CN116444408B - 一种多靶点型双硫仑衍生物、药物组合物及其抗肿瘤应用 - Google Patents
一种多靶点型双硫仑衍生物、药物组合物及其抗肿瘤应用 Download PDFInfo
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
本发明属于肿瘤抑制活性化合物技术领域,具体涉及一种多靶点型双硫仑衍生物、药物组合物及其抗肿瘤应用。现有研究表明,在DSF的结构片段上引入ROS清除剂NAC活性基团的新型衍生物设想与DSF通过产生ROS而发挥其抗肿瘤的作用机制相矛盾。本发明基于片段药物分子设计方法,将DSF结构片段引入NAC活性基团,获得了一系列具有优异抗肿瘤活性、并且神经毒性低的CPD12C系列衍生物。经本发明验证,上述衍生物具有良好的肿瘤增殖抑制活性,与铜联用效果优于双硫仑与Cu联用,且具有更低的神经毒性以及增强的逆转耐药潜力,具有良好的医药开发前景。
Description
技术领域
本发明属于肿瘤抑制活性化合物技术领域,具体涉及一种多靶点型双硫仑衍生物、药物组合物及其抗肿瘤应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
双硫仑(Disulfiram,DSF),又名戒酒硫,已经在临床上广泛应用于抗酗酒。研究人员近年来发现DSF除有戒酒作用外还有抗肿瘤作用。DSF能在体内外杀伤多种肿瘤细胞,包括直肠癌、黑色素瘤、脑胶质瘤、乳腺癌及前列腺癌等。铜是多种生物过程的基本元素,是一种重要的血管生成因子,在炎症和肿瘤生长中起重要作用,铜也会导致细胞毒性,可通过靶向脂化三羧酸(Tricarboxylic acid,TCA)循环蛋白诱导细胞发生铜死亡。DSF与二价铜离子(Copper ion,Cu)联合,可形成铜离子螯合物双(二乙基二硫代氨基甲酸酯)-铜,简称CuET,抗肿瘤活性增强。具有抑制肿瘤细胞生长,促进肿瘤细胞凋亡,阻止肿瘤细胞的迁移和侵袭,减少血管生成,逆转肿瘤多药耐药,以及抑制肿瘤干细胞等特点,且药物安全毒性低。
肿瘤具有高度异质性,其活化的肿瘤细胞通路纷繁复杂,基于疾病的网格药理学理论,调控某一靶点的药物不能满足治疗复杂疾病的需求,因此“一病一靶点,一药一靶点”的传统治疗模式不能满足癌症的治疗需求。而多靶点药物可以同时调节多种通路,对于疾病网络的多个靶点、多个节点蛋白同时干预,从而调控整个疾病机制网络,在抗肿瘤方面表现出更大的潜力。DSF潜在的抗肿瘤作用机制很多,包括抑制乙醛脱氢酶ALDH、蛋白酶体、DNA甲基转移酶、p-糖蛋白的表达,调节ROS-MARK,NF-κB、P97-NPL4等多种通路,发挥抗肿瘤作用。虽然DSF是一个潜在的具有高安全性的多靶点抗肿瘤药物,有较好的抗肿瘤活性,但因DSF所产生的氧化应激等所致的神经病变是最常见的毒副作用,如脑病、周围神经病变、脱髓鞘和基底节区白质损伤等。给药剂量的限制性副作用通常是在开始使用DSF治疗的几周到几个月内出现远端感觉运动神经病变,通常会有手脚感觉丧失和/或疼痛感、肌肉力量丧失和协调性丧失等。
N-乙酰-L-半胱氨酸(NAC)是细胞内谷胱甘肽(GSH)的前体,是一种抗氧化剂,可以消除自由基并有助于GSH的合成,NAC能降低活性氧(ROS)的产生,除了在缺血再灌注损伤、急性呼吸窘迫综合征和化疗引起的毒性中的应用,也已被广泛用作抗ROS的抗氧化剂。NAC除了抑制对氧化还原敏感的信号传导,例如NF-κB和MAPK通路,用于治疗与氧化应激相关的多种疾病,也广泛参与多种癌症的预防和治疗。NAC可以减弱癌细胞的增殖、迁移和侵袭,可作为抗癌剂单独使用或作为佐剂来降低多种癌症的侵袭性。Notch受体是一类高度保守的跨膜受体,与胶质瘤的发生发展密切相关,据报道NAC可能通过Itch依赖性溶酶体途径靶向Notch2,降低Notch2及其下游靶标Hes1和Hey1的蛋白质水平,从而抑制体内胶质瘤的生长。此外,NAC也可以负调节Notch3的表达,参与癌症的预防和治疗。NAC对肿瘤起始期和促进期的作用:①抑制诱变剂/致癌剂的作用,增加机体对直接作用诱变剂的解毒;②NAC能预防DNA的氧化损伤,并增强损伤DNA的修复;③增加抑癌基因的表达,抑制原癌基因的诱导。④NAC能抑制血管内皮生长因子的产生,抑制MMP-2及MMP-9的活性,从而抑制肿瘤的进展和转移。增加化学预防药物或化疗药物的作用,拮抗其毒副作用,减弱细胞毒化疗药物的毒性,如环磷酰的膀胱毒性及阿霉素诱导的突变作用及心脏毒性、诱裂性、致脱发作用。
众多研究(如British Journal of Cancer, 2011, 104(10), 1564)表明DSF能够在生物体内产生大量ROS,杀死各类肿瘤细胞,当NAC与DSF联合用药后不仅没有提升DSF的抗肿瘤疗效,而且由于NAC清除了DSF所产生的ROS而起到了相反的抵消作用。因此,在带有NAC片段的新型DSF衍生物的设计研究中,不仅所合成的新型DSF衍生物在肿瘤细胞中应具有显著的抗肿瘤疗效,而且该类新型DSF衍生物还应具备特殊的选择性,能够选择地抑制DSF功能团在像神经细胞等非肿瘤细胞中所产生的氧化应激,进而实现其保留DSF的抗肿瘤疗效以及降低DSF功能团所致的神经毒性等与氧化应激相关毒副作用的目标。
发明内容
为了获得具有良好抗肿瘤活性、神经毒性低且具有增强逆转耐药潜力的抗肿瘤药物,本发明采用基于片段的药物分子设计方法,在DSF的结构片段上引入ROS清除剂NAC的活性基团,合成得到CPD12C系列化合物(即下式I)。该CPD12C系列化合物保留了双硫仑多靶点抗肿瘤的活性,并引入新的抗肿瘤机制,如靶向Notch2等,经验证,上述系列化合物能够联合Cu发挥基于多重机制的抗肿瘤活性。
基于上述技术效果,本发明提供如下的技术方案:
本发明第一方面,提供一种化合物,所述化合物选自式I所示化合物或其药学上可接受的盐或酯或溶剂化物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物或前药;所述式I如下:
式I;
其中,A为N原子取代的基团,具体为N取代的侧链基团或含氮杂环,即式I所示化合物结构选自下式Ⅱ或式Ⅲ:
式Ⅱ,
式Ⅲ;
式Ⅱ所示的化合物中,R1、R2独立的选自取代或未取代的脂肪烃、芳香烃;
所述脂肪烃如:、/>、/>、/>、/>、/>或/>;
所述芳香烃如:
、/>、/>、/>、/>或;
式Ⅲ所示的化合物中,包括取代和未取代情形,如:
、/>、/>、/>、/>、、/>、/>、/>、
、/>、/>、/>或。
上述第一方面提供的化合物中,还包括该化合物药学上可接受的盐,根据本领域通常的理解,表示所述化合物与无机盐如盐酸、硫酸、磷酸、硝酸或氢溴酸形成的盐,或钙盐、钠盐、钾盐、镁盐等,以及与有机酸,例如醋酸、马来酸、酒石酸、柠檬酸形成的盐。
本发明一种具体的实施方式中,提供一种上述化合物的钙盐,所述钙盐的结构如下式Ⅳ所示:
式Ⅳ;
所述钙盐的合成方式如下:
;
具体的合成方式如下:将Ca(OH)2溶液加入式I所示化合物的二氯甲烷溶液中,室温下搅拌反应3~5h,反应结束后获取水相部分进行干燥得到固体部分即为上述钙盐。
优选的,所述干燥优选低温干燥的方式,例如冻干,得到的白色絮状固体即为钙盐。
本发明验证的一种实施方式中,式I所示化合物具体选自以下结构:
本发明第二方面,提供第一方面所述化合物的合成路线,所述合成路线选自以下路线一或路线二:
路线一:
;
路线二:
。
上述路线一的合成步骤如下:
将起始原料AH与二硫化碳(CS2)、氢氧化钾(KOH)、水(H2O)混合后,加热搅拌,加入含NaNO2的甲醇溶液并将反应体系冷却到0-5℃,向反应体系中缓慢滴加浓硫酸,过滤得到固体产物,加入乙醇重结晶得到中间体;将中间体与N-乙酰-L-半胱氨酸(NAC)溶于含甲醇或乙醇的溶液中,室温搅拌15~17h得到目标化合物。
进一步的,所述加热温度为45~55℃,加热搅拌时间为5~7h;更进一步的,加热温度为48~52℃,加热时间为5.5~6.5h。
进一步的,所述起始原料AH、二硫化碳(CS2)、氢氧化钾(KOH)、NaNO2加入剂量的摩尔比优选为0.8~1.2:0.8~1.2:2~3:0.5~1,具体实例如1.0:1.0:2.2:0.85。第二步反应中,第一步反应得到的中间体与NAC加入剂量的摩尔比优选为1~2:1;具体实例如1.25:1。
上述路线二的合成步骤如下:
将起始原料AH与NAC加入有机溶液中,在冰浴条件下,逐滴加入CS2,再缓慢加入三乙胺(Et3N),分散均匀后加入四溴化碳(CBr4),室温搅拌过夜,得到目标化合物。
进一步的,上述合成方法中,所述起始原料AH、NAC、CS2、Et3N及CBr4的加入量的摩尔比优选为0.8~1.2:0.8~1.2:0.8~1.2:1~2:1.5~2.5,具体实例如1.0:1.0:1.0:1.0:2.0。
进一步的,所述有机溶液为二氯甲烷和甲醇的混合溶液或四氢呋喃(THF)溶液。
上述路线一或路线二中,所述起始原料AH为包括但不限于二乙胺、二丙胺、二丁胺、二异丁胺、N-甲基对甲基苯胺、N-甲基对甲氧基苯胺、N-甲基环己胺、吡咯烷、环己亚胺、二甲胺、N-乙基甲基胺、N-甲基正丙胺、N-甲基苯胺、吗啉、硫代吗啉、N-乙基环己烷、N-甲基邻甲苯胺、N-乙基苄胺、N-甲基-1-萘甲胺、4-苄基哌啶、哌啶、1,2,3,4-四氢异喹啉、2,5-二氢-1H-吡咯、3-甲基哌啶、4-甲基哌啶、二烯丙基胺、4-哌啶甲酸、3-羟甲基哌啶、1-苯基哌嗪、1,4-氧杂氮杂环庚烷、1,4-硫杂氮杂环庚烷中的一种。
本发明第三方面,提供一种药物组合物,所述药物组合物包括第一方面所述化合物及药学上所必须的载体。
上述“药物组合物”或文中所称“组合物”,可施用于受试者以实现预防、改善或治疗相关疾病,所述受试者优选为哺乳动物,例如鼠、猴、兔、狗及人,更优选为人;所述组合物中,第一方面所述化合物作为活性成分,应当为有效剂量,该剂量为依据施用目的、受试者情况可基于常规手段获知的技术内容。
优选的,所述药学上所必须的载体应当是无毒且安全的,所述载体类型可由本领域技术人员根据实际情况能够确定的;合适的载体的实例如葡萄糖、水、乳糖、蔗糖、甘油、乙醇、丙二醇、甘露醇、玉米淀粉、明胶、海藻酸、微晶纤维素、高岭土、磷酸二钙、氯化钠、交联羧甲基纤维素钠和淀粉羟乙酸钠等;还包括亲水载体、疏水载体或其组合,其中,疏水载体例如脂肪乳剂、脂质、聚乙二醇化磷脂、生物相容的聚合物、脂质球、脂质体、小囊泡、聚合物颗粒等。
所述药物组合物可采用的给药方式包括但不限于口服、鼻腔给药、吸入给药、直肠给药、局部给药、注射给药等。
优选的,所述药物组合物中,还包括其他活性成分;本发明验证的一种实施方式中,所述其他活性成分为Cu;所述Cu的应用形式为铜离子,可以铜的有机盐或无机盐形式加入,如氯化铜、葡萄糖酸铜等,给药方式包括口服、皮下注射、肌肉注射、瘤内注射、静脉注射等。依据裸鼠实验结果,上述铜离子的口服给药剂量为0.061 mg/kg~10 mg/kg,药物组合物中铜离子的剂量可依据动物实验结果,依据常规研究思路确定。
本发明第四方面,提供第一方面所述化合物或第三方面所述药物组合物在制备抗肿瘤药物方面的应用。
上述应用中,所述肿瘤为包括但不限于皮肤癌、头颈癌、肺癌、肝癌、胃癌、前列腺癌、食道癌、宫颈癌、子宫癌、胰腺癌、乳腺癌、肾癌、输尿管癌、膀胱癌、咽鳞状细胞癌、基底细胞癌或黑色素瘤、舌癌、咽鳞状细胞癌、恶性淋巴瘤、喉鳞状细胞癌、肺鳞状细胞、小细胞癌、食道鳞状细胞癌、宫颈癌、脑瘤中的一种或多种。
抗肿瘤药物的施用方式包括但不限于口服、注射或采用介入手段将上述化合物或药物组合物递送至病灶部位。
抗肿瘤药物包括但不限于药物制剂、模型药剂或检测器械;本发明验证的一种实施方式中,所述抗肿瘤药物为肺癌、肝癌、胃癌、乳腺癌、胰腺癌、脑胶质瘤等肿瘤治疗药物。
此外,所述化合物或药物组合物应用于制备模型药剂,所述模型药剂为用于过氧化抑制途径或肿瘤细胞、组织增殖抑制模型。
以上一个或多个技术方案的有益效果是:
(1)上述技术方案提供一种新型抗肿瘤药物及其制备方法,其制备工艺稳定、可行,新化合物方便运输和储存。
(2)CPD12C系列化合物联合Cu对脑胶质瘤细胞C6、U87细胞及肺癌细胞A549和H460细胞现出优异的抗肿瘤活性。
(3)CPD12C系列化合物可降低常用神经细胞PC12细胞内ROS的产生,增加GSH水平的表达,有利于降低药物的神经毒性。
(4)CPD12C系列化合物可以通过成盐的方式,增加水溶性(如钙盐),便于用药。
(5)CPD12C系列化合物具有更强的逆转耐药能力。
附图说明
构成本发明的一部分的说明书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。
图1为CPD12C15批次20230310液相色谱分析色谱图;
图2为CPD12C15对PC12细胞内ROS含量的影响;
图3为CPD12C15对PC12细胞内GSH含量的影响;
图4为顺铂(DDP)、CPD12C15+Cu对肺癌细胞A549和DDP耐药细胞A549-DDP的抗肿瘤活性;其中,图4中A为CPD12C15+Cu对肺癌细胞A549的抗肿瘤活性;图4中B为CPD12C15+Cu对DDP耐药细胞A549-DDP的抗肿瘤活性;图4中C为顺铂对肺癌细胞A549的抗肿瘤活性;图4中D为顺铂对DDP耐药细胞A549-DDP的抗肿瘤活性;
图5为DSF+Cu、CPD12C08+Cu对肺癌细胞A549和DDP耐药细胞A549-DDP的抗肿瘤活性;其中,图5中A为DSF+Cu对肺癌细胞A549的抗肿瘤活性;图5中B为DSF+Cu对DDP耐药细胞A549-DDP的抗肿瘤活性;图5中C为CPD12C08+Cu对肺癌细胞A549的抗肿瘤活性;图5中D为CPD12C08+Cu对DDP耐药细胞A549-DDP的抗肿瘤活性;
图6为CPD12C15对U87脑胶质瘤裸鼠移植瘤的影响;
图7为CPD12C15对荷原位C6脑胶质瘤雄性大鼠生存周期的影响;
图8为CPD12C15和多西他赛抑制A549肺癌裸鼠原位瘤的疗效;
图9为CPD12C15和多西他赛治疗A549肺癌裸鼠原位瘤的肝损伤毒副作用;其中,图9中(a)为各实验组药物对肝脏AST的影响;图9中(b)为各实验组药物对肝脏ALT的影响;
图10为CPD12C15和多西他赛治疗A549肺癌裸鼠原位瘤的免疫抑制毒副作用;
图11为CPD12C15对裸鼠脑组织系数的影响;
图12为CPD12C15对裸鼠脑组织的影响;其中,图12中A为对照组裸鼠脑组织染色结果;图12中B为DSF组裸鼠脑组织染色结果;图12中C为CPD12C15-L组裸鼠脑组织染色结果;图12中D为CPD12C15-H组裸鼠脑组织染色结果。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
针对现化合物存在的不足,本发明提供一种多靶点型双硫仑衍生物及其应用。本发明的化合物保留了DSF和NAC的有效结构片段,推测其与二价铜联用,能够通过抑制乙醛脱氢酶、蛋白酶体、DNA甲基转移酶、P-糖蛋白的表达、肿瘤干细胞、靶向Notch以及抑制P97-NPL4通路等多种机制发挥抗肿瘤作用。与其他抗肿瘤药物相比,具有突出的抗肿瘤活性、多靶点抗肿瘤作用机制、能够逆转耐药性,并且能够降低DSF引起的神经毒性,因此具有良好的实际应用之价值。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
本发明第一方面,提供一种多靶点型双硫仑衍生物,命名为CPD12C系列化合物,所述衍生化合物的结构如式Ⅱ或式Ⅲ所示:
式Ⅱ
式Ⅲ;
另外,本发明还提供了上述衍生化合物的钙盐;进一步的,本发明提供了32种具体的化合物,化合物的1H NMR及联合Cu抑制肿瘤增殖的活性如下表1所示;为了比较仅相差一个元素的两个衍生物CPD12C14和CPD12C15的构效关系,进一步测定了其抗肝癌、胃癌、乳腺癌、胰腺癌的活性,其结果见表2。
表1
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表2
实施例1 目标化合物CPD12C02的制备。
N-乙酰基-S-((二丙基氨基甲硫基)硫代)-L-半胱氨酸。
在4 mL二氯甲烷和4 mL甲醇的混合溶液的圆底烧瓶中,溶解691 μL二丙胺(5.0mmol)和815 mg NAC(5.0 mmol),在冰浴条件下,逐滴加入302 μL CS2(5.0 mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 g CBr4(10.0 mmol),5 min后室温搅拌过夜,旋蒸除去溶剂,油相溶于200 mL水中,1N NaOH调pH为9,二氯甲烷萃取,水相用1NHCl调pH为3,二氯甲烷萃取,用1N柠檬酸洗涤,水洗,干燥过滤得到CPD12C02,为黄绿色固体,产率为37.4%。Mp: 106-107℃。
实施例2 目标化合物CPD12C05的制备。
N-乙酰基-S-((甲基(对甲苯基)氨基甲硫基)硫代)-L-半胱氨酸。
在4 mL二氯甲烷和4 mL甲醇的混合溶液的圆底烧瓶中,溶解633 μL N-甲基对甲基苯胺(5.0 mmol)和815 mg NAC(5.0 mmol),在冰浴条件下,逐滴加入302 μL CS2(5.0mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 g CBr4(10.0 mmol),5 min后室温搅拌过夜,旋蒸去除溶剂,水洗后所得粗产品经硅胶柱层析纯化得到目标化合物CPD12C05,为淡黄绿色固体,产率为23.7%。Mp: 139-141℃。
实施例3 目标化合物CPD12C10的制备。
N-乙酰基-S-((二甲基氨基甲硫基)硫代)-L-半胱氨酸。
本实施例中,分别提供基于路线一和路线二合成CPD12C10的方法:
路线一:
将5.01 g 40%二甲胺(44.4 mmol)、3.37 g CS2(44.4 mmol)、5.40 g KOH(96.2mmol)混合后,45~55℃条件下加热搅拌反应5~7h,加入含2.63g NaNO2(38.1 mmol)的甲醇溶液并将反应体系冷却到0-5℃,向反应体系中缓慢滴加浓硫酸,过滤得到固体产物,加入乙醇重结晶得到中间体二硫化四甲基秋兰姆;将2.40 g中间体(10.0 mmol)与1.30 g NAC(8.0 mmol)溶于甲醇和二氯甲烷溶液中,室温搅拌15~17h得到目标化合物CPD12C10,为白色固体,产率为16.5%。Mp: 115-117℃。
路线二:
在4 mL二氯甲烷和4 mL甲醇的混合溶液的圆底烧瓶中,溶解225 mg二甲胺(5.0mmol)和815 mg NAC(5.0 mmol),在冰浴条件下,逐滴加入302 μL CS2(5.0 mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 g CBr4(10.0 mmol),5 min后室温搅拌过夜,旋蒸去除溶剂,水洗后所得粗产品经硅胶柱层析纯化得到目标化合物CPD12C10,为白色固体,产率为29.5%。Mp: 115-117℃。
实施例4 目标化合物CPD12C15的制备。
N-乙酰基-S-((硫代吗啉-4-硫代羰基)硫代)-L-半胱氨酸。
50 mL圆底烧瓶中,加入6 mL甲醇溶液溶解0.815 g NAC(5.0 mmol),再加入5 mL二氯甲烷,加入503 μL硫代吗啉(5.0 mmol),使NAC和吗啉完全溶解。在冰浴条件下,逐滴加入302 μL CS2(5.0 mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 gCBr4(10.0 mmol),5 min后室温搅拌过夜,旋蒸除去溶剂,水洗三次,用二氯甲烷萃取,得到目标化合物CPD12C15,为白色固体,产率为27.4%。Mp: 130-133℃。
实施例5 目标化合物CPD12C21的制备。
N-乙酰基-S-((哌啶-1-硫代羰基)硫代)-L-半胱氨酸。
在4 mL二氯甲烷和4 mL甲醇的混合溶液的圆底烧瓶中,分别加入458 μL哌啶(5.0mmol)和0.815 g NAC(5.0 mmol),使二者完全溶解,在冰浴条件下,逐滴加入302 μL CS2(5.0 mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 g CBr4(10.0mmol),5 min后室温搅拌过夜,旋蒸除去溶剂,水洗三次,然后经硅胶柱层析纯化得到目标化合物CPD12C21,为白色固体,产率为22.9%。Mp: 138-139℃。
实施例6 目标化合物CPD12C24的制备。
N-乙酰基-S-((3-甲基哌啶-1-硫代羰基)硫代)-L-半胱氨酸。
在4 mL二氯甲烷和4 mL甲醇的混合溶液的圆底烧瓶中,分别加入0.5 g 3-甲基哌啶(5.0 mmol)和0.815 g NAC(5.0 mmol),在冰浴条件下,逐滴加入302 μL CS2(5.0mmol),再缓慢加入690 μL Et3N(5.0 mmol),搅拌5 min,最后加入3.3 g CBr4(10.0 mmol),5 min后室温搅拌过夜,旋蒸除去溶剂,用二氯甲烷溶解,水洗三次,然后经硅胶柱层析纯化得到目标化合物CPD12C24,为绿色固体,产率为21.9%。Mp: 59-60℃。
上述实施例1-6中具体描述了6种化合物的制备方法,应当说明的是,表1中其他化合物的合成方式与实施例1-6相同,依据实施例1-6中反应物的摩尔比对起始反应物的剂量进行常规调整即可。表1中序号1-31的化合物,其起始原料AH依次为二乙胺、二丙胺、二丁胺、二异丁胺、N-甲基对甲基苯胺、N-甲基对甲氧基苯胺、N-甲基环己胺、吡咯烷、环己亚胺、二甲胺、N-乙基甲基胺、N-甲基正丙胺、N-甲基苯胺、吗啉、硫代吗啉、N-乙基环己烷、N-甲基邻甲苯胺、N-乙基苄胺、N-甲基-1-萘甲胺、4-苄基哌啶、哌啶、1,2,3,4-四氢异喹啉、2,5-二氢-1H-吡咯、3-甲基哌啶、4-甲基哌啶、二烯丙基胺、4-哌啶甲酸、3-羟甲基哌啶、1-苯基哌嗪、1,4-氧杂氮杂环庚烷、1,4-硫杂氮杂环庚烷。
另外,本发明提供的路线一及路线二合成方法可适用于表1中所示31种化合物,依据实施例3中起始反应物的摩尔比进行剂量调整即可,不同化合物的产率存在差异,技术人员可依据实际生产需求选择相应的合成路线即可。
性能测试
表1中,DSF衍生物CPD12C系列化合物联合CuCl2对脑胶质瘤细胞C6、U87细胞和肺癌细胞A549、H460细胞的抗增殖活性。研究结果表明,CPD12C01、CPD12C09、CPD12C11、CPD12C15、CPD12C21、CPD12C24、CPD12C30七个化合物具有较好的抗肿瘤增殖活性。
表2显示了采用MTT法测定所得的两个结构较为接近的衍生物CPD12C14和CPD12C15对肝癌、胃癌、乳腺癌、胰腺癌抗肿瘤活性(IC50)的比较研究结果。
图1显示了CPD12C15批次20230310液相色谱分析色谱图。所用液相色谱条件如下:色谱柱: Luna 5µ C18, 250×4.6 mm,流动相:0.2%甲酸水:乙腈 (40%:60%,v/v),流速:1mL/min,进样量: 10 μL,检测波长:284 nm。所测得的CPD12C15批次20230310的色谱纯度为99.8%。
图2显示了CPD12C15联合Cu或CPD12C01的钙盐(CPD12C01Ca)+Cu处理后PC12细胞内ROS变化,所述Cu为CuCl2。化合物与Cu的摩尔比为1:1,将空白对照组、Cu给药组、NAC给药组(200 nM)、DSF+Cu(摩尔比1:1)给药组(200 nM)、CPD12C15+Cu(图中C15+Cu,摩尔比1:1)给药组(80、160、200 nM)、CPD12C01Ca+Cu(图中C01Ca+Cu,摩尔比1:1)给药组(100、150、200nM)分别加入PC12细胞中,培育24小时后,加入ROS荧光探针(DCFH-DA)来制备待测样品,采用流式细胞仪来测定ROS的相对荧光强度。选用常用的神经细胞株PC12细胞做细胞模型,其来源于鼠嗜铬细胞瘤。研究发现,Cu对ROS的浓度无明显影响,200 nM的DSF+Cu可以显著增加PC12细胞内ROS的产生。而CPD12C15+Cu可显著降低ROS的产生,且该影响呈浓度依赖性,CPD12C15+Cu或CPD12C01Ca+Cu处理后PC12细胞内ROS的含量显著降低。据文献报道降低神经细胞内ROS的产生有利于降低药物神经毒性,因此,推测CPD12C15化合物具有较好的抗脑胶质瘤活性,同时可显著降低药物神经毒性。
图3显示了CPD12C15+Cu或CPD12C01Ca+Cu处理后PC12细胞内GSH含量的变化,所述Cu为CuCl2。将空白对照组、Cu给药组、NAC给药组(200 nM)、DSF+Cu(摩尔比1:1)给药组(200nM)、CPD12C15+Cu(图中C15+Cu,摩尔比1:1)给药组(100、150、200 nM)、CPD12C01Ca+Cu(图中C01Ca+Cu,摩尔比1:1)给药组(100、150、200 nM)分别加入PC12细胞,培育24小时后,按照GSH检测试剂盒的说明书来测定GSH的含量。研究结果表明,Cu对细胞内GSH的浓度无明显影响,200 nM的DSF+Cu可以显著降低PC12细胞内GSH的表达。而CPD12C15+Cu可显著促进GSH的产生。与DSF+Cu比,CPD12C15+Cu或CPD12C01Ca+Cu处理后PC12细胞内GSH含量明显提高,提高神经细胞内GSH的含量有利于降低药物神经毒性。
图4显示了顺铂(DDP)、CPD12C15+Cu(图中CPD12C15,摩尔比1:1)对肺癌细胞A549和DDP耐药细胞A549-DDP的抗肿瘤活性,所述Cu为CuCl2。依据MTT抗肿瘤活性检测结果,计算顺铂(DDP)、CPD12C15+Cu的耐药指数分别为5.42、1.04,表明CPD12C15具有增强的逆转耐药潜力。
图5显示了DSF+Cu(图中DSF,摩尔比1:1)、CPD12C08+Cu(图中CPD12C08,摩尔比1:1)对肺癌细胞A549和DDP耐药细胞A549-DDP的抗肿瘤活性,所述Cu为CuCl2。依据MTT抗肿瘤活性检测结果,计算DSF+Cu、CPD12C08+Cu的耐药指数分别为1.72、1.31,表明CPD12C08具有增强的逆转耐药潜力。
图6显示了CPD12C15对U87胶质瘤裸鼠皮下移植瘤的影响。裸鼠抑瘤实验分组及给药方案如下:(1)阴性空白对照组:腹腔注射生理盐水;(2)阳性对照组(DSF):每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于羟丙基-β-环糊精(HP-β-CD)的50 mg/kg双硫仑;(3)低剂量组(CPD12C15-L):每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于HP-β-CD的25 mg/kgCPD12C15;(4)高剂量组(CPD12C15-H):每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于HP-β-CD的50 mg/kg CPD12C15;U87胶质瘤裸鼠皮下移植瘤建模后给药21天,称量移植瘤的重量。计算可知,相比于对照组,DSF组的相对肿瘤增殖率为26.1%,CPD12C15-L低剂量组的相对肿瘤增殖率为21.7%,CPD12C15-H高剂量组的相对肿瘤增殖率为30.4%,说明低和高剂量的CPD12C15均能明显抑制肿瘤生长。
图7显示了CPD12C15对荷原位C6脑胶质瘤雄性大鼠生存周期的影响。大鼠生成周期实验分组及给药方案如下:(1)空白对照组:每日早晨灌胃给予0.15 mg/kg的葡萄糖酸铜溶液,晚上鼻腔注射生理盐水;(2)阳性对照组(TMZ):口服给予40 mg/kg替莫唑胺溶液;(3)尾静脉给药组(CPD12C15-IV):每日早晨灌胃给予0.15 mg/kg的葡萄糖酸铜溶液,晚上尾静脉注射给予注射溶解于HP-β-CD的40 mg/kg CPD12C15;(4)CPD12C15低剂量组(CPD12C15-L):每日早晨灌胃给予0.15 mg/kg葡萄糖酸铜溶液,晚上鼻腔给予溶解于HP-β-CD的20 mg/kg CPD12C15;(5) CPD12C15高剂量组(CPD12C15-H):每日早晨灌胃给予0.15 mg/kg葡萄糖酸铜溶液,晚上鼻腔给予溶解于HP-β-CD的40 mg/kg CPD12C15;在接种荷原位C6肿瘤后的第6天开始按照上述分组进行给药,每天一次,连续5天,记录大鼠的生存周期。如图7所示,相同剂量条件下鼻腔给药治疗效果(CPD12C15-H )优于注射给药(CPD12C15-IV),高剂量鼻腔给药治疗效果(CPD12C15-H)优于注射给药的一线抗胶质瘤药物替莫唑胺。
图8显示了CPD12C15和多西他赛抑制A549肺癌裸鼠原位瘤的疗效。裸鼠抑瘤实验分组及给药方案如下:(1)对照组:傍晚腹腔注射生理盐水;(2)氯化铜组(Cu):每日早晨肌肉注射0.06 mg/kg氯化铜溶液;(3)阳性对照组(DTX):傍晚腹腔注射给予10 mg/kg多西他赛(DTX);(4) CPD12C15组(图中C15):傍晚腹腔注射溶解于HP-β-CD的40 mg/kg CPD12C15;(5) CPD12C15联合铜组(图中C15+Cu):每日早晨肌肉注射0.06 mg/kg氯化铜溶液,傍晚腹腔注射溶解于HP-β-CD的40 mg/kg CPD12C15;通过肺部注射A549-Luc建立裸鼠原位瘤后,每两天给药1次,给药20天后,使用IVIS全身成像仪测得裸鼠原位瘤的生物荧光强度。如图8所示,CPD12C15+Cu治疗组的抑瘤效果与一线抗肺癌治疗药物多西他赛组(DTX)相似。
图9显示了CPD12C15和多西他赛治疗A549肺癌裸鼠原位瘤的肝脏毒副作用。裸鼠肝脏毒副作用研究与图8裸鼠抑瘤实验分组及给药方案相同,给药20天后,采用AST和ALT检测试剂盒测定裸鼠血液中的AST和ALT的含量。如图9所示,CPD12C15及CPD12C15+Cu(图中C15及C15+Cu)治疗组对肝脏(AST和ALT)均无影响,而一线抗肺癌治疗药物多西他赛治疗组(DTX)对肝脏(ALT)均有不良影响,表明CPD12C15无肝损伤等毒副作用。
图10显示了CPD12C15和多西他赛治疗A549肺癌裸鼠原位瘤的免疫抑制毒副作用。裸鼠免疫抑制毒副作用研究与图8裸鼠抑瘤实验分组及给药方案相同,给药20天后,采用自动血液细胞计数仪测定裸鼠血液中的中性粒细胞的数量。如图10所示,CPD12C15组以及CPD12C15联合铜(图中C15及C15+Cu)治疗组对中性粒细胞均无影响,而一线抗肺癌治疗药物多西他赛治疗组(DTX)对中性粒细胞具有不良影响,表明CPD12C15无免疫抑制的毒副作用。
图11显示了CPD12C15对裸鼠脑组织系数的影响。裸鼠脑组织系数实验分组及给药方案如下:(1)阴性对照组:腹腔注射生理盐水;(2)阳性对照组:每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于HP-β-CD的50 mg/kg双硫仑(DSF);(3)低剂量组(CPD12C15-L):每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于HP-β-CD的25 mg/kgCPD12C15;(4)高剂量组(CPD12C15-H):每日清早灌胃给予2 mg/kg葡萄糖酸铜溶液,傍晚腹腔注射溶解于HP-β-CD的50 mg/kg CPD12C15。连续腹腔注射给药8周后,记录体重,剥离脑组织后称重,计算得到脑组织系数。相比于对照组,DSF组裸鼠的脑组织系数明显降低(**p<0.01)。CPD12C15低、高剂量给药组与对照组比较后发现无显著性差异,与DSF组比较则具有显著差异(##p<0.01)。结果证明,DSF连续给药会使裸鼠脑组织萎缩,脑重量降低,而CPD12C15低、高剂量连续给药均不会影响裸鼠脑部组织的正常生长与发育。
图12显示了CPD12C15对裸鼠脑组织的影响。该项研究的动物分组及给药方案与图11相同,连续腹腔注射给药8周后,剥离脑组织,进行苏木精-伊红组织染色实验。在DSF组中,裸鼠皮层和海马区的神经元呈现皱缩状态,染色程度加深,胞体变小,说明DSF组裸鼠脑部出现了一定的病变。而CPD12C15低、高剂量给药组中脑组织皮层、海马区结构完整,细胞体积较大,染色程度较浅,未见变性和坏死现象。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。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 (9)
1.一种多靶点型双硫仑衍生物,其特征在于,所述衍生物选自式Ⅱ或式Ⅲ所示化合物或其药学上可接受的盐;所述式Ⅱ结构如下:
式Ⅱ,
式Ⅱ中,R1、R2独立的选自脂肪烃、芳香烃;
所述脂肪烃选自、/>、/>、/>或/>;
所述芳香烃选自、/>、/>、/>、或/>;
所述式Ⅲ结构如下:
式Ⅲ,
式Ⅲ所示的化合物中,选自/>、/>、/>、、/>、/>、/>、/>、/>、
、/>、/>、/>或/>。
2.如权利要求1所述多靶点型双硫仑衍生物,其特征在于,所述药学上可接受的盐,包括所述化合物与无机盐形成的盐,还包括与有机酸形成的盐。
3.如权利要求1所述多靶点型双硫仑衍生物,其特征在于,所述药学上可接受的盐为钙盐,结构如下式Ⅳ所示:
式Ⅳ;
所述钙盐的合成方式如下:
;
式I
将Ca(OH)2溶液加入式I所示化合物的二氯甲烷溶液中,室温下搅拌反应3~5h,反应结束后获取水相部分进行干燥得到固体部分即为上述钙盐;
所述式I化合物中A为或/>。
4.权利要求1-3任一项所述多靶点型双硫仑衍生物的合成路线,其特征在于,所述合成路线选自以下路线一或路线二:
路线一:
;
路线二:
;
所述起始原料AH选自二丙胺、二丁胺、二异丁胺、N-甲基对甲基苯胺、N-甲基对甲氧基苯胺、N-甲基环己胺、吡咯烷、环己亚胺、二甲胺、N-乙基甲基胺、N-甲基正丙胺、N-甲基苯胺、吗啉、硫代吗啉、N-乙基环己胺、N-甲基邻甲苯胺、N-乙基苄胺、N-甲基-1-萘甲胺、哌啶、1,2,3,4-四氢异喹啉、2,5-二氢-1H-吡咯、3-甲基哌啶、4-甲基哌啶、4-哌啶甲酸、3-羟甲基哌啶、1-苯基哌嗪、1,4-氧杂氮杂环庚烷或1,4-硫杂氮杂环庚烷。
5.如权利要求4所述多靶点型双硫仑衍生物的合成路线,其特征在于,所述路线一的合成步骤如下:
将起始原料AH与二硫化碳、氢氧化钾、水混合后,加热搅拌,加入含NaNO2的甲醇溶液并将反应体系冷却到0-5℃,向反应体系中缓慢滴加浓硫酸,过滤得到固体产物,加入乙醇重结晶得到中间体;将中间体与N-乙酰-L-半胱氨酸溶于甲醇和二氯甲烷溶液中,室温搅拌15~17h得到目标化合物;
加热温度为45~55℃,加热搅拌时间为5~7h;
所述起始原料AH、二硫化碳、氢氧化钾、NaNO2加入剂量的摩尔比为1.0:1.0:2.2:0.85;第二步反应中,第一步反应得到的中间体与N-乙酰-L-半胱氨酸加入剂量的摩尔比为1.25:1;
或,所述路线二的合成步骤如下:
将起始原料AH与N-乙酰-L-半胱氨酸加入有机溶液中,在冰浴条件下,逐滴加入CS2,再缓慢加入三乙胺,分散均匀后加入四溴化碳,室温搅拌过夜,得到目标化合物;
所述起始原料AH、N-乙酰-L-半胱氨酸、CS2、三乙胺及四溴化碳的加入量的摩尔比为1.0:1.0:1.0:1.0:2.0;所述有机溶液为二氯甲烷和甲醇的混合溶液或四氢呋喃溶液。
6. 一种药物组合物,其特征在于,所述药物组合物包括权利要求1-3任一项所述多靶点型双硫仑衍生物及药学上所必须的载体和 Cu;所述Cu的应用形式为铜离子,来源于氯化铜或葡萄糖酸铜。
7.权利要求1-3任一项所述多靶点型双硫仑衍生物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为肺癌、肝癌、胃癌、胰腺癌、乳腺癌、脑胶质瘤中的一种或多种。
8.权利要求6所述药物组合物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为肺癌、肝癌、胃癌、胰腺癌、乳腺癌、脑胶质瘤中的一种或多种。
9.化合物CPD12C01与铜离子的组合物或化合物CPD12C26与铜离子的组合物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为肺癌、肝癌、胃癌、胰腺癌、乳腺癌、脑胶质瘤中的一种或多种,所述铜离子来源于氯化铜或葡萄糖酸铜;所述化合物CPD12C01的结构如下式所示:
;
所述化合物CPD12C26的结构如下式所示:
。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101238137A (zh) * | 2005-05-27 | 2008-08-06 | 安泰碧治疗公司 | 4-或5-氨基水杨酸的衍生物 |
CN102250045A (zh) * | 2010-05-21 | 2011-11-23 | 复旦大学附属华山医院 | 抗结核分支杆菌的化合物及其应用 |
CN111349033A (zh) * | 2018-12-20 | 2020-06-30 | 杜剑平 | 基于双硫仑结构的衍生物广谱抗肿瘤药物及其制备方法 |
WO2020161337A1 (en) * | 2019-02-07 | 2020-08-13 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Improved dithiocarmabate based compounds, therapies and diagnostics |
CN113683541A (zh) * | 2021-07-09 | 2021-11-23 | 华南理工大学 | 一种基于双硫仑的两亲性嵌段共聚物前药及其制备方法和应用 |
CN115974832A (zh) * | 2023-02-27 | 2023-04-18 | 山东大学 | 一种含有二硫键的n-乙酰- l-半胱氨酸衍生物及其制备方法与应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11007273B2 (en) * | 2017-07-05 | 2021-05-18 | Duke University | Prochelators as targeted prodrugs for prostate cancer and methods of making and using same |
-
2023
- 2023-06-14 CN CN202310698764.1A patent/CN116444408B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101238137A (zh) * | 2005-05-27 | 2008-08-06 | 安泰碧治疗公司 | 4-或5-氨基水杨酸的衍生物 |
CN102250045A (zh) * | 2010-05-21 | 2011-11-23 | 复旦大学附属华山医院 | 抗结核分支杆菌的化合物及其应用 |
CN111349033A (zh) * | 2018-12-20 | 2020-06-30 | 杜剑平 | 基于双硫仑结构的衍生物广谱抗肿瘤药物及其制备方法 |
WO2020161337A1 (en) * | 2019-02-07 | 2020-08-13 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Improved dithiocarmabate based compounds, therapies and diagnostics |
CN113683541A (zh) * | 2021-07-09 | 2021-11-23 | 华南理工大学 | 一种基于双硫仑的两亲性嵌段共聚物前药及其制备方法和应用 |
CN115974832A (zh) * | 2023-02-27 | 2023-04-18 | 山东大学 | 一种含有二硫键的n-乙酰- l-半胱氨酸衍生物及其制备方法与应用 |
Non-Patent Citations (3)
Title |
---|
Preventive Effects of a Mixed Disuiphide from Dithiocarbamate and N-Acetylcysteine on the Genotoxicity of N-Nitrosodiethylamine;Byung-Hoon Lee et al.;《J. Pharm. Pharmacol.》;第51卷;第105-106页 * |
STN检索报告;Columbus, Ohio, US Registry[Online];《STN Registry》;第1-5页 * |
双硫仑抗肿瘤作用及其机制研究进展;骆玲玲 等;《中国药理学与毒理学杂志》;第36卷(第1期);第71-78页 * |
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