CN115252611B - 一种酰胺类化合物、其应用及抗肿瘤药物组合物 - Google Patents
一种酰胺类化合物、其应用及抗肿瘤药物组合物 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体涉及一种酰胺类化合物、其应用及抗肿瘤药物组合物。采用酰胺类化合物制备抗肿瘤化疗药物增敏剂,所述酰胺类化合物分离自胡椒属植物荜茇及胡椒中,属于天然产物,这些化合物都具有增加几种化疗药物的敏感性、逆转肿瘤细胞耐药、促进细胞凋亡的作用。本发明涉及的22种酰胺类化合物可作为化疗药物的增敏剂使用,与抗肿瘤药物(化疗药物)联用,可以增强化疗药物抗肿瘤的作用效果,逆转肿瘤细胞耐药,为解决肿瘤耐药问题提供新途径和新手段。本发明的22种酰胺类化合物具有增加紫杉醇、长春新碱及阿霉素对肿瘤细胞的敏感性,以及逆转肿瘤细胞耐药性的作用。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种酰胺类化合物、其应用及抗肿瘤药物组合物。
背景技术
癌症是世界上各国人口的主要死亡原因,也是提高预期寿命的重要障碍。紫杉醇,是第一个来自天然植物用来治疗癌症的化学药物,可抑制微管蛋白的解聚,引起细胞周期阻滞,促进肿瘤凋亡。紫杉醇类化疗药物是目前临床常用的抗肿瘤药物。随着化疗药物广泛使用,很多病人产生耐药性,癌症预后不良,最终死亡。因此,寻找具有逆转紫杉醇类药物耐药作用的化合物,具有极为重要的意义。长春新碱也是临床上作用于微管蛋白系统的化疗药物。与紫杉醇作用机制不同,长春新碱抑制微管蛋白形成微管,介导细胞周期阻滞,导致细胞死亡。阿霉素是一种临床上常用的抗生素类广谱抗肿瘤药物,可抑制RNA和DNA的合成,属周期非特异性药物。肿瘤患者的治疗中,单药治疗易导致患者耐药,开发新的药物与化疗药联合治疗有利于克服耐药性,降低单药剂量毒性,提高药物疗效。
酰胺类化合物是胡椒属植物的主要化学成分,活性显著,生物利用度高。研究表明酰胺类化合物具有抗炎,止痛,抗肿瘤等多种生物活性,是天然药物生物活性成分的重要来源。胡椒科胡椒属植物,其酰胺类化合物含量非常丰富。
发明内容
本发明的目的之一在于提供一种酰胺类化合物的应用,用于制备化疗药物增敏剂。
本发明的目的之二在于提供一种抗肿瘤药物组合物。
本发明的目的之三在于提供一种酰胺类化合物,具有增加几种化疗药物的敏感性、逆转肿瘤细胞耐药、促进细胞凋亡的作用。
本发明实现目的之一所采用的方案是:一种酰胺类化合物的应用,采用酰胺类化合物制备抗肿瘤化疗药物增敏剂,所述酰胺类化合物为以下化合物1-22中的任意一种:
优选地,所述化疗药物是细胞周期特异性药物或者细胞周期非特异性药物。
优选地,所述化疗药物包括长春新碱、阿霉素、紫杉醇及其衍生物中的任意一种。
优选地,所述肿瘤包括子宫癌、卵巢癌、乳腺癌、肝癌、肺癌、鼻咽癌、胃癌、结肠直肠癌、胰腺癌、皮肤癌、肾癌、食道癌中的至少一种。
本发明实现目的之二所采用的方案是:一种抗肿瘤药物组合物,包括化疗药物及增敏剂,所述化疗药物包括长春新碱、阿霉素、紫杉醇及其衍生物中的任意一种,所述增敏剂为所述的酰胺类化合物1-22中的任意一种。
优选地,所述药物的剂型为口服液、片剂、注射剂、胶囊剂、颗粒剂、散剂中的至少一种。
优选地,所述药物组合物的给药方式为口服给药或注射给药。
本发明实现目的之三所采用的方案是:一种酰胺类化合物,所述酰胺类化合物分离自胡椒属植物荜茇及胡椒,其结构式为所述的化合物1-12中的任意一种。
本发明具有以下优点和有益效果:
本发明涉及的22种酰胺类化合物分离自胡椒属植物荜茇及胡椒中,属于天然产物,这些化合物都具有增加几种化疗药物的敏感性、逆转肿瘤细胞耐药、促进细胞凋亡的作用。
本发明涉及的22种酰胺类化合物可作为化疗药物的增敏剂使用,与抗肿瘤药物(化疗药物)联用,可以增强化疗药物抗肿瘤的作用效果,逆转肿瘤细胞耐药,为解决肿瘤耐药问题提供新途径和新手段。
本发明的22种酰胺类化合物具有增加紫杉醇、长春新碱及阿霉素对肿瘤细胞的敏感性,以及逆转肿瘤细胞耐药性的作用。
附图说明
图1为本发明中新化合物1-12(10μM)与紫杉醇联用对宫颈癌紫杉醇耐药细胞(HeLa/PTX)的协同及增敏作用;
图2为本发明中已知化合物13-21(10μM)与紫杉醇联用对宫颈癌紫杉醇耐药细胞(HeLa/PTX)的协同及增敏作用;
图3为化合物1、5、7、15、17及21(10μM)与紫杉醇联用对宫颈癌细胞(HeLa)的协同及增敏作用;
图4为化合物1、9、10、16、18及19(10μM)与长春新碱联用对宫颈癌细胞(HeLa)的协同及增敏作用;
图5为化合物2、4、6、10、13及18(10μM)与阿霉素联用对宫颈癌细胞(HeLa)的协同及增敏作用;
图6为化合物2、5、8、14及17(10μM)与紫杉醇联用对卵巢癌细胞(SKOV-3)的协同及增敏作用;
图7为化合物3、6、11、16及20(10μM)与长春新碱联用对卵巢癌细胞(SKOV-3)的协同及增敏作用;
图8为化合物1、10、12、18及19(10μM)与阿霉素联用对卵巢癌细胞(SKOV-3)的协同及增敏作用;
图9为化合物10及16(10μM)与紫杉醇联用对肝癌细胞(HepG2)的协同及增敏作用;
图10为化合物10及16(10μM)与阿霉素联用对肝癌细胞(HepG2)的协同及增敏作用;
图11为化合物3及15(10μM)与紫杉醇联用促进紫杉醇耐药细胞宫颈癌紫杉醇耐药细胞(HeLa/PTX)凋亡;
图12为化合物22(10μM)与阿霉素或长春新碱联用对宫颈癌细胞(HeLa)及卵巢癌细胞(SKOV3)的协同及增敏作用。
具体实施方式
为更好的理解本发明,下面的实施例是对本发明的进一步说明,但本发明的内容不仅仅局限于下面的实施例。
本发明在具体实施中,所述的胡椒属植物中具有增加化疗药物药效的酰胺类化合物的制备方法,包括以下步骤:
实施例1:
用95%乙醇提取荜茇根,减压浓缩收集浸膏,采用大孔树脂初步分为4个组分。组分1经过凝胶、正反相硅胶柱色谱反复分离得到化合物1及9。组分2经过正向硅胶及凝胶柱色谱反复分离得到化合物10及11。组分3经过凝胶色谱以及正反相硅胶柱色谱反复分离后,通过高效液相色谱分离得到化合物12。组分4经过凝胶色谱分离,然后通过硅胶柱色谱分离得到化合物13及22。化合物1及9-12为新化合物,其13C NMR数据见表1。
实施例2:
用95%乙醇提取胡椒茎4次,减压浓缩收集浸膏,采用小孔树脂初步分离,获得4个组分;组分1采用正相硅胶、凝胶及反相硅胶柱色谱反复分离得到化合物2及3。组分2经过凝胶色谱、正相硅胶柱色谱及高效液相色谱分离得到化合物4、5及6。组分3经过凝胶色谱分离,然后使用正反相硅胶柱色谱分离得到化合物7,高效液相色谱分离得到化合物8。组分4经过大孔树脂、正反相硅胶及凝胶色谱分离得到化合物14及15。化合物2-8为新化合物,其1H NMR数据见表2。
实施例3:
用95%乙醇提取胡椒果实白胡椒,减压浓缩收集浸膏,采用大孔树脂初分为3个组分。组分1首先经过凝胶色谱分离,然后使用正反相硅胶柱色谱反复分离得到化合物16及17。组分2通过正反相硅胶及凝胶柱色谱反复分离得到化合物18及19。组分3经过凝胶色谱以及正反相硅胶柱色谱反复分离后,通过高效液相色谱分离得到化合物20及21。
表1.13C NMR(100MHz)Spectroscopic Data for Compounds 1and 9-12in CDCl3.
表2.1H(400MHz)NMR[δ,mult(J in Hz)]Data for Compound 2-8
a Recorded in CDCl3,b Recorded in pyridine-d5.
实施例4:本发明中酰胺类化合物与紫杉醇联用对宫颈癌紫杉醇耐药细胞(HeLa/PTX)的协同及增敏作用
宫颈癌紫杉醇耐药细胞(HeLa/PTX)用DMEM高糖培养基培养。用二聚酰胺化合物与紫杉醇联合处理HeLa/PTX细胞72小时后,更换新鲜培养基100μL,每孔加入MTT(5mg/mL)溶液20μL孵育4小时,去上清,每孔加入100μL DMSO,用酶标仪在570nm测定OD值。化合物1-21与紫杉醇联用的作用效果见图1及2。
图1为新化合物1-12(10μM)与紫杉醇联用对宫颈癌紫杉醇耐药细胞(HeLa/PTX)的协同及增敏作用。
图2为已知化合物13-21(10μM)与紫杉醇联用对宫颈癌紫杉醇耐药细胞(HeLa/PTX)的协同及增敏作用。
从图中可以看出:酰胺类化合物或紫杉醇单独作用对细胞的活性的影响很小,化合物1-21联用紫杉醇时明显抑制细胞存活率。细胞存活率=药物处理组OD值/对照组OD值×100%。
实施例5:本发明中酰胺类化合物与几种化疗药对宫颈癌细胞(HeLa)的协同及增敏作用
宫颈癌细胞(HeLa)用DMEM高糖培养基培养。采用二聚酰胺化合物与紫杉醇、长春新碱或阿霉素联合作用,处理HeLa细胞72小时后,每孔加入MTT(5mg/mL)溶液20μL,孵育4小时,去上清,每孔加入100μL DMSO,用酶标仪在570nm测定OD值。细胞存活率=药物处理组OD值/对照组OD值×100%。
图3为化合物1、5、7、15、17及21(10μM)与紫杉醇联用对宫颈癌细胞(HeLa)的协同及增敏作用。
图4为化合物1、9、10、16、18及19(10μM)与长春新碱联用对宫颈癌细胞(HeLa)的协同及增敏作用。
图5为化合物2、4、6、10、13及18(10μM)与阿霉素联用对宫颈癌细胞(HeLa)的协同及增敏作用。
从图中可以看出:所用酰胺类化合物对宫颈癌细胞活性无明显抑制作用,但可明显增加三种化疗药紫杉醇、长春新碱及阿霉素对宫颈癌细胞活性的抑制作用。
实施例6:本发明中酰胺类化合物与化疗药对卵巢癌细胞(SKOV3)的协同及增敏作用
卵巢癌细胞SKOV-3用DMEM/F12培养基培养。采用二聚酰胺化合物与紫杉醇,长春新碱或阿霉素联合作用,对卵巢癌细胞SKOV-3处理72小时后,每孔加入MTT(5mg/mL)溶液20μL孵育4小时,去上清,每孔加入100μL DMSO,用酶标仪在570nm测定OD值。细胞存活率=药物处理组OD值/对照组OD值×100%。
图6为化合物2、5、8、14及17(10μM)与紫杉醇联用对卵巢癌细胞(SKOV-3)的协同及增敏作用。
图7为化合物3、6、11、16及20(10μM)与长春新碱联用对卵巢癌细胞(SKOV-3)的协同及增敏作用。
图8为化合物1、10、12、18及19(10μM)与阿霉素联用对卵巢癌细胞(SKOV-3)的协同及增敏作用。
从图中可以看出:所用酰胺类化合物对卵巢癌细胞无明显抑制作用,但可明显增加三种化疗药紫杉醇、长春新碱及阿霉素对卵巢癌细胞的抑制作用。
实施例7:本发明中酰胺类化合物与化疗药对肝癌细胞(HepG2)的协同及增敏作用
肝癌细胞(HepG2)用RPMI 1640培养基培养。采用二聚酰胺化合物与紫杉醇或阿霉素联合作用,对肝癌细胞HepG2处理72小时后,每孔加入MTT(5-mg/mL)溶液20μL孵育4小时,去上清,每孔加入100μL DMSO,用酶标仪在570nm测定OD值。细胞存活率=药物处理组OD值/对照组OD值×100%。
图9为化合物10及16(10μM)与紫杉醇联用对肝癌细胞(HepG2)的协同及增敏作用。
图10为化合物10及16(10μM)与阿霉素联用对肝癌细胞(HepG2)的协同及增敏作用。
从图中可以看出:所用酰胺类化合物对肝癌细胞活性无明显抑制作用,但可明显增加两种化疗药紫杉醇及阿霉素对肝癌细胞活性的抑制作用。
实施例8:本发明中酰胺类化合物与紫杉醇联用促进宫颈癌紫杉醇耐药细胞(HeLa/PTX)凋亡
酰胺类化合物与紫杉醇联合作用于Hela/PTX细胞24小时后,PBS洗两遍,Hoechst33258(5μg/mL)染色30分钟,PBS洗两遍后在荧光显微镜下观察细胞形态并拍照。图11结果显示,化合物3、15(10μM)与紫杉醇(20、40nM)单独处理组的细胞形态与对照组无明显区别。相比之下,化合物3、15与紫杉醇(20、40nM)联合作用后的细胞明显碎裂,出现凋亡小体。
图11为化合物3及15(10μM)与紫杉醇联用促进紫杉醇耐药细胞宫颈癌紫杉醇耐药细胞(HeLa/PTX)凋亡。
从图中可以看出:酰胺类化合物或紫杉醇单独作用于宫颈癌耐药细胞时,细胞核无明显变化。当化合物与紫杉醇联用时,细胞核开始皱缩,凋亡小体出现,细胞发生凋亡。
实施例9:酰胺类化合物22与阿霉素及长春新碱联用对宫颈癌细胞(HeLa)及卵巢癌细胞(SKOV3)的协同及增敏作用。
采用化合物22与长春新碱或阿霉素联合作用,处理HeLa细胞72小时后,每孔加入MTT(5mg/mL)溶液20μL,孵育4小时,去上清,每孔加入100μL DMSO,用酶标仪在570nm测定OD值。细胞活力=药物处理组OD值/对照组OD值×100%。
图12为化合物22(10μM)与阿霉素或长春新碱联用对宫颈癌细胞(HeLa)及卵巢癌细胞(SKOV3)的协同及增敏作用。从图中可以看出化合物22可明显增加两种化疗药长春新碱及阿霉素对宫颈癌细胞及卵巢癌细胞活性的抑制作用。
以上所述是本发明的优选实施方式而已,当然不能以此来限定本发明之权利范围,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和变动,这些改进和变动也视为本发明的保护范围。
Claims (5)
1.一种酰胺类化合物的应用,其特征在于:采用酰胺类化合物制备抗肿瘤化疗药物增敏剂,所述酰胺类化合物为以下化合物1-22中的任意一种:
化合物1
化合物2
化合物3
化合物4
化合物5
化合物6
化合物7
化合物8
化合物9
化合物10
化合物11
化合物12
化合物13
化合物14
化合物15
化合物16
化合物17
化合物18
化合物19
化合物20
化合物21
化合物22;
所述化疗药物为长春新碱、阿霉素、紫杉醇中的任意一种;所述肿瘤选自宫颈癌、卵巢癌、肝癌中的至少一种。
2.一种抗肿瘤药物组合物,其特征在于:包括化疗药物及增敏剂,所述化疗药物为长春新碱、阿霉素、紫杉醇中的任意一种,所述增敏剂为权利要求1所述的酰胺类化合物1-22中的任意一种。
3.根据权利要求2所述的抗肿瘤药物组合物,其特征在于:所述药物的剂型为口服液、片剂、注射剂、胶囊剂、颗粒剂、散剂中的至少一种。
4.根据权利要求2所述的抗肿瘤药物组合物,其特征在于:所述药物组合物的给药方式为口服给药或注射给药。
5.一种酰胺类化合物,其特征在于:所述酰胺类化合物分离自胡椒属植物荜茇及胡椒,其结构式为权利要求1中所述的化合物1-12中的任意一种。
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