CN109422652A - 氯乙酰氧基水杨酸的衍生物在药物中的应用 - Google Patents
氯乙酰氧基水杨酸的衍生物在药物中的应用 Download PDFInfo
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- CN109422652A CN109422652A CN201710789028.1A CN201710789028A CN109422652A CN 109422652 A CN109422652 A CN 109422652A CN 201710789028 A CN201710789028 A CN 201710789028A CN 109422652 A CN109422652 A CN 109422652A
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- acid derivatives
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- salicyclic acid
- chloroethene acyloxy
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Abstract
本发明涉及一种水杨酸的衍生物的制备及其新用途的开发,具体为氯乙酰氧基水杨酸衍生物(其合成路线及结构如下表示)在治疗癌症及其相关疾病中的应用。氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯,以及其药物组合物作为制备治疗癌症的有效药物,可以显著抑制癌症细胞的生长,诱导细胞凋亡。氯乙酰氧基水杨酸在与抗癌药物联合使用时,可以增强药物抗癌作用,并降低现有抗癌药物的副作用,因此有希望开发成治疗癌症及相关疾病的药物,与现有技术相比具有突出的实质性特点和显著的进步。
Description
技术领域
本发明涉及生物技术与医学应用领域,具体涉及为氯乙酰氧基水杨酸的衍生物、及其药物组合物在生物医药中的应用。
背景技术
水杨酸类药物(Salicylates)如阿司匹林(Aspirin)是一种常用的非甾体抗炎镇痛药,起到抗炎、抗风湿和解热镇痛及抗血栓作用。阿司匹林可以抑制环氧化酶-1(COX-1)和环氧化酶-2(COX-2)。它能不可逆地抑制COX-1并且改变COX-2的酶活性。COX-2通常产生的大多是会促进发炎的前列腺素类激素,但受阿司匹林作用后则产生能抗炎的脂氧素。阿司匹林还有三种作用方式。一是使线粒体的氧化磷酸化解偶联。阿司匹林会携带质子从线粒体膜间隙扩散进入线粒体基质,然后再次电离释放质子。简而言之,阿司匹林作为缓冲剂运输质子,因此高剂量服用时会因电子传递链释放的热量而造成发热,这和低剂量服用的退烧作用相反。二是阿司匹林会促进一氧化氮自由基的生成。一氧化氮自由基本身在小鼠体内也有抗炎的作用,它能减少白细胞粘附,后者是免疫系统应对感染的重要一步。第三,最新的研究表明水杨酸及其衍生物能通过NF-κB调节细胞信号。NF-κB是一种转录因子复合体,在许多生物过程(包括发炎)中起重要作用。根据阿司匹林的作用机制,阿司匹林被用于治疗多种疾病,包括发烧、疼痛、风湿热,也可治疗一些炎症,如类风湿性关节炎、心包炎和川崎病。低剂量服用还可减少心脏病发作的死亡风险,某些情况下也可减少发生中风的风险。
近年来,多项研究表明日常服用小剂量阿司匹林具有抗癌作用,可降低多种癌症的发病率;同时个体的死亡率也成下降趋势,表明阿司匹林能够抑制肿瘤的生长和转移。体外试验研究也表明,阿司匹林可以抑制许多癌细胞的生长,促进其凋亡。目前阿司匹林防治癌症的机理还不十分清楚,可能原因是:阿司匹林刺激免疫系统产生免疫反应,从而能够抑制肿瘤组织微血管形成。同时阿司匹林对肿瘤细胞的抑制作用与其抑制环氧化酶有关,环氧化酶可促进肿瘤血管生长,给肿瘤提供营养,同时增加细胞的侵袭转移。阿司匹林抗癌作用的新发现,对癌症的治疗和预防具有现实意义,因而引起了广泛关注。
近年来,随着研究的深入,肿瘤细胞的能量代谢途径作为一个新的抗肿瘤药物作用靶点正日益受到人们的重视。研究发现用于治疗乳酸酸中毒的小分子药物二氯乙酸(DCA),不但能特异性地作用于肿瘤细胞,促进肿瘤细胞氧化磷酸化、诱导凋亡及抑制肿瘤细胞生长,而且还具有可口服、安全性好等特点。DCA发挥抗肿瘤作用主要通过促进肿瘤细胞氧化磷酸化、诱导凋亡,抑制肿瘤细胞生长。细胞的能量主要来自糖代谢,葡萄糖在体内氧化分解的途径包括糖酵解和氧化磷酸化。细胞活性和能量状态密切相关,由于恶性肿瘤生长迅速,常常出现葡萄糖摄取量增高、糖酵解增加和乳酸堆积现象。研究表明DCA不但能促进细胞葡萄糖氧化,而且作为线粒体丙酮酸脱氢酶激酶(pyruvate dehydrogenasekinase,PDK)的抑制剂,能够抑制人乳腺癌、非小细胞肺癌和胶质母细胞瘤细胞株的生长。其作用机制主要为:DCA能通过抑制PDK去磷酸化激活丙酮酸脱氢酶(pyruvatedehydrogenase,PDH),从而产生大量的乙酰CoA,乙酰CoA进入线粒体后启动柠檬酸循环,促进葡萄糖的氧化磷酸化,在这一过程中释放大量的活性氧簇(reactive oxygen species,ROS)和细胞色素C,再加上线粒体膜去极化、膜电位降低,从而激活了线粒体介导的凋亡通路。同时还发现DCA能降低细胞内Ca2+浓度、抑制活化T细胞核因子(nuclear factor ofactivated T cell,NFAT)及增加延迟整流钾通道的表达(促进K+外流)从而进一步促进凋亡、抑制肿瘤细胞生长。另外,实验再次证明DCA能促进乳腺癌细胞氧化磷酸化,显著增加凋亡蛋白酶caspase-3和caspase-7的活性,从而促进凋亡,在体内外均能抑制转移性乳腺癌细胞生长,具有抗肿瘤细胞增殖和诱导凋亡的特性。随后的一系列研究进一步发现DCA对子宫内膜癌、卵巢上皮癌、结肠癌、神经母细胞瘤等多种恶性肿瘤细胞也具有抗肿瘤作用。
由于DCA在体内外实验中获得了令人满意的抗肿瘤效果,因此人们尝试通过DCA联合或结合化疗、放疗、溶瘤病毒、DNA甲基化抑制剂、碳酸氢盐等其他治疗方法来进一步提高抗肿瘤疗效。绝大部分研究均显示DCA联合或结合其他治疗能发挥协同作用、增加抗肿瘤效果。与化疗药物联合缺氧微环境下,HIF-1α能通过上调PDK1减少肿瘤细胞线粒体的氧耗,导致化疗疗效降低及耐药,而DCA却能抑制PDK1活性,因此,DCA与传统细胞毒化疗药物联合,可能会提高抗肿瘤治疗的效果和减少化疗药物剂量以减少不良反应发生。目前DCA与化疗药物联合治疗恶性肿瘤的研究主要集中在铂类药物上,大部分研究发现DCA在体外能增加某些铂类药物的细胞毒作用、减少肿瘤细胞耐药。
越来越多的临床前期研究证实,小分子药物DCA在多种恶性肿瘤中发挥着独特的抗肿瘤作用,能特异性地抑制肿瘤细胞线粒体丙酮酸脱氢酶激酶(PDK),促进葡萄糖的氧化磷酸化,使线粒体膜去极化、膜电位降低,释放ROS和细胞色素C等,使细胞内Ca2+浓度和K+浓度降低,进一步诱导肿瘤细胞凋亡,抑制肿瘤细胞生长。将DCA与其他治疗方法如化疗、放疗、溶瘤病毒、DNA甲基化抑制剂等联合也显示出比单一治疗更为显著的抗肿瘤作用。同时,DCA在临床上用于乳酸酸中毒治疗已有40余年,安全性较好,而且具有可口服和价格低廉的特点,这说明DCA作为抗癌药物的临床应用与开发具有一定前景。
本发明报道的氯乙酰氧基水杨酸衍生物是将水杨酸与氯乙酸(包括一氯乙酸、二氯乙酸、以及三氯乙酸)结合制备成小分子化合物(结构见下图),并将氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯,及其药物组合物用于制备治疗癌症及其相关疾病的药物。
发明内容
本发明的目的是提供一种水杨酸衍生物,具体为氯乙酰氧基水杨酸衍生物(其合成及结构式如下)或其药学上可接受的盐、酯,及其药物组合物,其中药物组合物含有氯乙酰氧基水杨酸衍生物和一种或几种已知抗肿瘤药物,可以协同治疗癌症及相关疾病。
R=-CHCl2,CH2Cl,CHCl3
本发明的目的是提供氯乙酰氧基水杨酸衍生物的新用途。
本发明所提供的氯乙酰氧基水杨酸衍生物的一个新用途是:氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯在预防或治疗癌症及其相关疾病中的应用。
所述的盐包括氯乙酰氧基水杨酸形成的无机盐或有机盐。
所述的酯包括氯乙酰氧基水杨酸与醇形成的酯。
所述的无机盐包括氯乙酰氧基水杨酸形成的Li盐、Na盐、K盐、Mg盐、Zn盐、Ca盐、Fe盐等,但不限于举例范围。
所述的有机盐包括氯乙酰氧基水杨酸与有机碱形成的氨盐、伯胺盐、仲胺盐、叔胺盐、季胺盐,有机碱的优选实例,包括三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺、N,N′-二苄基亚乙基二胺等,但不限于举例范围。
所述的酯包括氯乙酰氧基水杨酸与C1-C30烷基醇、取代的C1-C30烷基醇、C3-C10碳环醇或取代的C3-C10碳环醇、多元醇(羟基数目大于等于2)等形成的酯,但不限于举例范围。
上述氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物在制备治疗癌症及相关疾病药物的用途及相关应用。
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯在作为治疗癌症及相关疾病药物的用途及相关应用
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物刺激免疫系统产生免疫反应,能够抑制肿瘤组织微血管形成,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物抑制环氧化酶,抑制肿瘤血管生长,抑制细胞的侵袭转移,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物抑制丙酮酸脱氢酶激酶,控制肿瘤细胞代谢,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物能促进葡萄糖氧化磷酸化,提高凋亡蛋白酶caspase-3和caspase-7的活性,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物能降低细胞内Ca2+浓度、抑制活化T细胞核因子及增加延迟整流钾通道促进K+外流,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
本发明还提供了一种药物组合物,所述药物组合物含有治疗有效剂量的氯乙酰氧基水杨酸或其药学上可接受的盐、酯以及一种或多种治疗癌症及其相关疾病的药物。
所述的药物组合物在制备预防或治疗癌症及其相关疾病的药物中的应用。
所述的治疗癌症药物,包括烷化剂类:盐酸氮芥、环磷酰胺、异环磷酰胺、曲磷胺、顺铂;抑制DNA合成类:5-氟尿嘧啶、巯嘌呤、溶癌呤、巯鸟嘌呤、甲氨蝶呤、叶酸;多肽类抗生素:放线菌素D、博莱霉素;蒽醌类抗生素:盐酸多柔比星(盐酸阿霉素)、米托蒽醌;天然植物:喜树碱和羟基喜树碱、长春碱和长春新碱、紫杉醇等,但不限于举例范围。
以氯乙酰氧基水杨酸或其药学上可接受的盐、酯或其药物组合物为有效成分制备的治疗癌症及其相关疾病的药物,也属于本发明的保护范围。
所述预防或治疗癌症及其相关疾病的药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织、或是被其他物质混合或包裹后导入机体等,但不限于举例范围。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等,但不限于举例范围。
用氯乙酰氧基水杨酸或其药学上可接受的盐、酯或其药物组合物为活性成分制备的治疗癌症及其相关疾病的药物可以制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式,但不限于举例范围。上述各种剂型的药物均可以按照药学领域的常规方法制备。
除非另有说明,否则说明书和权利要求书中的术语具有下述含义。
“C1-C30烷基”可以为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、葵基等,但不限于举例范围。
“多元醇”可以为乙二醇、丙三醇、苯二酚、苯三酚、单糖、寡聚糖、多聚糖、多聚醇等,但不限于举例范围。
“C3-C10碳环”可以提及例如环丙烷、环丁烷、环戊烷、环己烷等饱和碳环;环丁烯、环戊烯、环己烯等不饱和碳环及苯环、萘环等芳香碳环等,但不限于举例范围。
“杂环”可以提及例如5-10元杂环,构成杂环的原子除了含有碳原子外,还含有一种或两种选自N、S、O的1至4个杂原子,优选5-10元非芳香杂环或5-10元芳香杂环等。具体地,非芳香杂环,例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等;芳香杂环,例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等,但不限于举例范围。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有氯乙酰氧基水杨酸或其可药用的盐、酯联合一种或多种治疗癌症及其相关疾病药物与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性,降低副作用。
本发明的优点:本发明提供的氯乙酰水杨酸衍生物的药物组合物中含有氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯和一种或多种已知的抗肿瘤药物,已知抗肿瘤药物和氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯单独作用时,对癌症疾病具有治疗作用;二者联合作用时,对癌症疾病的治疗效果进一步提高,可以开发成治疗癌症疾病及相关应用的药物。
附图说明
图1是本发明所述的2-(2,2-二氯乙酰氧基)水杨酸的合成路线图
图2是2-(2-一氯乙酰氧基)水杨酸的合成路线图
图3是2-(2,2,2-三氯乙酰氧基)水杨酸的合成路线图
具体实施例
以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常用试剂。
本发明的技术方案如下:
实施例1:本发明中氯乙酰氧基水杨酸衍生物可以通过如下所述的方法合成
本发明的水杨酸分子结构,具体为一种氯乙酰氧基水杨酸衍生物:
制备氯乙酰氧基水杨酸衍生物的通用步骤为:
水杨酸加入到吡啶溶液中,搅拌溶解形成透明溶液,在冰浴条件下滴加氯乙酰氯的二氯甲烷溶液,滴加完后升入室温反应,反应结束后,减压悬蒸除去吡啶,再溶解于二氯甲烷中,再用稀盐酸水洗三次,再用二氯甲烷萃取三次,收集有机层,加干燥剂干燥,将有机相减压悬蒸,硅胶层析柱纯化得到目标产物(见图1-3)
具体实验例1.1:2-(2,2-二氯乙酰氧基)水杨酸的合成(R=-COCHCl2)
将3g(0.0217mol)水杨酸加入到50ml吡啶溶液中,搅拌溶解形成透明溶液,在冰浴条件下滴加3.84g 2,2-二氯乙酰氯(0.026mol)的二氯甲烷溶液,滴加完后升入室温反应,反应结束后,减压悬蒸除去吡啶,再溶解于二氯甲烷20ml中,再用稀盐酸水洗三次(20ml×3),再用二氯甲烷萃取三次(20ml×3),收集有机层,加干燥剂干燥,将有机相减压悬蒸,硅胶层析柱纯化得到目标产物2-(2,2-二氯乙酰氧基)水杨酸。黄色固体,3g,产率为55.5%。熔点为115℃;ESI-MS(m/z)247.96;IR(KBr)vcm-1:1744(C=O),1200(C-O);1H-NMR(DMSO-d6)δ:12.04(s,1H,-OH),8.24~7.9(m,4H,H-Ph),6.29(s,1H,-CH-);13C-NMR(DMSO-d6):166.1(Ph-COOH),162.6(Ph-COO-),150.8~123.9(6C,Ph),63.6(-CHCl2).
具体实验例1.2:2-(2-氯乙酰氧基)水杨酸的合成(R=-COCH2Cl)
水杨酸(3g,0.0217mol)开始,加入到吡啶(10ml)溶液中,搅拌溶解形成透明溶液,在冰浴条件下滴加2-氯乙酰氯(4.67g,0.026mol)的二氯甲烷溶液,滴加完后升入室温反应,反应结束后,减压悬蒸除去吡啶,再溶解于二氯甲烷20ml中,再用稀盐酸水洗三次(20ml×3),再用二氯甲烷萃取三次(20ml×3),收集有机层,加干燥剂干燥,将有机相减压悬蒸,硅胶层析柱纯化得到目标产物2-(2-氯乙酰氧基)水杨酸。黄色固体,2.5g,产率为53.6%。熔点为115℃;ESI-MS(m/z)214;IR(KBr)vcm-1:1744(C=O),1200(C-O);1H-NMR(DMSO-d6)δ:12.04(s,1H,-OH),8.24~7.9(m,4H,H-Ph),4.54(s,2H,-CH2-);13C-NMR(DMSO-d6):166.1(Ph-COOH),163.4(Ph-COO-),150.8~123.9(6C,Ph),40.0(-CH2Cl).
具体实验例1.3:2-(2,2,2-三氯乙酰氧基)水杨酸(R=-COCCl3)
水杨酸(3g,0.0217mol)开始,加入到吡啶(10ml)溶液中,搅拌溶解形成透明溶液,在冰浴条件下滴加2,2,2-三氯乙酰氯(2.91g,0.026mol)的二氯甲烷溶液,滴加完后升入室温反应,反应结束后,减压悬蒸除去吡啶,再溶解于二氯甲烷20ml中,再用稀盐酸水洗三次(20ml×3),再用二氯甲烷萃取三次(20ml×3),收集有机层,加干燥剂干燥,将有机相减压悬蒸,硅胶层析柱纯化得到目标产物2-(2,2-二氯乙酰氧基)水杨酸。黄色固体,3g,产率为48.7%。熔点为115℃;ESI-MS(m/z)281.93;IR(KBr)vcm-1:1744(C=O),1200(C-O);1H-NMR(DMSO-d6)δ:12.04(s,1H,-OH),8.24~7.9(q,4H,H-Ph);13C-NMR(DMSO-d6):166.1(Ph-COOH),160.0(-COO-Ph),150.8~123.9(6C,Ph),89.4(-CCl3).
实施例2:本发明中化合物的抗癌效果可以通过使用如下所述的测定系统测定。
(1)MTT实验表明二氯乙酰氧基水杨酸具有抑制肿瘤生长的作用
取对数生长期细胞(包括HCT116、A549、HepG2),接种于96孔培养板(5000个细胞/孔),放入37℃细胞培养箱中恒温培养24h后,加入二氯乙酰氧基水杨酸,取4个浓度梯度(0.1mM、1mM、5mM、10mM),加完药后将96孔细胞板放入细胞培养箱中培养48h,在96孔板的每孔加入20μl的四甲基偶氮唑蓝(MTT),继续放入细胞培养箱中培养4h后,吸弃培养基,每孔加入100μl二甲基亚砜,震荡10min,使结晶物充分溶解。用酶标仪检测570nm处的吸光值,记录结果。通过以下的公式计算抑制率:
抑制率=(1-药物OD值/对照OD值)x100%;
抑制率≥20%判定药物敏感实验为阳性,反之为阴性。
表1.二氯乙酰氧基水杨酸对肿瘤细胞的抑制结果
(2)MTT实验表明二氯乙酰氧基水杨酸联合阿霉素给药明显增强了抗癌效果
取对数生长期细胞(包括HCT116、A549、HepG2),接种于96孔培养板(5000个细胞/孔),放入37℃细胞培养箱中恒温培养24h后,加入样品(组1:5mM二氯乙酰氧基水杨酸;组2:1.5μM阿霉素;组3:5mM二氯乙酰氧基水杨酸+0.5μM阿霉素),加完药后将96孔细胞板放入细胞培养箱中培养48h,在96孔板的每孔加入20μl的四甲基偶氮唑蓝(MTT),继续放入细胞培养箱中培养4h后,吸弃培养基,每孔加入100μl二甲基亚砜,震荡30min,使结晶物充分溶解。用酶标仪检测490nm处的吸光值,记录结果。通过上述公式计算抑制率,结果见表2:
表2二氯乙酰氧基水杨酸联合阿霉素对肿瘤细胞的抑制结果
上述结果表明,氯乙酰氧基水杨酸具有抗癌效果,同时,氯乙酰氧基水杨酸联合已知抗肿瘤药物组合物具有更强的抑制肿瘤增殖的效果,诱导肿瘤细胞的凋亡,且效果优于抗肿瘤药物和氯乙酰氧基水杨酸衍生物单独作用的结果,可以开发成治疗癌症疾病及相关应用的药物。
Claims (15)
1.一种水杨酸衍生物,具体为氯乙酰氧基水杨酸衍生物,其结构式如下:
2.氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯在制备治疗癌症及其相关疾病的药物中的应用。
3.权利要求1中所述的盐包括氯乙酰氧基水杨酸衍生物形成的无机盐或有机盐;所述的酯包括氯乙酰氧基水杨酸衍生物与醇形成的酯。
4.权利要求2中所述的无机盐包括氯乙酰氧基水杨酸衍生物形成的Li盐、Na盐、K盐、Mg盐、Zn盐、Ca盐、Fe盐等,但不限于举例范围;所述的有机盐包括氯乙酰氧基水杨酸衍生物与有机碱形成的氨盐、伯胺盐、仲胺盐、叔胺盐、季胺盐等,有机碱的优选实例包括三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺、N,N′-二苄基亚乙基二胺等,但不限于举例范围。
5.权利要求2中所述的酯包括氯乙酰氧基水杨酸衍生物与C1-C30烷基醇、取代的C1-C30烷基醇、C3-C10碳环醇或取代的C3-C10碳环醇、多元醇(羟基数目大于等于2)等形成的酯,但不限于举例范围。
6.氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯可以治疗癌症及其相关疾病。
7.一种药物组合物,所述药物组合物含有治疗有效剂量的氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯以及一种或多种治疗癌症及其相关疾病的药物。
8.权利要求6所述的药物组合物在制备治疗癌症及其相关疾病的药物中的应用。
9.权利要求2和权利要求6所述的治疗癌症的药物包括烷化剂类:盐酸氮芥、环磷酰胺、异环磷酰胺、曲磷胺、顺铂;抑制DNA合成类:5-氟尿嘧啶、巯嘌呤、溶癌呤、巯鸟嘌呤、甲氨蝶呤、叶酸;多肽类抗生素:放线菌素D、博莱霉素;蒽醌类抗生素:盐酸多柔比星(盐酸阿霉素)、米托蒽醌;天然植物:喜树碱和羟基喜树碱、长春碱和长春新碱、紫杉醇等,但不限于举例范围。
10.权利要求2和权利要求6所述预防或治疗癌症及其相关疾病的药物,其特征在于,所述的药物还包括药学上可以接受的载体如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体或润滑剂,但不限于举例范围。
11.权利要求2和权利要求6中所述的预防或治疗癌症及其相关疾病的药物,其特征在于,该药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织,或是被其他物质混合或包裹后导入机体等,但不限于举例范围。
12.权利要求2和权利要求6中所述的预防或治疗癌症及其相关疾病的药物,其特征在于,该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式,但不限于举例范围。
13.权利要求6~8所述的氯乙酰氧基水杨酸衍生物的药物组合物在制备治疗癌症及其相关疾病药物的应用,但不局限于举例范围。
14.权利要求6~8所述的氯乙酰氧基水杨酸衍生物在制备治疗癌症及其相关疾病药物的应用,其特征在于:氯乙酰氧基水杨酸衍生物的氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯的药物组合物能够在癌症细胞中抑制丙酮酸脱氢酶激酶的活性,使肿瘤细胞代谢失常;能够刺激免疫系统产生免疫反应,能够抑制肿瘤组织微血管形成,从而具有抗肿瘤细胞增殖和诱导凋亡活性;抑制环氧化酶,抑制肿瘤血管生长,抑制细胞的侵袭转移,从而具有抗肿瘤细胞增殖和诱导凋亡活性;能够抑制丙酮酸脱氢酶激酶,控制肿瘤细胞的代谢,从而具有抗肿瘤细胞增殖和诱导凋亡活性;能促进葡萄糖氧化磷酸化,提高凋亡蛋白酶caspase-3和caspase-7的活性,从而具有抗肿瘤细胞增殖和诱导凋亡活性;降低细胞内Ca2+浓度、抑制活化T细胞核因子及增加延迟整流钾通道促进K+外流,从而具有抗肿瘤细胞增殖和诱导凋亡活性。
15.权利要求6~8所述的氯乙酰氧基水杨酸衍生物的药物组合物在制备治疗癌症及其相关疾病药物的应用,其特征在于:氯乙酰氧基水杨酸衍生物的氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯能激活癌细胞中的线粒体,激活细胞凋亡机制,促使癌变细胞死亡;氯乙酰氧基水杨酸衍生物的氯乙酰氧基水杨酸衍生物或其药学上可接受的盐、酯联合一种或多种治疗癌症的药物可以更有效诱导癌细胞凋亡。
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