于干燥DMF中,加入十二烷基异氰酸酯,常温搅拌24h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱,DCM和MA的比例为10:1作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物c。
1H-NMR(400MHz,DMSO-d6):δ(ppm)=9.65(d,J=85.5Hz,1H),8.72(s, 1H),8.34-7.93(m,4H),7.70(s,1H),7.14(d,J=2.1Hz,1H),6.90(dd,J=9.0,2.2 Hz,1H),6.77(t,J=5.2Hz,1H),3.81(s,3H),3.40-3.35(m,2H),2.95-2.82(m,2H), 2.78(t,J=7.1Hz,2H),2.74-2.67(m,2H),2.11(d,J=0.5Hz,2H),1.81(s,3H), 1.62-1.06(m,28H),0.85(t,J=6.6Hz,3H).13C-NMR(101MHz,DMSO-d6):δ(ppm) =170.31,169.30,164.03,163.04,155.70,131.58,129.99,123.71,118.96,116.36, 112.70,101.68,55.30,40.75,38.15,31.26,30.78,29.61,29.05,26.26,24.80,23.38, 22.65,22.05,13.90.
实施例四
本实施例的褪黑素-铂(IV)-碳氮长链配合物d结构式如下式:
本实施例所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法合成路线如下:
步骤1,将奥沙利铂(Oxaliplatin)在双氧水的条件下氧化6h,结束后在0-4 ℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Pt(DACH)(OH)2, d1。
步骤2,将褪黑素(MT)与戊二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀d2。
步骤3,将步骤2中的产物d2与干燥的二甲基亚砜(DMSO)混合,加入 o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物d1(Pt(DACH)(OH)2),50℃加热反应24h,加三氯甲烷,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀d3。
步骤4,将步骤3中的产物d3溶于干燥DMF中,加入十二烷基异氰酸酯,常温搅拌24h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱,DCM和MA的比例为10:1作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物d。
1H-NMR(400MHz,DMSO-d6):δ(ppm)=9.77(d,J=85.9Hz,1H),8.63(s, 1H),8.18(dd,J=57.4,48.7Hz,4H),7.64(s,1H),7.14(s,1H),6.92(d,J=8.4Hz, 1H),6.84-6.64(m,1H),3.81(s,3H),3.37(s,2H),3.05-2.71(m,6H),2.12(d,J= 9.6Hz,2H),1.94-1.83(m,2H),1.81(s,3H),1.68-0.93(m,28H),0.84(d,J=6.3Hz, 3H).13C-NMR(101MHz,DMSO-d6):δ(ppm)=179.82,170.48,169.18,163.48, 155.84,131.31,129.78,123.58,118.96,116.61,112.87,101.82,54.92,38.17,33.82, 31.26,29.05,28.68,26.25,24.78,23.40,22.64,22.06,20.44,13.92.
实施例五
本实施例的褪黑素-铂(IV)-碳氮长链配合物e结构式如下式:
本实施例所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法合成路线如下:
步骤1,将顺铂(Cisplatin)在双氧水的条件下氧化6h,结束后在0-4℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Oxoplatin (c,c,t-[Pt(NH3)2Cl2(OH)2]),e1。
步骤2,将褪黑素(MT)与戊二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀e2。
步骤3,将步骤2中的产物e2与干燥的二甲基亚砜(DMSO)混合,加入 o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物a1(Oxoplatin),常温反应24h,加乙醇,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀e3。
步骤4,将e4(5-氨基酮戊酸甲酯盐酸盐)与DMF混合,加入Boc酸酐和 Et3N,0℃活化2h,后常温反应12h,反应液为黄色悬浊液。用乙酸乙酯萃取反应液,旋干得到e5。将e5与THF混合,缓慢滴加LiOH溶液,常温反应3h。用乙酸乙酯萃取反应液,旋干乙酸乙酯后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,旋干得到e6。
步骤5,将步骤3中的产物e3溶于干燥DMF中,加入步骤4中的产物e6,常温搅拌24h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱,PE和EA的比例为1:2作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物e。
1H-NMR(400MHz,DMSO-d6):δ(ppm)=8.21(d,J=8.9Hz,1H),8.05(s,3H), 7.69(s,1H),7.15(s,1H),6.92(d,J=8.3Hz,1H),6.50(s,6H),3.99(s,2H),3.81(s, 3H),3.11(d,J=5.9Hz,4H),2.77(dd,J=16.1,7.0Hz,4H),2.62(d,J=5.6Hz,2H), 2.57(d,J=5.6Hz,2H),1.82(s,3H).13C-NMR(101MHz,DMSO-d6):δ(ppm)= 203.25,179.41,179.15,170.33,169.21,155.83,131.40,129.76,123.54,119.10, 116.69,112.87,101.77,55.25,46.99,45.68,38.18,35.24,30.67,29.31,22.66.
实施例六
本实施例的褪黑素-铂(IV)-碳氮长链配合物f结构式如下式:
本实施例所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法合成路线如下:
步骤1,将顺铂(Cisplatin)在双氧水的条件下氧化6h,结束后在0-4℃下冷藏过夜,再用水,冰乙醇,***洗,得到淡黄色沉淀Oxoplatin (c,c,t-[Pt(NH3)2Cl2(OH)2]),f1。
步骤2,将褪黑素(MT)与戊二酸酐反应,反应中加入4-二甲氨基吡啶 (DMAP),三乙胺(Et3N),反应过程中用氩气保护,反应温度为50℃反应48h,反应液通过浓缩成油状通过硅胶层析柱分离,洗脱液为二氯甲烷与甲醇,得到乳白色沉淀f2。
步骤3,将步骤2中的产物f2与干燥的二甲基亚砜(DMSO)混合,加入o-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),活化一段时间后加入Et3N 与步骤1中的产物a1(Oxoplatin),常温反应24h,加乙醇,***出沉淀,干燥后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,得到淡黄色沉淀f3。
步骤4,将f4(5-氨基酮戊酸甲酯盐酸盐)与DMF混合,加入Boc酸酐和 Et3N,0℃活化2h,后常温反应12h,反应液为黄色悬浊液。用乙酸乙酯萃取反应液,旋干得到f5。将f5与THF混合,缓慢滴加LiOH溶液,常温反应3h。用乙酸乙酯萃取反应液,旋干乙酸乙酯后通过硅胶层析柱进一步纯化,洗脱剂为二氯甲烷与甲醇,旋干得到f6。
步骤5,将步骤3中的产物f3溶于干燥DMF中,加入步骤4中的产物f6,常温搅拌24h,用旋转蒸发仪除去DMF,加入少许DCM溶解,通过硅胶柱层析色谱,PE和EA的比例为1:2作为展开剂,纯化产物,最后浓缩后为油状,加入水出固体,离心得到淡黄色产物。
1H-NMR(400MHz,DMSO-d6):δ(ppm)=8.22(d,J=8.9Hz,1H),8.05(d,J= 9.6Hz,3H),7.67(s,1H),7.14(d,J=2.3Hz,1H),6.92(dd,J=9.0,2.3Hz,1H), 6.53(s,6H),4.00(d,J=4.7Hz,2H),3.81(s,3H),3.02(t,J=7.2Hz,2H),2.78(t,J =7.4Hz,2H),2.63(t,J=5.9Hz,2H),2.61-2.51(m,4H),2.38(t,J=7.0Hz,2H), 1.88(dd,J=15.7,8.6Hz,2H),1.82(s,3H).13C-NMR(101MHz,DMSO-d6):δ(ppm) =203.46,179.79,178.94,170.82,168.99,155.50,131.27,129.61,123.46,118.61, 116.44,112.67,101.88,55.25,46.91,45.58,38.26,35.35,33.70,29.37,24.56,22.36, 20.48.
实施例七
一种新型抗肿瘤前药褪黑素-铂(IV)-碳氮长链配合物1-8,其特征在于具体的合成步骤如下:
(1)化合物1的合成与上述实例一、二步骤类似,化合物a3与异氰酸己酯反应,产物35mg(56.5%).1H NMR(400MHz,DMSO-d6):δ8.21(d,J=9.0Hz,1H),8.06 (t,J=5.6Hz,1H),7.69(s,1H),7.14(d,J=2.5Hz,1H),6.92(dd,J=9.0,2.5Hz, 1H),6.63(s,6H),6.57(m,1H),3.81(s,3H),3.38(d,J=7.2Hz,2H),3.11(t,J=6.5 Hz,2H),2.88(dd,J=12.6,6.3Hz,2H),2.78(t,J=7.1Hz,2H),2.72(t,J=6.2Hz, 2H),1.81(s,3H),1.34(d,J=8.2Hz,2H),1.26(s,6H),0.85(t,J=6.8Hz,3H).13C NMR(101MHz,DMSO-d6):δ179.48,170.43,169.20,163.85,155.80,131.39, 129.82,123.56,119.07,116.77,112.86,101.82,55.32,40.95,38.17,31.10,30.74, 29.78,26.09,24.79,22.67,22.09,13.94.HR-MS calcd for C24H39Cl2N5O7Pt(M+H)+, 775.5880;found:776.1926.
(2)化合物2的合成与上述实例一、二步骤类似,化合物a3与异氰酸辛酯反应,产物29.8mg(46.4%).1H NMR(400MHz,DMSO-d6):δ8.21(d,J=8.9Hz,1H), 8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J=8.3Hz,1H),6.63(s,6H),6.56(m, 1H),3.81(s,3H),3.36(s,2H),3.12(s,2H),2.88(d,J=5.3Hz,2H),2.78(t,J=6.5 Hz,2H),2.73(s,2H),1.82(s,3H),1.33(s,2H),1.23(s,10H),0.85(d,J=6.4Hz, 3H).13C NMR(101MHz,DMSO-d6):δ179.48,170.42,169.20,163.86,155.80, 131.39,129.82,123.56,119.07,116.76,112.86,101.82,55.32,40.96,38.17,31.25, 30.75,29.83,28.78,28.71,26.44,24.79,22.67,22.09,13.95.HR-MS(m/s):calcd for C26H43Cl2N5O7Pt(M+H)+,803.6420;found:804.2245.
(3)化合物3的合成与上述实例一、二步骤类似,化合物a3与十二烷基异氰酸酯反应,产物33mg(48.1%)。1H NMR(400MHz,DMSO-d6):δ8.21(d,J=8.9Hz, 1H),8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(dd,1H),6.63(s,6H),6.56(m,1H), 3.81(s,3H),3.37(s,2H),3.12(s,2H),2.88(d,J=4.9Hz,2H),2.79(t,J=6.5Hz, 2H),2.73(s,2H),1.82(s,3H),1.33(s,2H),1.23(s,18H),0.85(s,3H).13C NMR (101MHz,DMSO-d6):δ179.48,170.42,169.20,163.85,155.80,131.39,129.82, 123.55,119.06,116.76,112.85,101.81,55.31,40.96,38.17,31.28,30.74,29.83, 29.07,29.04,29.02,28.90,28.71,26.45,24.79,22.67,22.09,13.95.HR-MS calcd for C30H51Cl2N5O7Pt(M+H)+,859.7500;found:860.2859.
(4)化合物4的合成与上述实例一、二步骤类似,化合物a3与十六烷基异氰酸酯反应,产物40mg(54.7%)。1H NMR(400MHz,DMSO-d6):δ8.21(d,J=9.0Hz, 1H),8.03(t,J=5.6Hz,1H),7.68(s,1H),7.14(d,J=2.4Hz,1H),6.92(dd,J=9.0, 2.5Hz,1H),6.61(s,6H),6.55(d,J=5.4Hz,1H),3.81(s,3H),3.44–3.34(m,2H), 3.12(t,J=6.5Hz,2H),2.93–2.83(m,2H),2.78(t,J=7.1Hz,2H),2.72(t,J=6.3 Hz,2H),1.81(s,3H),1.33(s,2H),1.23(s,26H),0.85(t,J=6.7Hz,3H).13C NMR (101MHz,DMSO-d6):δ179.48,170.42,169.19,163.85,155.79,131.39,129.82, 123.56,119.06,116.76,112.85,101.81,55.30,40.96,38.16,31.27,30.72,29.83, 29.04,28.98,28.90,28.69,26.45,24.79,22.67,22.08,13.94.HR-MS calcd for C34H59Cl2N5O7Pt(M+H)+,915.8580;found:916.3496.
(5)化合物5的合成与上述实例一、二步骤类似,化合物b3与异氰酸己酯反应,产物30mg(47.6%)。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=8.9Hz,1H),8.04 (t,J=5.2Hz,1H),7.69(s,1H),7.14(d,J=1.9Hz,1H),6.92(dd,J=8.9,2.0Hz, 1H),6.67(s,6H),6.53(s,1H),3.81(s,3H),3.39(s,2H),3.02(t,J=7.1Hz,2H), 2.89(d,J=5.1Hz,2H),2.78(t,J=7.0Hz,2H),2.37(t,J=6.6Hz,2H),1.92–1.83 (m,2H),1.82(s,3H),1.35(d,J=5.9Hz,2H),1.23(s,6H),0.86(t,J=6.6Hz,3H). 13C NMR(101MHz,DMSO-d6):δ179.99,171.21,169.23,163.99,155.79,131.39, 129.74,123.84,118.91,116.71,112.86,101.83,55.32,40.95,38.25,34.53,33.99, 31.10,29.78,26.09,24.81,22.69,22.09,20.74,13.95.HR-MS calcd for C25H41Cl2N5O7Pt(M+H)+,790.6150;found:790.2081.
(6)化合物6的合成与上述实例一、二步骤类似,化合物b3与异氰酸辛酯反应,产物21mg(32.2%)。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=8.0Hz,1H),8.04 (s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J=7.6Hz,1H),6.60(d,J=54.7Hz,7H), 3.81(s,3H),3.36(s,2H),3.02(s,2H),2.89(dd,J=1.0,0.4Hz,2H),2.78(s,2H), 2.37(s,2H),1.86(s,2H),1.82(s,3H),1.34(s,2H),1.23(s,10H),0.86(s,3H).13C NMR(101MHz,DMSO-d6):δ180.00,171.21,169.23,163.97,155.79,131.39, 129.74,123.84,118.91,116.72,112.86,101.83,55.32,40.94,38.26,34.53,34.00, 31.26,29.83,28.85 28.72,26.45,24.81,22.69,22.09,20.74,13.96.HR-MS calcd for C26H43Cl2N5O7Pt(M+H)+,818.6690;found:818.2401.
(7)化合物7的合成与上述实例一、二步骤类似,化合物b3与十二烷基异氰酸酯反应,产物36mg(51.6%)。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=8.8Hz, 1H),8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J=8.3Hz,1H),6.68(s,6H), 6.53(s,1H),3.81(s,3H),3.36(s,2H),3.02(t,J=6.2Hz,2H),2.88(d,J=3.8Hz, 2H),2.78(t,J=6.3Hz,2H),2.37(s,2H),1.92–1.84(m,2H),1.82(s,3H),1.34(s, 2H),1.23(s,18H),0.85(d,J=6.4Hz,3H).13C NMR(101MHz,DMSO-d6):δ 180.01,171.20,169.22,163.98,155.79,131.39,129.75,123.84,118.91,116.71, 112.85,101.83,55.31,40.95,38.26,34.53,34.00,31.28,29.83,29.07,29.04,29.02, 28.90,28.71,26.45,24.81,22.68,22.08,20.75,13.94.HR-MS calcd for C31H53Cl2N5O7Pt(M+H)+,874.7770;found:874.3028.
(8)化合物8的合成与上述实例一、二步骤类似,化合物b3与十六烷基异氰酸酯反应,产物43mg(57.9%)。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=8.9Hz, 1H),8.02(t,J=5.5Hz,1H),7.68(s,1H),7.14(d,J=2.0Hz,1H),6.66(s,1H),6.53 (m,1H),3.81(s,3H),3.38(d,J=7.0Hz,2H),3.02(t,J=7.2Hz,2H),2.88(d,J= 6.0Hz,2H),2.78(t,J=7.2Hz,2H),2.37(t,J=6.7Hz,2H),1.90–1.84(m,2H),1.82 (s,3H),1.33(s,2H),1.23(s,26H),0.86(d,J=6.0Hz,3H).13C NMR(101MHz, DMSO-d6):δ180.00,171.20,169.21,163.96,155.79,131.39,129.75,123.83,118.91, 116.72,112.85,101.82,55.31,40.96,38.26,43.52,34.00,31.28,29.84,29.05,29.00, 28.91,28.70,26.46,24.82,22.68,22.09,20.74,13.94.HR-MS calcd for C35H61Cl2N5O7Pt(M+H)+,930.8850;found:930.3652.
实施例八体外抗肿瘤活性测定
为了更好的理解本发明的实质,下面进行体外抗肿瘤活性测定。
本实验通过MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐)法对实施例3中8种合成的化合物以及配体MT和顺铂,MT与顺铂的联合(1:1)用药的抗肿瘤活性进行研究,本实验采用5种癌细胞HepG-2(人肝癌细胞)、MCF-7(人乳腺癌细胞)、HCT-116(人结肠癌细胞)、HeLa(人***细胞细胞)和A549(非小细胞肺癌细胞)和一种正常人细胞HUVEC(人脐静脉血细胞)进行细胞毒实验研究,所有细胞株均在5%CO2浓度下,37℃饱和湿度的培养箱中培养。具体实验步骤如下:
收集对数生长期细胞,计数后,调整细胞浓度为3×104cells/mL接种至96孔板,每孔100μL,设置空白组(Blank,纯培养基)和对照组(Control,不加药组)。板子于细胞培养箱培养过夜。贴壁后,用培养基将化合物稀释至首列给药孔所需浓度,之后倍半稀释进行后续孔给药,轻轻吹打混匀。孵育72h后,分别向各孔加入10μL(5mg/mL)MTT溶液。孵箱内再培养4h,除去上清,加入100 μL/wellDMSO,充分震荡后用酶标仪λ=570nm测定OD值。进行三次独立重复实验来保证实验结果的可靠性。
表1化合物作用细胞72小时后的IC50值
a FI,fold increase,IC50(cisplatin)/IC50(compound 7).b FI,IC50(cisplatin+MT)/IC50 (compound 7).c SI,selectivity index,IC50(in HUVEC)/IC50(in MCF-7).
如表1所示实验结果,本实验结果显示随着化合物的碳链长度的增加并没有呈现细胞毒逐渐增加的趋势,但是较顺铂以及顺铂和MT的联合给药组相比细胞毒性均大大提高,化合物1在A549细胞中的IC50为0.799±0.133,与顺铂组相比提高的倍数最低,提高3.89倍;而化合物7在MCF-7中的IC50为0.068±0.004,较顺铂比提高的倍数最高,提高87.21倍;据文献报道,MT受体在MCF-7中的含量高,这与其在MCF-7中的作用能力强有一定的关系,化合物7对正常细胞 HUVEC的选择指数为MCF-7的3.19倍,而顺铂的选择指数为0.46,化合物7较顺铂的选择指数相比提高了约7倍,这个结果展示了7不仅提高了对肿瘤细胞的杀伤力而且减少了对正常细胞的损伤。同时,基于褪黑素自身的免疫调控作用,抗焦虑催眠,调节昼夜节律等。与其他四价铂药物比,褪黑素-铂(IV)-碳氮长链更能减轻病人的精神压力,降低副作用,对于四价铂来说是一个很好的发展药物。总之本发明的褪黑素-铂(IV)-碳氮长链孪药是一种新型高效抗肿瘤药物,具有广谱的抗癌作用,疗效好、副作用小,且制备方法简单,成本低廉,易于工业化生产。
实施例九:胞内还原实验
探索前药的胞内释放能力对于研究四价铂的作用机制至关重要,四价铂只有在体内还原成二价铂形式才能发挥作用。为了探究褪黑素-铂(IV)-碳氮长链是否能在细胞内被还原型物质(谷胱甘肽、抗坏血酸等)还原,释放出二价铂同时起到药物缓释效果,我们进行了胞内还原实验。以化合物7为例,具体实验步骤如下:
将1×106个MCF-7细胞接种于6孔板中,细胞贴壁后,100μM化合物11 作用于细胞,继续培养4h,弃去培养基,用PBS洗三次细胞,离心除去PBS,将细胞用一定的甲醇和二氯甲烷重悬,转入研磨器中研磨十分钟至细胞完全裂解,研磨完毕后静置一段时间,离心收集上清液,室温下挥干溶剂,然后用200μL 的色谱甲醇重悬固体,用液相进行检测,液相分析条件:紫外(UV)检测波长 260nm,流动相甲醇和水(含0.1%的甲酸),Venusil XBP C18柱(50×4.6mm, 5μm),日本岛精(LC-20A)高效液相分析仪,梯度洗脱,甲醇5%-95%(0-10min),95%甲醇25min,流速1mL/min。
HPLC检测结果如图1所示,图中,从下向上条带依次代表无药物处理的细胞空白对照组,MT配体中间体标准品,褪黑素-铂(IV)-碳氮长链标准品化合物7 和化合物7的胞内提取样品。从化合物7的胞内提取样品所示条带上可以观察到两个主峰,一个峰的出峰时间在13.7min,与MT配体中间体标准品的出峰时间相同,另一个峰的出峰时间在17.0min与褪黑素-铂(IV)-碳氮长链化合物7出峰时间相同,证明化合物7在体内能被释放。由于药物处理时长仅4h,中间体的释放比较少,7还会在后续作用时间内被进一步释放。该结果表明,与前一项专利(一种褪黑素-铂(IV)配合物、其制备方法及应用,申请号:201811515822.8) 相比,本专利所合成的褪黑素-铂(IV)-碳氮长链配合物可以在细胞内达到缓释效果。
实施例十药物体内抗肿瘤的活性研究
为了探究本发明所述褪黑素-铂(IV)-碳氮长链的抗肿瘤效果,我们进行了药物体内抗肿瘤的活性研究,具体步骤如下:
首先用4-5周龄Balb/c裸鼠建立MCF-7肿瘤模型,待肿瘤体积达到50-100 cm3后,将小鼠随机分为4组,分别为PBS,cisplatin,cisplatin+MT,MT,7 组。按2.5mg/kg Pt浓度配置药物,每3天给一次药,每两天测量小鼠体重及肿瘤体积,共给药6次。最后一次给药后三天,处死小鼠,提取器官(心、肝、脾、肺、肾)及肿瘤。器官及肿瘤用于H&E染色组织学分析及ICP-MS铂含量测定。
实验结果如上述图2-8所示。从肿瘤生长曲线图3、肿瘤重量图4及肿瘤最终图片图7可以看出,化合物7对肿瘤的抑制效果较空白组明显提升,与顺铂组和联合给药组基本持平。最重要的是,化合物7组小鼠较顺铂和联合组毒性明显下降。从小鼠体重变化图2可以看出,化合物7给药组的小鼠体重基本维持稳定,与空白组小鼠体重无明显差异,而顺铂及联合给药组小鼠体重呈明显下降趋势。从存活率曲线图5分析,化合物7组小鼠最终存活率为100%,而联合组最终存活率为16.67%,顺铂组存活率下降0%(其中死亡的小鼠包括死亡鼠和体重下降到自身体积的20%的小鼠)。从ICP-MS结果图6可以看出,化合物7与顺铂相比在肾脏中和脾中的累积量明显下降,顺铂的肾毒性是最严重的毒性之一,化合物7在肾脏中低的累积量将能有效的缓解对肾脏的毒副作用,这一结果从图8 中H&E染色结果也能被观察到。H&E中能观察到7与顺铂对肿瘤组织的严重损伤,对于肾脏顺铂有严重的损伤,而化合物7对肾脏的损伤很小,其它器官没有明显差别。以上体内抗肿瘤实验充分证明了11较临床用药顺铂毒副作用明显下降,初步达成了抗肿瘤药物高效、低毒的治疗目标,在治疗过程中实现了安全且有效。
以上对本发明的实施例进行了详细说明,但所述内容仅为本发明的较佳实施例,不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等,均应仍归属于本发明的专利涵盖范围之内。
Claims (10)
1.一种褪黑素-铂(IV)-碳氮长链配合物,其特征在于:铂(IV)配位中心轴向一侧连接有褪黑素分子,另一侧连接有碳氮长链基团。
3.根据权利要求2所述的褪黑素-铂(IV)-碳氮长链配合物,其特征在于:n≤2,-CnH2n-为直链基团。
4.根据权利要求2所述的褪黑素-铂(IV)-碳氮长链配合物,其特征在于:m≤17,优选地,2≤m≤17,-NH-CmH2m+1为直链基团。
8.根据权利要求6或7所述的褪黑素-铂(IV)-碳氮长链配合物的制备方法,其特征在于:所述第一缩合剂为TBTU;所述第一缚酸剂为三乙胺;反应中原料比为:式21化合物:式22化合物:第一缩合剂:第一缚酸剂为1-1.2:1:1.2-2:1.2-2;优选地,反应在避光且惰性气体保护的条件下进行。
9.权利要求1-5中任一所述的褪黑素-铂(IV)-碳氮长链配合物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的褪黑素-铂(IV)-碳氮长链配合物在制备抗肿瘤药物中的应用,其特征在于:用于制备抗卵巢癌、***、乳腺癌、肺癌、肝癌、肠胃癌药物。
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CN115838386A (zh) * | 2022-11-24 | 2023-03-24 | 天津医科大学 | 一种芦竹碱-铂(iv)配合物的制备方法及其在肿瘤药物中的应用 |
WO2024109935A1 (zh) * | 2022-11-24 | 2024-05-30 | 天津市肿瘤医院(天津医科大学肿瘤医院) | 芦竹碱-铂(iv)配合物及其制备方法和抗肿瘤用途 |
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