CN107686498B - 阿霉素-胆酸缀合物,其合成,活性和应用 - Google Patents
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Abstract
Description
技术领域
本发明涉及阿霉素-胆酸缀合物(BCBAOLys),涉及它的制备方法,涉及它的抗肿瘤活性,涉及它的抗炎活性。与已有的发明将赖氨酸的羧基和氨基分别连接阿霉素的氨基和胆酸的羧基不同,本发明的特征在于将赖氨酸的羧基和氨基分别连接阿霉素的14位羟基和胆酸的羧基。这种连接方式不仅使BCBAOLys有抗肿瘤活性和抗炎活性,而且完全消除了阿霉素的肝毒性、肾毒性和心脏毒性。因而本发明公开了BCBAOLys在制备没有肝毒性、没有肾毒性和没有心脏毒性的抗肿瘤和抗炎药物中的应用。本发明属于生物医药领域。
背景技术
临床上,阿霉素广泛用于治疗多种实体瘤和血液肿瘤的。可是,阿霉素的肝毒性、肾毒性和心脏毒性严重影响阿霉素的临床疗效。曾经采取各种各样的化学修饰,企图降低阿霉素的肝毒性、肾毒性和心脏毒性。不过,成效甚微。例如有的专利将赖氨酸的羧基和氨基分别连接阿霉素的3位氨基和胆酸的羧基。可是这个专利没有公开在动物模型上这种连接方式在抗肿瘤活性、抗炎活性和毒性方面有什么优势。为了确认这种连接是否合理,发明人按照它的连接方式制备了赖氨酸的羧基和氨基分别连接阿霉素的3位氨基和胆酸的羧基的化合物。虽然在细胞模型上发明人重复出了该专利公开的抗肿瘤细胞增殖活性,但是在S180小鼠肿瘤模型和耳肿胀炎症小鼠模型上赖氨酸的羧基和氨基分别连接阿霉素的3位氨基和胆酸的羧基的化合物确实没有任何活性。为了找到有效的连接方式,发明人经过5年摸索发现,只要将赖氨酸的羧基和氨基分别连接阿霉素的14位羟基和胆酸的羧基生成的化合物在S180小鼠肿瘤模型和耳肿胀炎症小鼠模型上有抗肿瘤活性和抗炎活性,而且可完全消除了阿霉素的肝毒性、肾毒性和心脏毒性。根据这个发现发明人提出了本发明。
发明内容
本发明的第一个内容是提供下式的阿霉素-胆酸缀合物BCBAOLys。
本发明的第二个内容是提供BCBAOLys的制备方法,该方法包括:
(1)采用二环己基碳二亚胺(DCC)为缩合剂,1-羟基苯并三氮唑(HOBt)为催化剂液相合成胆酸酰-Lys(Fmoc)-OBzl;
(2)在氢氧化钠-甲醇溶液中(1M)脱除胆酸酰-Lys(Fmoc)-OBzl中的苄基和Fmoc制备胆酸酰-Lys;
(3)用Fmoc保护阿霉素的3’-NH2制备Fmoc-阿霉素;
(4)用戊二酸偶联Fmoc-阿霉素的14位OH;
(5)Fmoc-阿霉素的14位OH偶联的戊二酸在DCC存在下与N-羟基琥珀酰亚胺(HOSu)形成活泼酯;
(6)Fmoc-阿霉素的14位OH偶联的戊二酸的OSu活泼酯与胆酸酰-Lys缩合制备Fmoc保护的阿霉素-胆酸缀合物;
(7)在10%哌啶/无水N,N-二甲基甲酰胺(DMF)中Fmoc保护的阿霉素-胆酸脱除Fmoc制备权利要求1的BCBAOLys。
本发明的第三个内容是评价BCBAOLys在S180小鼠模型上的抗肿瘤活性。
本发明的第四个内容是评价BCBAOLys在小鼠耳肿胀模型上的抗炎活性。
本发明的第五个内容是阐明BCBAOLys消除了阿霉素的肝毒性、肾毒性和心脏毒性。
附图说明
图1BCBAOLys的合成路线。i)二环己基羰二亚胺(DCC),1-羟基苯并三氮唑(HOBt),无水四氢呋喃(THF),N-甲基吗啉(NMM),冰浴;ii)氢氧化钠-甲醇溶液(1M),冰浴;iii)9-芴甲氧羰酰琥珀酰亚胺(Fmoc-OSu),二异丙基乙胺(DIPEA),无水N,N-二甲基甲酰胺(DMF),冰浴,避光;iv)戊二酸酐(GA),DIPEA,无水DMF,冰浴,避光;v)N-羟基琥珀酰亚胺(HOSu),DCC,无水DMF,避光;vi)无水DMF,DIPEA,冰浴,避光;vii)10%哌啶/无水DMF,冰浴,避光。
图2BCBAOLys对小鼠生存率的影响。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备胆酸酰-Lys(Fmoc)-OBzl(1)
将4.09g(10mmol)胆酸用75mL无水THF溶解,冰浴下搅拌,向得到的溶液中依次加入1.42g(10.5mmol)HOBt和2.47g(12mmol)DCC,将此反应液冰浴下搅拌10min。加入4.82g(10.5mmol)Lys(Fmoc)-OBzl,用NMM调节pH 8室温搅拌8h。TLC(二氯甲烷/甲醇,15:1,加2滴冰醋酸)监测反应完成。反应混合物减压浓缩,黄色油状物用石油醚处理,弃上清。残留物用200mL乙酸乙酯溶解,过滤除DCU。滤液依次用5%NaHCO3水溶液洗3次,饱和NaCl水溶液洗2次,5%KHSO4水溶液洗3次,饱和NaCl水溶液洗2次,5%NaHCO3水溶液洗3次,饱和NaCl水溶液洗3次(70mL/次)。乙酸乙酯相用无水Na2SO4干燥过夜,过滤,滤液减压浓缩,残留物用柱层析纯化(二氯甲烷/甲醇,20:1)。得到6.69g(79%)无色粉末状标题化合物。ESI-MS(m/e):849[M+H]+。
实施例2制备胆酸酰-Lys(2)
将1.75g(2.06mmol)胆酸酰-Lys(Fmoc)-OBzl溶解在10mL甲醇中,冰浴下搅拌冷却,加入氢氧化钠-甲醇溶液(1M)调节pH=12,搅拌12h,反应液用饱和KHSO4中和至pH=7,减压浓缩除去甲醇,减压抽滤滤取滤饼。黄白色滤饼用石油醚磨洗,减压抽滤滤取滤饼。滤饼用乙醚磨洗,减压抽滤滤取滤饼。晾干得到1.07g(97%)无色粉末状标题化合物。ESI-MS(m/e):537[M+H]+。
实施例3制备Fmoc-氨基阿霉素(3)
将1.16g(2mmol)阿霉素溶解在15mL无水DMF中,冰浴下搅拌并滴加500μL DIPEA,加入1.012g Fmoc-OSu,冰浴下搅拌15h,TLC(二氯甲烷/甲醇,20:1,加2滴冰醋酸)监测反应完成。反应混合物重复用石油醚/乙醚洗,静置,弃上清除DIPEA和DMF。暗红色油状物用二氯甲烷/甲醇30:1溶解,经柱层析纯化(二氯甲烷/甲醇,50:1),得1.12g(73%)红色粉末状标题化合物。ESI-MS(m/e):788[M+Na]+。
实施例4制备Fmoc-氨基阿霉素-14-O-戊二酸单酯(4)
将1.53g(2mmol)Fmoc-氨基阿霉素溶解在10mL无水DMF中,冰浴下搅拌并加入228mg戊二酸酐,反应混合物用DIPEA调pH 8,冰浴反应36h,TLC(二氯甲烷/甲醇,20:1)监测反应完成。反应混合物重复用石油醚/乙醚洗,静置弃上清除去DIPEA和DMF。暗红色油状物用二氯甲烷溶解经柱层析纯化(二氯甲烷/甲醇,40:1),得到884mg(50%)红色粉末状标题化合物。ESI-MS(m/e)879[M-H]-。
实施例5制备1-(Fmoc-氨基阿霉素-14-O)-5-OSu-戊二酸酯(5)
将1.319g(1.5mmol)Fmoc-氨基阿霉素-14-O-戊二酸单酯溶解在10mL无水DMF中,冰浴下搅拌,加入259mg(2.25mmol)HOSu和464mg(2.25mmol)DCC,冰浴下避光搅拌24h,TLC(二氯甲烷/甲醇,30:1)监测反应完成。反应混合物重复用石油醚/乙醚洗,静置弃上清除去DMF。得到的暗红色粉末用二氯甲烷溶解,经柱层析纯化(二氯甲烷/甲醇,50:1),得到1.0g(68%)红色粉末状标题化合物。ESI-MS(m/e):974[M-H]-。
实施例6制备1-(Fmoc-氨基阿霉素-14-O)-5-(胆酰-Lys)-戊二酰(6)
将976mg(1mmol)1-(Fmoc-氨基阿霉素-14-O)-5-OSu-戊二酸酯溶解在15mL无水吡啶中,冰浴搅拌,加入644mg(1.2mmol)胆酰-Lys,滴加DIPEA调节pH 8,冰浴搅拌30h,TLC(二氯甲烷/甲醇,5:1,加2滴冰醋酸)监测反应完成。反应混合物重复用石油醚/乙醚洗,静置弃上清除DIPEA和吡啶。得到的暗红色粉末用二氯甲烷磨洗,过滤,取滤饼,干燥,得1.74g(100%)红色粉末状标题化合物。直接投下步反应。ESI-MS(m/e):1396[M-H]-。
实施例7制备1-(阿霉素-14-O)-5-(胆酰-Lys)-戊二酰(BCBAOLys)
将500mg(0.426mmol)1-(Fmoc-氨基阿霉素-14-O)-5-(胆酰-Lys)-戊二酰溶解在10mL无水DMF中,冰浴下搅拌并滴加1mL哌啶,冰浴下搅拌30min,TLC(乙酸乙酯/H2O/醋酸,3/1/1)监测反应完成。冰浴下加6mL无水DMF、1mL TFA和2.4mL吡啶。混合液用稀盐酸酸化。混合液重复用石油醚/乙醚洗,静置弃上清除。得到的暗红色粉末用色谱乙腈/三蒸水(1/3)混合溶剂溶解,经制备柱纯化(乙腈/H2O,40/60加1‰HAc),得到162mg(39%)红色粉末状标题化合物。ESI-MS(m/e):1175[M-H]-。Mp:196-197℃;(C=1.0,乙腈/三蒸水,1/1);IR(cm-1):3353.17,3309.17,2931.89,2866.41,1726.99,1615.16,1578.64,1406.04,1283.20,1209.49,986.41,791.08;1H NMR(800MHz,DMSO-d6):δ/ppm=7.851(m,2H),7.729(t,J=5.6Hz,1H),7.596(d,J=7.2Hz,1H),7.358(d,J=6.4Hz,1H),5.273(d,J=17.6Hz,1H),5,251(s,1H),5.135(d,J=17.6Hz,1H),4.888(s,1H),4.252(d,J=6.4Hz,1H),4.075(s,1H),3.963(s,3H),3.936(m,2H),3.769(s,2H),3.586(d,J=12.8Hz,3H),3.272(d,J=12.0Hz,2H),3.175(m,2H),3.048(d,J=17.6Hz,1H),2.995(m,1H),2.951(m,1H),2.806(d,J=17.6Hz,1H),2.393(m,2H),2.32(d,J=17.6Hz,1H),2.212(q,J=12.0Hz,1H),2.143-2.115(m,4H),1.970(m,3H),1.887(m,1H),1.814-1.761(m,4H),1.720(m,1H),1.635-1.622(m,5H),1.545(m,1H),1.454-1.402(m,3H),1.365-1.231(m,10H),1.164(d,J=5.6Hz,3H),1.138(m,2H),0.926(m,1H),0.912(d,J=6.4Hz,3H),0.827(m,1H),0.791(s,3H),0.560(s,3H);13C NMR(125MHz,DMSO-d6):δ/ppm=208.61,186.86,174.41,173.11,172.66,172.54,171.76,161.26,156.48,155.04,136.63,135.88,135.11,134.32,120.42,120.18,119.45,111.10,99.97,75.64,71.54,70.93,69.69,66.74,65.96,56.97,52.38,47.08,46.73,46.24,42.03,41.82,38.77,35.79,35.62,35.35,34.85,34.78,33.16,32.17,30.89,29.28,28.99,27.75,26.69,23.26,23.05,21.19,17.61,17.20,12.78;HPLC纯度为99%(流动相为乙腈/H2O,50/50加1‰HAc,色谱柱为WatresMS C18 5μm,2.1×150mm柱,流速为0.3mL/min,UV=478nm,保留时间为7.7min)。
实施例8评价BCBAOLys的抗肿瘤活性
采用自行传代的S180腹水瘤模型小鼠,在无菌条件下,处死腹水瘤小鼠,于75%酒精中浸泡5min消毒,取出小鼠仰面置于表面皿中,棉球擦拭腹部,晾干酒精,打开腹腔,抽取接种7天后生长旺盛的S180腹水瘤瘤液,用生理盐水稀释成(1:2)的液体充分混合,1000r/min离心3min,去除细胞碎片,沉降血细胞,用生理盐水重悬肿瘤细胞,将肿瘤细胞悬液稀释一定倍数后用新鲜配制的0.2%台盼蓝染色,混匀后按白细胞计数方法计数,染蓝色者为死细胞,不染色外观晶亮者为活细胞,按如下公式计算细胞浓度和细胞存活率。将存活率大于90%的瘤液用生理盐水制备成1.5×107个/mL的细胞悬液,往健康雄性ICR小鼠右腋皮下接种,0.2mL/只(小鼠体重为20±2g),制成实体瘤动物模型。肿瘤接种24h后,阴性对照为生理盐水,腹腔注射,每天一次,0.2mL/20g,连续给药12天,共给药12次。阳性对照为阿霉素,腹腔注射,每天一次,2μmol/kg,连续给药12天,共给药12次。本发明的BCBAOLys,腹腔注射,每天一次,2μmol/kg,连续给药12天,共给药12次。各组小鼠于第13天称取体重(处死前体重),摘眼球取血,经乙醚麻醉之后脱颈椎处,钝性剥离肿瘤并称重数据采用t检验和方差分析列入表1。结果表明,在2μmol/kg剂量下,BCBAOLys和阿霉素一样可显著抑制S180小鼠的肿瘤生长,即BCBAOLys有阿霉素一样强的抗肿瘤活性。说明,按照本发明的方式用赖氨酸的羧基和氨基分别连接阿霉素的14位羟基和胆酸可保持阿霉素的抗肿瘤活性。
表1 BCBAOLys对S180肉瘤小鼠瘤重的影响
n=12;a)与生理盐水组比p<0.01,与阿霉素组比p>0.05。
实施例9评价BCBAOLys的抗炎活性
体重20±2g雄性ICR小鼠口服生理盐水或20μmol/kg胆酸钠或2μmol/kg胆酸钠或2μmol/kg BCBALys或0.2μmol/kg BCBALys或0.002μmol/kg BCBALys。30分钟后,往小鼠左耳外廓涂40μL二甲苯,2小时后将小鼠乙醚麻醉颈椎脱臼处死。剪下小鼠的左耳和右耳,用直径7mm的打孔器在两耳的相同位置取圆形耳片,分别称重,求出两圆耳片的重量差作为肿胀度(肿胀度=左耳原片重量-右耳原片重量)。以肿胀度表示抗炎活性。数据采用t检验和方差分析,数据列入表2。结果表明,BCBAOLys剂量呈依赖地抑制二甲苯诱导的小鼠炎症反应。在2μmol/kg剂量下BCBAOLys的抗炎活性与20μmol/kg胆酸钠的抗炎活性相当。说明,按照本发明的方式用赖氨酸的羧基和氨基分别连接阿霉素的14位羟基和胆酸可使胆酸的抗炎活性增强10倍。
表2 BCBAOLys的体内抗炎活性
n=10;a)与生理盐水组比p<0.01;b)与生理盐水及0.2μmol/kg BCBAOLys组比p<0.01,与20μmol/kg胆酸钠组比p>0.05;c)与生理盐水及0.002μmol/kg BCBAOLys组比p<0.05;d)与生理盐水组比p>0.05。
实施例10单次大剂量BCBAOLys对小鼠的毒性
体重为20~22g的ICR雄性小鼠,适应性喂养2天,随机分为生理盐水组、阿霉素组和BCBAOLys组,每组10只。三组小鼠分别一次性腹腔注射生理盐水、34.5μmol/kg阿霉素和34.5μmol/kg BCBAOLys。之后连续观察6天,观察各组小鼠的饮食、皮毛和活动力等。每天记录体重和存活率。于第6天称重后摘眼球取血,4℃冰箱中静置2h后离心,离心温度10℃,转速3000r/min,离心15min取上清,用谷丙转氨酶(ALT)试剂盒测定血清ALT、用谷草转氨酶(AST)试剂盒测定血清AST;用尿素氮(BUN)试剂盒测定血清BUN、用肌酐(Cr)试剂盒测定血清Cr;用肌酸激酶同工酶(CK-MB)试剂盒测定血清CK-MB,用乳酸脱氢酶(LDH)试剂盒测定血清LDH、用心肌肌钙蛋白I(cTnI)酶联免疫检测试剂盒测定血清cTnI、用小鼠肌红蛋白(MB)酶联免疫检测试剂盒测定血清MB。
测定结果表明,生理盐水组和BCBAOLys组小鼠摄食正常、活动正常、毛发光滑,小鼠100%存活。阿霉素组小鼠逐渐出现毛发干涩、摄食减少、活动减少的现象,第5天死亡1只,第6天死亡6只,存活率为30%。
BCBAOLys对小鼠血清ALT和AST的影响见表3。与阿霉素不同,34.5μmol/kgBCBAOLys不升高血清ALT和AST,没有肝脏毒性。
表3 BCBAOLys对小鼠血清ALT和AST的影响
组别 | ALT(IU/L) | AST(IU/L) |
生理盐水 | 11.9±1.6 | 25.2±4.4 |
阿霉素 | 50.8±24.0<sup>a</sup> | 81.5±32.0<sup>a</sup> |
BCBAOLys | 10.5±1.2<sup>b</sup> | 28.1±2.2<sup>b</sup> |
阿霉素组n=3,生理盐水组和BCBAOLys组n=10;a)与生理盐水组比p<0.01;b)与阿霉素组比p<0.01,与生理盐水组比p>0.05。
BCBAOLys对小鼠血清的影响见表4。与阿霉素不同,34.5μmol/kg BCBAOLys不升高血清Cr和BUN,没有肾脏毒性。
表4 BCBAOLys对小鼠血清Cr和BUN的影响
组别 | Cr(μmol/L) | BUN(mmol/L) |
生理盐水 | 6.45±1.8 | 11.6±1.9 |
阿霉素 | 34.3±14<sup>a</sup> | 18.7±3.7<sup>a</sup> |
BCBAOLys | 6.7±2.1<sup>b</sup> | 10.8±2.7<sup>b</sup> |
阿霉素组n=3,生理盐水组和BCBAOLys组n=10;a)与生理盐水组比p<0.01;b)与阿霉素组比p<0.01,与生理盐水组比p>0.05。
BCBAOLys对小鼠血清CK-MB、LDH、cTnI和MB的影响见表5。与阿霉素不同,34.5μmol/kg BCBAOLys不升高血清CK-MB、LDH、cTnI和MB,没有心脏毒性。
表5 BCBAOLys对小鼠血清CK-MB,LDH,cTnI和MB的影响
组别 | CK-MB(U/L) | LDH(10<sup>3</sup>U/L) | cTnI(pg/mL) | MB(ng/mL) |
生理盐水 | 109±18 | 6.02±1.9 | 208±29 | 120±5.8 |
阿霉素 | 463±46<sup>a</sup> | 14.6±2.1<sup>a</sup> | 316±29<sup>a</sup> | 254±30<sup>a</sup> |
BCBAOLys | 102±27<sup>b</sup> | 6.80±1.4<sup>b</sup> | 219±16<sup>b</sup> | 124±12<sup>b</sup> |
阿霉素组n=3,生理盐水组和BCBAOLys组n=10;a)与生理盐水组比p<0.01;b)与阿霉素组比p<0.01,与生理盐水组比p>0.05。
总之,按照本发明的方式用赖氨酸的羧基和氨基分别连接阿霉素的14位羟基和胆酸可保持阿霉素的抗肿瘤活性,完全消除了阿霉素的肝、肾和心脏毒性,提高了胆酸的抗炎活性。因而,本发明获得了意想不到的技术效果。
Claims (4)
2.权利要求1的阿霉素-胆酸缀合物的制备方法,该方法包括:
(1)采用二环己基碳二亚胺为缩合剂,1-羟基苯并三氮唑为催化剂液相合成胆酸酰-Lys(Fmoc)-OBzl;
(2)在氢氧化钠-甲醇溶液中(1M)脱除胆酸酰-Lys(Fmoc)-OBzl中的苄基制备胆酸酰-Lys(Fmoc);
(3)用Fmoc保护阿霉素的3’-NH2制备Fmoc-阿霉素;
(4)用戊二酸偶联Fmoc-阿霉素的14位OH;
(5)Fmoc-阿霉素的14位OH偶联的戊二酸在DCC存在下与N-羟基琥珀酰亚胺形成活泼酯;
(6)Fmoc-阿霉素的14位OH偶联的戊二酸的OSu活泼酯与胆酸酰-Lys(Fmoc)缩制备Fmoc保护的阿霉素-胆酸缀合物;
(7)在10%哌啶/无水N,N-二甲基甲酰胺中Fmoc保护的阿霉素-胆酸缀合物脱除Fmoc制备权利要求1的阿霉素-胆酸缀合物。
3.权利要求1的阿霉素-胆酸缀合物在制备抗肿瘤药物中的应用。
4.权利要求1的阿霉素-胆酸缀合物在制备抗炎药物中的应用。
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US20230226031A1 (en) * | 2021-11-18 | 2023-07-20 | Nammi Therapeutics, Inc. | Formulated and/or Co-Formulated Liposome Compositions Containing Immunogenic Cell Death (ICD) Inducing Prodrugs Useful In The Treatment of Cancer and Methods Thereof |
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