CN113527368A - 化合物、抗癌药物的制备方法和用途 - Google Patents
化合物、抗癌药物的制备方法和用途 Download PDFInfo
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- CN113527368A CN113527368A CN202110928404.7A CN202110928404A CN113527368A CN 113527368 A CN113527368 A CN 113527368A CN 202110928404 A CN202110928404 A CN 202110928404A CN 113527368 A CN113527368 A CN 113527368A
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Abstract
本公开提供了一种化合物，该化合物为由铂药和共价连接到铂药的轴向位置的具有解除免疫负调功能的小分子药物形成的孪药，具有式I所示的结构：
其中虚线框内为铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。本公开通过将具有解除免疫负调功能的小分子药物共价连接到铂药的轴向位置，形成孪药，在肿瘤部位同时发挥铂药的肿瘤杀伤作用和小分子药物的解除免疫负调的功能；该孪药与免疫治疗联合使用，可以有效的提高免疫治疗的响应，显著地提高对肿瘤的治疗效果。本公开中铂类抗癌孪药的制备方法简单，成本低，适合工业化生产，具有临床转化潜力。
Description
技术领域
本公开涉及生物医药技术领域，具体涉及一种化合物、抗癌药物的制备方法和用途。
背景技术
癌症是威胁人类生命健康的第二大疾病。根据世界卫生组织国际癌症研究机构IACR的最新统计数据，2020年全球癌症死亡病例约996万例，其中中国的癌症死亡病例超过300万例。铂类化疗药物是一类应用最广泛的化疗药物，如顺铂、卡铂和奥沙利铂已经在全世界范围内用于治疗各类癌症。免疫治疗被认为是最有希望治愈癌症的方法，而化疗联合免疫治疗可以产生协同作用，已有多例化疗联合免疫治疗的方案被FDA批准并进入临床，与此同时，根据在clinicaltrials.gov中检索到的信息，免疫治疗联合化疗的临床试验数量仍在逐渐增加。
但有多项研究表明，化疗与免疫治疗并不总是产生协同作用。如一项发表在《自然-医学》杂志(2019年第25期920-928页)上的研究显示，化疗药物多柔比星可以提高anti-pd-1的响应率，而环磷酰胺反而会降低anti-pd-1的响应率。目前对化疗与免疫治疗相互影响的研究还很不充分，还没有一项行之有效的策略，用于设计增强免疫治疗的化疗药物。本公开就是针对这一问题，设计出了一类新型铂类孪药。
发明内容
(一)要解决的技术问题
针对上述问题，本公开提供了一种化合物、抗癌药物的制备方法和用途，用于至少部分解决传统药物难以提高临床中化疗联合免疫治疗的治疗效果等技术问题。
(二)技术方案
本公开一方面提供了一种化合物，化合物为由铂药和共价连接到铂药的轴向位置的具有解除免疫负调功能的小分子药物形成的孪药，具有式I所示的结构：
其中虚线框内为铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
进一步地，铂药选自顺铂、卡铂和奥沙利铂；具有解除免疫负调功能的小分子药物包括吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂，肽基脯氨酰顺反异构酶抑制剂，诱导型一氧化氮合酶抑制剂，精氨酸酶抑制剂，转化生长因子-β抑制剂，棕榈酰转移酶抑制剂中的一种或多种。
进一步地，具有解除免疫负调功能的小分子药物包括：1-甲基-D-色氨酸、乙酰水杨酸、全反式维甲酸中的一种或多种。
本公开还有一方面提供了一种抗癌药物的制备方法，包括：S1，将铂药与双氧水进行氧化反应，得到固体前驱体；S2，将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物或其对应的酸酐进行反应，得到小分子药物共价连接到铂药的轴向位置的孪药结构，如式I所示：
其中虚线框内为铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
进一步地，S1中铂药选自顺铂、卡铂和奥沙利铂；S2中具有解除免疫负调功能的小分子药物包括：吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂，肽基脯氨酰顺反异构酶抑制剂，诱导型一氧化氮合酶抑制剂，精氨酸酶抑制剂，转化生长因子-β抑制剂，棕榈酰转移酶抑制剂中的一种或多种。
进一步地，具有解除免疫负调功能的小分子药物包括：1-甲基-D-色氨酸、乙酰水杨酸、全反式维甲酸中的一种或多种。
进一步地，S2包括：将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物、催化剂进行第一脱水缩合反应，或者是加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应；减压蒸馏除去溶剂后，再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个小分子药物共价连接的铂类孪药。
进一步地，S2包括：将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；将固体产物与固体前驱体溶解在溶剂中，加入催化剂进行第三脱水缩合反应；减压蒸馏除去溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个1-甲基-D-色氨酸共价连接的铂类孪药。
进一步地，S2包括：将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应，控制固体前驱体与小分子药物对应的酸酐的摩尔比，以得到轴向有一个乙酰水杨酸共价连接的铂类药物；将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；将固体产物与一个乙酰水杨酸共价连接的铂类药物进行第四脱水缩合反应；减压蒸馏除去溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；再次溶解、沉淀，洗涤、干燥得到轴向分别为乙酰水杨酸、1-甲基-D-色氨酸共价连接的铂类孪药。
本公开还有一方面提供了一种根据前述化合物用于制备药物的用途，药物用于预防和治疗癌症，或与免疫治疗联合使用，提高免疫治疗的响应。
(三)有益效果
本公开中的铂类孪药进入癌细胞后，会在还原物质的作用下生成铂药和小分子药物；铂药会作用于DNA，抑制DNA的复制，造成癌细胞凋亡；小分子药物会作用于细胞中的信号通路，发挥其解除免疫负调的功效，抑制肿瘤细胞的免疫逃逸；两种机制协同作用，会产生更优于单药的治疗效果；且与免疫治疗联合使用时，由于孪药抑制肿瘤细胞的免疫逃逸，会进一步增强免疫治疗的响应率。且该铂类孪药制备方法简单，成本低廉，适合工业化生产，具有临床转化潜力。
附图说明
图1示意性示出了根据本公开实施例中三种铂类孪药的合成路线图；
图2示意性示出了根据本公开实施例1制备[Oxaliplatin(IV)(Aspirin)2](DAOP)的核磁共振氢谱图；
图3示意性示出了根据本公开实施例2制备[Oxaliplatin(IV)(D-1-MT)2](DMOP)的核磁共振氢谱图；
图4示意性示出了根据本公开实施例3制备[Oxaliplatin(IV)(Aspirin)(D-1-MT)](AMOP)的核磁共振氢谱图；
图5示意性示出了根据本公开实施例4中给药计划的示意图；
图6示意性示出了根据本公开实施例中三种化疗孪药与免疫检查点抑制剂α-PD-1联用对比单独使用α-PD-1的肿瘤生长和生存曲线；
图7示意性示出了根据本公开实施例4中药物治疗15天后实际肿瘤大小拍照图。
具体实施方式
为使本公开的目的、技术方案和优点更加清楚明白，以下结合具体实施例，并参照附图，对本公开进一步详细说明。
本公开的实施例提供了一种化合物，化合物为由铂药和共价连接到铂药的轴向位置的具有解除免疫负调功能的小分子药物形成的孪药，具有式I所示的结构：
其中虚线框内为铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
将具有解除免疫负调功能的小分子药物共价连接到铂药的轴向位置，形成孪药，在肿瘤部位同时发挥铂药的肿瘤杀伤作用和小分子药物的解除免疫负调的功能，相比于对应的单药组合，这种孪药显示出更好的增强免疫治疗的效果。需要说明的是，铂药的轴向配位是指将平面正方形配位结构的Pt(II)，氧化为正八面体配位结构的Pt(IV)时，引入新基团的Z轴方向。
具体地，该铂类孪药进入癌细胞后，会在还原物质作用下生成铂药和小分子药物；铂药会作用于DNA，抑制DNA的复制，造成癌细胞凋亡；小分子药物会作用于细胞中的信号通路，发挥其解除免疫负调的功效，抑制肿瘤细胞的免疫逃逸。两种机制协同作用，会产生更优于单药的治疗效果；且与免疫治疗联合使用时，由于孪药抑制肿瘤细胞的免疫逃逸，会进一步增强免疫治疗的响应率。
在上述实施例的基础上，铂药选自顺铂、卡铂和奥沙利铂；具有解除免疫负调功能的小分子药物包括吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂，肽基脯氨酰顺反异构酶抑制剂，诱导型一氧化氮合酶抑制剂，精氨酸酶抑制剂，转化生长因子-β抑制剂，棕榈酰转移酶抑制剂等中的一种或多种。
相比于顺铂，奥沙利铂可以引起肿瘤细胞的免疫原性死亡，使肿瘤细胞在凋亡时释放出HMGB1，CRT，ATP等损伤相关分子模式，这些损伤相关分子模式作为天然免疫系统的刺激信号，可以刺激树突状细胞捕获并呈递肿瘤抗原，增强免疫应答，最终提高免疫治疗的响应。
这些具有解除免疫负调功能的小分子药物主要作用于细胞中的信号通路，发挥其解除免疫负调的功效，抑制肿瘤细胞的免疫逃逸，并最终提高免疫治疗的响应。具体的具有解除免疫负调功能的小分子药物包括：环氧化酶-2抑制剂，如塞来昔布、阿米洛芬、NS-398、20(S)-人参皂苷Rg3、没食子酸、水杨酸、吴茱萸次碱、美洛昔康、瑞巴派特、艾拉莫德、罗非考昔、非诺贝特酸、萘丁美酮、异荭草素、尼古昔苷、人参皂苷C-K、依托考昔、异嗪皮啶、尼美舒利、人参皂苷Rg5、人参皂苷Rd、姜酮酚、愈创木酚、艾瑞昔布、托芬那酸、伐地考昔、SC-236、8-姜烯酚、柳穿鱼黄素、安五脂素、人参皂苷Rb3、阿地米屈、丁香醛、帕瑞昔布、升麻素苷、依托度酸、地拉考昔、补骨脂定、S-(+)-异紫花前胡内酯、FK 3311、N-叔丁基-α-苯基硝酮、古伦宾、六氢姜黄素、非罗考昔、帕瑞昔布、CAY10404、氨芬酸、GW-406381、吗伐考昔、替尼达帕、2，5-二叔丁基对苯二酚、10-姜烯酚、α-菠甾醇、SC57666、旋覆花素、牛防风素、甲芬那酸、α-卡茄碱、α-蛇麻烯、DuP-697、去甲塞来昔布、水杨酸、SC-58125、堪非醇3，4′-二-O-甲醚、RWJ 63556、氟舒胺、L-745337、S-2474、替马考昔、COX-2-IN-2、对乙酰氨基酚、吲哚美辛、阿司匹林、布洛芬、没食子酸、双氯芬酸、萘普生、舒林酸、SC-560、卡洛芬、新绿原酸、吡罗昔康、氟比洛芬、酮洛芬、酮咯酸氨丁三醇、溴芬酸、甲芬那酸、棕矢车菊素、双氯芬酸二乙胺，萘普生钠、S-(+)-酮洛芬、白当归脑、奥沙普秦、细辛醛、氯诺昔康、替诺昔康、玄参苷、托美丁、普拉洛芬、扎托布洛芬、(S)-(+)-布洛芬、β-岚香酮酸、咖啡酸乙酯、醋氯芬酸、咖啡醇、酮咯酸、伊索昔康、(E)-对甲氧基肉桂酸乙酯、洛索洛芬、痛灭定、3′4′7-三甲氧基-5-羟基黄酮、栎樱酸、N-反式-阿魏酰酪胺、亥茅酚、知母皂苷B、莫苯唑酸、醋酸蒲公英霜、培比洛芬、4，4′-二羟基-2，6-二甲氧基二氢查耳酮、AG-024322、酮咯酸、黄腐酚、芍药花素；吲哚胺2，3-双加氧酶抑制剂，如1-甲基-色氨酸、黄连碱、IDO-IN-3、IDO-IN-11、巴马汀、EOS200271、GNF-PF-3777、NLG919、IACS-8968、Nec-1；肽基脯氨酰顺反异构酶抑制剂，如全反式维甲酸、AP-1、KPT-6566、TAB-29；诱导型一氧化氮合酶抑制剂，如次野鸢尾黄素、GW274150、INO-1001、脱水穿心莲内酯、王百合苷B、3-O-乙酰基-16α-羟基松苓新酸、S-甲基异硫脲半硫酸盐、NOS-IN-1、(Rac)-MRI-1867、MEG、三白草酮、堪非醇3，4′-二-O-甲醚、α-卡茄碱、异嗪皮啶、2-乙酰基-3，5-二羟基苯乙酸乙酯、常春藤皂苷元、迷迭香酚、新隐丹参酮、地黄苦苷元、葳岩仙皂苷D、葳岩仙皂苷C、车叶草苷、软骨素、升麻素苷、去氧穿心莲内酯、整联蛋白序列Arg-Gly-Asp-Ser、阿卡地新、(S)-MRI-1867洛塞琳、α-石竹烯、AR-C102222、表儿茶素、氧化苦参碱、RV01、藏红花素II、L-NMMA、13-甲基小檗碱、去氢吴茱萸碱、咖啡酸乙酯、洋芹苷、羟基积雪草酸、新绿原酸、L-NIO、人参皂苷Rb3、木犀草素-5-O-葡萄糖苷、2-亚氨基生物素、人参皂苷C-K、知母皂苷B、β-脱水淫羊藿素、人参皂苷Rd、L-NIL；精氨酸酶抑制剂，如BEC、精氨酸酶抑制剂1、nor-NOHA、白皮杉醇3′-O-葡萄糖苷、2-氨基咪唑、DL-正缬氨酸；转化生长因子-β抑制剂，如吡非尼酮、(E)-SIS3、布他前列腺素、常山酮、氧化苦参碱、氢氯噻嗪、P144、AMR69、10，11-马唐生防菌画眉草弯孢霉毒素；棕榈酰转移酶抑制剂，如2-溴十六烷酸。
本公开还提供了一种抗癌药物的制备方法，请参见图1，包括：S1，将铂药与双氧水进行氧化反应，得到固体前驱体；S2，将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物或其对应的酸酐进行反应，得到小分子药物共价连接到铂药的轴向位置的孪药结构，如式I所示：
其中虚线框内为铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
铂药首先要与1～100％双氧水在0～99℃下进行氧化反应1～72h，然后减压蒸馏溶剂，得到固体产物；Pt上先形成两个羟基，易于与后续的小分子药物进行反应；氧化反应完成后，将得到的产物溶解在1～100ml二甲亚砜或N，N-二甲基甲酰胺中，加入适量的小分子药物，在0～100℃下反应1～48h，减压蒸馏溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3～10次，在20～100℃下干燥，得到固体产物(如轴向有一个或两个小分子药物的铂类孪药)。通过控制小分子药物与铂药的用量，可以得到轴向只有一个小分子的药物，轴向的另一边为羟基。
在上述实施例的基础上，S1中铂药选自顺铂、卡铂和奥沙利铂；S2中具有解除免疫负调功能的小分子药物包括：吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂中的一种或多种。具有解除免疫负调功能的小分子药物包括：1-甲基-D-色氨酸、乙酰水杨酸、全反式维甲酸中的一种或多种。
铂药本身会作用于癌细胞的DNA，抑制DNA的复制，造成癌细胞凋亡。以经典铂药(如顺铂、卡铂以及奥沙利铂)为母体，将具有解除免疫负调功能的小分子药物共价连接到铂药的轴向位置，即形成孪药。具有解除免疫负调功能的小分子药物主要作用于细胞中的信号通路，发挥其解除免疫负调的功效，抑制肿瘤细胞的免疫逃逸。小分子药物包括但不限于吲哚胺2，3-双加氧酶抑制剂1-甲基-D-色氨酸以及环氧化酶-2抑制剂乙酰水杨酸等。
还需要说明的是，将铂药与双氧水进行氧化反应后，然后减压蒸馏溶剂，得到固体前驱体；这里S1中双氧水的浓度为1～100％，氧化反应的温度为0～100℃，氧化反应的时间为1～72h。
在上述实施例的基础上，S2包括：将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物、催化剂进行第一脱水缩合反应，或者是加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应；减压蒸馏除去溶剂后，再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个小分子药物共价连接的铂类孪药。
固体前驱体可以与小分子药物在催化剂的作用下进行脱水缩合反应，具体包括：将上一步得到的固体前驱体溶解在1～100ml N，N-二甲基甲酰胺中，加入适量小分子药物(如乙酰水杨酸)、三乙胺和O-苯并三氮唑-四甲基脲六氟磷酸盐，0～100℃下搅拌1～48h。减压蒸馏溶剂，用10～100ml乙醇溶解，过滤去除不溶物。减压蒸馏溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3～10次，在20～100℃下干燥，得到固体产物(如轴向有一个或两个阿司匹林分子的铂类孪药)。
固体前驱体可以与小分子药物对应的酸酐进行酯化反应，请参见图1a具体包括：将上一步得到的固体前驱体溶解在1～100ml二甲亚砜或N，N-二甲基甲酰胺中，加入适量的小分子药物对应的酸酐(如乙酰水杨酸酐)，在20～100℃下反应1～48h，减压蒸馏溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3～10次，在20～100℃下干燥，得到固体产物(如轴向有一个或两个阿司匹林分子的铂类孪药)。
在上述实施例的基础上，请参见图1b，S2包括：将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；将固体产物与固体前驱体溶解在溶剂中，加入催化剂进行第三脱水缩合反应；减压蒸馏除去溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个1-甲基-D-色氨酸共价连接的铂类孪药。
将含有氨基的小分子药物(如1-甲基-D-色氨酸)与适量的二碳酸二叔丁酯和碳酸氢钠共同分散在1～100ml水和四氢呋喃的混合溶液中，0～100℃下搅拌1～48h，减压蒸馏四氢呋喃，得到的水溶液用HCl酸化，用10～100ml乙酸乙酯萃取。减压蒸馏乙酸乙酯，得到固体产物。
将固体前驱体和该固体产物按一定比例混合后溶解在1～100ml N，N-二甲基甲酰胺中，加入适量三乙胺和O-苯并三氮唑-四甲基脲六氟磷酸盐，0～100℃下搅拌1～48h。减压蒸馏溶剂，用10～100ml乙醇溶解，过滤去除不溶物。减压蒸馏溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3～10次，在20～100℃下干燥，得到固体产物。
将上一步得到的产物溶解在1～100ml氯仿中，加入1～50％三氟乙酸，搅拌1～24h。减压蒸馏溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3～10次，在20～100℃下干燥，得到固体产物(如轴向有一个或两个1-甲基-D-色氨酸的铂类孪药)。
在上述实施例的基础上，请参见图1c，S2包括：将固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应，控制固体前驱体与小分子药物对应的酸酐的摩尔比，以得到轴向有一个乙酰水杨酸共价连接的铂类药物；将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；将固体产物与一个乙酰水杨酸共价连接的铂类药物进行第四脱水缩合反应；减压蒸馏除去溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；再次溶解、沉淀，洗涤、干燥得到轴向分别为乙酰水杨酸、1-甲基-D-色氨酸共价连接的铂类孪药。
取轴向有一个小分子药物基团的铂类孪药作为原料，与另一种小分子药物按上述方法进行反应，得到轴向有两种不同的小分子药物基团的铂类孪药。
本公开还提供了一种根据前述化合物用于制备药物的用途，药物用于预防和治疗癌症。
该铂类孪药进入癌细胞后，会在还原物质作用下生成铂药和小分子药物；铂药会作用于DNA，抑制DNA的复制，造成癌细胞凋亡；小分子药物会作用于细胞中的信号通路，发挥其解除免疫负调的功效，抑制肿瘤细胞的免疫逃逸；两种机制协同作用，会产生更优于单药的治疗效果；且与免疫治疗联合使用时，由于孪药抑制肿瘤细胞的免疫逃逸，会进一步增强免疫治疗的响应率。
下面通过具体实施方式对本公开作进一步说明。本实施例公开了一类增强免疫检查点抑制剂的新型孪药制备方法仅供示范之用。实施例中使用的试剂均为市售产品，购自国药集团化学试剂有限公司，上海皓鸿生物医药科技有限公司，山东省铂源药业有限公司等。
实施例1：[Oxaliplatin(IV)(Aspirin)2](DAOP)的制备
请参见图1a，将10mL 30％w/v双氧水加入到1mmol奥沙利铂的悬液中，再加入10mL超纯水。室温下搅拌过夜，溶液由浑浊变为澄清透明。将水溶液蒸发至约2ml，冷却至0℃，滴入40ml乙醇中，得到大量白色沉淀。离心收集沉淀，烘干，得到白色粉末[Oxaliplatin(IV)(OH)2]。
将0.5mmol市售乙酰水杨酸酐加入含0.1mmol[Oxaliplatin(IV)(OH)2]的15mL N，N-二甲基甲酰胺悬浮液中。将混合物在70℃下搅拌4小时，然后在室温下过夜。旋蒸N，N-二甲基甲酰胺，加入丙酮溶解，用乙醚沉淀产物，再用乙醚洗涤3次，干燥后得到粗产物[Oxaliplatin(IV)(Aspirin)2]。
产物经高效液相色谱纯化，真空干燥，用核磁共振氢谱(H-NMR)和质谱(ESI-MS)表征。H-NMR(图2)(300MHz，DMSO)：δ8.39(d，J＝74.0Hz，2H)，7.82(dd，J＝7.7，1.4Hz，1H)，7.62-7.54(m，1H)，7.35(t，J＝7.5Hz，1H)，7.14(d，J＝8.0Hz，1H)，2.22(s，3H)，2.16(s，1H)，1.54(s，2H)，1.29-1.16(m，2H)。ESI-MS：MW[M+H]＝755.96。
实施例2：[Oxaliplatin(IV)(D-1-MT)2](DMOP)的制备
请参见图1b，将市售1mmol二碳酸二叔丁酯、1mmol 1-甲基-D-色氨酸和2mmol碳酸氢钠悬浮于10mL四氢呋喃与水的混合液中。将混合物在室温下搅拌24h，旋蒸溶剂四氢呋喃。在剩下的水溶液中加入盐酸至pH＝1，加入乙酸乙酯反复萃取三次，分液得到含有产物的淡黄色有机相，旋蒸乙酸乙酯，得到黄色固体Boc-D-1-MT。
将0.3mmol Boc-D-1-MT、0.1mmol[Oxaliplatin(IV)(OH)2]、0.3mmol三乙胺和0.3mmol O-苯并三氮唑-四甲基脲六氟磷酸盐悬浮于15mL N，N-二甲基甲酰胺中，将混合物在室温下搅拌至溶液澄清透明。旋蒸溶剂，将得到的油状物滴入乙醇中，过滤去除不溶物。旋蒸溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3次，干燥后得到固体产物[Oxaliplatin(IV)(Boc-D-1-MT)2]。
用10ml氯仿溶解上述产物，加入1ml三氟乙酸，搅拌2h后旋蒸溶剂。加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3次，干燥后得到粗产物[Oxaliplatin(IV)(D-1-MT)2]
产物经高效液相色谱纯化，真空干燥，用核磁共振氢谱(H-NMR)和质谱(ESI-MS)表征。H-NMR(图3)(300MHz，DMSO)：δ8.36(d，J＝7.3Hz，1H)，8.08(s，3H)，7.80-7.54(m，2H)，7.45(d，J＝8.2Hz，1H)，7.25-6.99(m，3H)，4.15(s，1H)，3.77(s，3H)，3.06(dd，J＝15.1，8.2Hz，1H)，2.22-1.90(m，1H)，1.69-1.38(m，2H)，1.17(d，J＝43.0Hz，3H)。ESI-MS：MW[M+H]＝832.02。
实施例3：[Oxaliplatin(IV)(Aspirin)(D-1-MT)](AMOP)制备
请参见图1c，将0.1mmol市售乙酰水杨酸酐加入含0.1mmol[Oxaliplatin(IV)(OH)2]的15mL N，N-二甲基甲酰胺悬浮液中。将混合物在70℃下搅拌4小时，然后在室温下过夜。旋蒸N，N-二甲基甲酰胺，加入丙酮溶解，用乙醚沉淀产物，再用乙醚洗涤3次，干燥后得到固体产物[Oxaliplatin(IV)(OH)(Aspirin)]。
将0.1mmol Boc-D-1-MT、0.1mmol[Oxaliplatin(IV)(OH)(Aspirin)]、0.1mmol三乙胺和0.1mmol O-苯并三氮唑-四甲基脲六氟磷酸盐悬浮于15mL N，N-二甲基甲酰胺中，将混合物在室温下搅拌至溶液澄清透明。旋蒸溶剂，将得到的油状物滴入乙醇中，过滤去除不溶物。旋蒸溶剂，加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3次，干燥后得到固体产物[Oxaliplatin(IV)(Aspirin)(Boc-D-1-MT)]。
用10ml氯仿溶解上述产物，加入1ml三氟乙酸，搅拌2h后旋蒸溶剂。加入丙酮溶解，用乙醚沉淀，再用乙醚洗涤3次，干燥后得到粗产物[Oxaliplatin(IV)(Aspirin)(D-1-MT)]。
产物经高效液相色谱纯化，真空干燥，用核磁共振氢谱(H-NMR)和质谱(ESI-MS)表征。H-NMR(图4)(400MHz，DMSO)：δ8.49(s，1H)，8.33(s，1H)，8.19(s，1H)，8.04(s，3H)，7.78(dd，J＝7.8，1.7Hz，1H)，7.60(ddd，J＝19.8，14.4，9.7Hz，3H)，7.37(ddd，J＝19.2，8.7，4.7Hz，2H)，7.25-6.96(m，4H)，4.16(s，1H)，3.76(s，3H)，3.05(dd，J＝15.2，8.5Hz，1H)，2.23(s，2H)，1.55(s，4H)，1.23(s，5H)。ESI-MS：MW[M+H]＝794.20。
实施例4：采用本公开方法所制备得到的铂类孪药的药效试验
在Balb/C小鼠皮下植入CT26结直肠癌细胞，待肿瘤达到50-100mm3后开始给药。每疗程6天，第1天给化疗药物，第3天、第6天给免疫检查点阻断剂anti-PD-1，其中化疗药物剂量以奥沙利铂2mg/kg计算，anti-PD-1以100ug/只次计。给药共三个疗程，给药计划详细见图5，共给药三个疗程，每个疗程6天，其中第0天给化疗药物，第2、5天给anti-PD-1。设定小鼠生存终点为肿瘤体积达到3000mm3，治疗效果主要通过肿瘤体积大小变化和生存曲线(图6)，可以看出，相比于对应的单药组合，孪药有更好的提高anti-PD-1治疗效果的功能，包括抑制肿瘤生长和延长小鼠的生存时间。在另一批次实验中，治疗15天后取出肿瘤直接对比治疗效果(图7)，分组H1：PBS+PBS，H2：PBS+ICB，H3：OXP+Asp+(D)-1-mt+ICB，H4：AMOP+PBS，H5：AMOP+ICB；可以看出，孪药与anti-PD-1联用，相比于对应的单药组合与anti-PD-1联用，有更好的抑制肿瘤生长的作用。
实验结果表明：采用本公开的方法制备得到的铂类孪药与免疫治疗产生协同作用，相比于对应的单药组合，可以更好的提高免疫治疗的效果。
以上所述的具体实施例，对本公开的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本公开的具体实施例而已，并不用于限制本公开，凡在本公开的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。
Claims (10)
1.一种化合物，其特征在于，所述化合物为由铂药和共价连接到所述铂药的轴向位置的具有解除免疫负调功能的小分子药物形成的孪药，具有式I所示的结构：
其中虚线框内为所述铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
2.根据权利要求1所述的化合物，其特征在于，所述铂药选自顺铂、卡铂和奥沙利铂；
所述具有解除免疫负调功能的小分子药物包括：吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂，肽基脯氨酰顺反异构酶抑制剂，诱导型一氧化氮合酶抑制剂，精氨酸酶抑制剂，转化生长因子-β抑制剂，棕榈酰转移酶抑制剂中的一种或多种。
3.根据权利要求1所述的化合物，其特征在于，所述具有解除免疫负调功能的小分子药物包括：1-甲基-D-色氨酸、乙酰水杨酸、全反式维甲酸中的一种或多种。
4.一种抗癌药物的制备方法，其特征在于，包括：
S1，将铂药与双氧水进行氧化反应，得到固体前驱体；
S2，将所述固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物或其对应的酸酐进行反应，得到小分子药物共价连接到所述铂药的轴向位置的孪药结构，如式I所示：
其中虚线框内为所述铂药的结构；R1与R2为相同或不同的具有解除免疫负调功能的小分子药物；或者是R1、R2其中一个为具有解除免疫负调功能的小分子药物，另一个为羟基。
5.根据权利要求4所述抗癌药物的制备方法，其特征在于，所述S1中铂药选自顺铂、卡铂和奥沙利铂；所述S2中具有解除免疫负调功能的小分子药物包括：吲哚胺2，3-双加氧酶抑制剂和环氧化酶-2抑制剂，肽基脯氨酰顺反异构酶抑制剂，诱导型一氧化氮合酶抑制剂，精氨酸酶抑制剂，转化生长因子-β抑制剂，棕榈酰转移酶抑制剂中的一种或多种。
6.根据权利要求4所述抗癌药物的制备方法，其特征在于，所述具有解除免疫负调功能的小分子药物包括：1-甲基-D-色氨酸、乙酰水杨酸、全反式维甲酸中的一种或多种。
7.根据权利要求6所述抗癌药物的制备方法，其特征在于，所述S2包括：
将所述固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物、催化剂进行第一脱水缩合反应，或者是加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应；
减压蒸馏除去所述溶剂后，再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个小分子药物共价连接的铂类孪药。
8.根据权利要求6所述抗癌药物的制备方法，其特征在于，所述S2包括：
将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；
将所述固体产物与所述固体前驱体溶解在溶剂中，加入催化剂进行第三脱水缩合反应；
减压蒸馏除去所述溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；
再次溶解、沉淀，洗涤、干燥得到轴向有一个或两个1-甲基-D-色氨酸共价连接的铂类孪药。
9.根据权利要求6所述抗癌药物的制备方法，其特征在于，所述S2包括：
将所述固体前驱体溶解在溶剂中，加入具有解除免疫负调功能的小分子药物对应的酸酐进行酯化反应，控制所述固体前驱体与所述小分子药物对应的酸酐的摩尔比，以得到轴向有一个乙酰水杨酸共价连接的铂类药物；
将1-甲基-D-色氨酸与二碳酸二叔丁酯和碳酸氢钠进行第二脱水缩合反应，得到固体产物；
将所述固体产物与所述一个乙酰水杨酸共价连接的铂类药物进行第四脱水缩合反应；
减压蒸馏除去所述溶剂后，再次溶解、沉淀，加入溶剂、三氟乙酸进行水解反应；
再次溶解、沉淀，洗涤、干燥得到轴向分别为乙酰水杨酸、1-甲基-D-色氨酸共价连接的铂类孪药。
10.根据权利要求1～3中任一项所述的化合物用于制备药物的用途，所述药物用于预防和治疗癌症。
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