CN103450164B - 格尔德霉素衍生物及其制备方法和用途 - Google Patents
格尔德霉素衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一类新的格尔德霉素类衍生物、制备该类化合物的方法,以及该类化合物用于制备细胞杀伤活性的细胞杀伤剂、细胞增殖抑制剂及抗肿瘤药物的用途,以及用于制备用于抑制细胞周期的生物探针中的用途。本发明还涉及包含本发明衍生物的药物组合物。本发明的衍生物可用于治疗细胞过度增殖的疾病例如癌症等。
Description
技术领域
本发明涉及一类新的格尔德霉素类衍生物、制备该类化合物的方法,以及该类化合物用于制备细胞杀伤活性的细胞杀伤剂、细胞增殖抑制剂及抗肿瘤药物的用途。
背景技术
格尔德霉素最早于1970年从链霉菌产物中发现[C.DeBoer,et al.;Geldanamycin,a new antibiotic:J.Antibiot.,1970,23(9),442-447],其后,从微生物产物中或通过人工合成陆续发现了许多同类化合物并发现该类化合物具有多种生物活性。如文献[M.Muroi,et al.;The structuresof macbecin I and II:Tetrahedron,1981,37,pp.1123-1131]、文献[R.C.Schnur,et al.;Inhibition of the oncogene productp185erbB-2 in vitro andin vivo by geldanamycin and dihydrogeldanamycinderivatives:J.Med.Chem.,1995,38,3806-3812]、文献[M.Bendin,et al.;Geldanamycin,aninhibitor of the chaperone activity of HS90,induces MAPK-independentcellcycle arrest:Int.J.Cancer,2004,109,643-652]、文献[Z.-Q.Tian etal.;Synthesisand biological activities of novel 17-aminogeldanamycinderivatives:Bioorg.Med.Chem.,2004,12,5317-5329]以及文献[J.-Y.L.Brazidec,et al.;Synthesisand biological evaluation of a new class ofgeldanamycin derivatives as potentinhibitors of Hsp90:J.Med.Chem.,2004,47,3865-3873]等都曾记载了天然或人工合成的格尔德霉素类化合物及其生物活性。该类化合物的生物活性多与热休克蛋白90有关。热休克蛋白90是细胞内最活跃的一种分子伴侣,许多信号传导途径均依赖于热休克蛋白90,并且,它在肿瘤细胞中的表达比正常细胞高出2~10倍,在肿瘤细胞生长和存活中可能起重要的调节作用。格尔德霉素类 化合物能与热休克蛋白90特异性结合并抑制其功能,导致多种癌基因产物和细胞周期调控蛋白的降解,从而显示抗癌等多种生物活性,因此,该类化合物受到了癌症研究者的极大关注和深入研究。其中,17-烯丙胺-17-脱甲氧格尔德霉素(17-AAG)在美国则正在进行治疗肿瘤的III期临床试验。
本发明的格尔德霉素衍生物属于安莎霉素类抗生素,从结构上看,在迄今已有记载的所有格尔德霉素类化合物中,尚未看到具有与本发明化合物相同的结构的同类化合物。
发明内容
本发明旨在提供一种具有细胞杀伤活性、细胞增殖抑制活性及抗肿瘤活性的格尔德霉素衍生物。具体地,
本发明的第一方面涉及一种新的格尔德霉素衍生物、或其光学异构体、或其药学上可接受的盐,其结构式如式I所示,
式I
其中,
R为H、C1~C6直链或支链烷基、C2~C6直链或支链烯基、或C3~C6环烷基,所述的烷基、烯基或环烷基可以任选被选自以下的取代基单或多取代:卤素、腈基、任选被卤素取代的C1~C6直链或支链烷基、任选被卤素取代的C2~C6直链或支链烯基、甲氧基、三氟甲基、三氟甲氧基、羟基、羟甲基、硝基、脒基、氰基、氨基、酰氨基、苯基、苯氧基、苄基、苄氧基;
GA如式(i)所示,
式(i)。
在本发明的一个优选的实施例中,R优选为H、任选被苯基取代的C1~C6直链或直链烷基;
在本发明的一个具体的实施例中,R为H、甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、苄基。
在本发明的一个具体的实施例中,所述的式I化合物为选自表1中的化合物1-10、其光学异构体或其药学上可接受的盐。
表1
本发明的第二方面涉及本发明的式I所示化合物的制备方法,其包括以下步骤:
(1)式III所示的乙二胺衍生物的合成:
从商品化的式IX所示的Boc保护氨基酸出发,通过下述合成步骤合成得到式III所示的乙二胺衍生物;
(2)式I所示化合物的合成:
将步骤(1)制备的式III所示的乙二胺衍生物与式II所示的格尔德 霉素化合物进行反应,制备得到式I化合物。
本发明的第三方面涉及药物组合物,其中至少含有本发明所述衍生物或者其光学异构体或者其药学上可接受的盐中的一种作为有效成分。同时还可以含有药学上允许的赋形剂,或其它肿瘤治疗药物。
本发明还涉及本发明所述衍生物或者其光学异构体或者其药学上可接受的盐在制备用于治疗肿瘤或癌症的药物中的用途。其中所述的癌症为肺癌、肺腺癌、胃癌、乳腺癌、肝癌或卵巢癌。
本发明还涉及本发明所述衍生物或者其光学异构体或者其药学上可接受的盐在制备用于细胞杀伤的杀伤剂中的用途。
本发明还涉及本发明所述衍生物或者其光学异构体或者其药学上可接受的盐在制备细胞生长抑制剂或细胞增殖抑制剂中的用途。
本发明还涉及本发明所述衍生物或者其光学异构体或者其药学上可接受的盐在制备用于抑制细胞周期的生物探针中的用途。
本发明中的术语“药学上可接受的盐”可以是药用无机或有机盐。本发明所述化合物中具有碱性基团的化合物可以与无机酸形成药用盐,例如硫酸盐、盐酸盐、氢溴酸盐、磷酸盐;也可与有机酸形成药用盐,例如乙酸盐、草酸盐、柠檬酸盐、葡萄糖酸盐、琥珀酸盐、酒石酸盐、对甲苯磺酸盐、甲磺酸盐、苯甲酸盐、乳酸盐、马来酸盐等。本发明所述化合物中具有酸性基团的化合物可以与碱金属或碱土金属形成药用盐,优选但不限于钠盐、钾盐、镁盐或钙盐。
本发明所述化合物可与各种药物上可接受的载体、赋形剂或辅料配伍制成抗肿瘤药物,用于肿瘤的治疗。
本发明化合物可单独或以药物组合物的形式给药。给药途径可以是口服、非肠道或局部给药。药物组合物可根据给药途径配成各种适 宜的剂型。
本发明化合物的药物组合物可以以下面的任意方式施用:口服,喷雾吸入,直肠用药,鼻腔用药,颊部用药,局部用药,非肠道用药,如皮下,静脉,肌内,腹膜内,鞘内,心室内,胸骨内和颅内注射或输入,或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时,本发明化合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
另外需要指出,本发明化合物使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.01~100mg/kg体重/天。
本发明所述化合物还可作为抑制细胞周期的低分子生物探针用于生命科学研究中。当把本发明所述化合物用于生命科学研究中时,可 溶于甲醇或含水甲醇中,也可溶于二甲基亚砜的含水溶液中加以应用。
发明的有益效果
本发明提供的新的格尔德霉素衍生物具有很好的细胞杀伤活性和细胞生长抑制活性,并且普遍具有很好的体外抗癌活性,尤其是对于肺癌(A549)、胃癌(AGS)、宫颈癌(Hela229)、肝癌(Bel7402,SMMC7721)和白血病(K562),其活性普遍与对照药物相当甚至比对照药物更好,表明本发明衍生物物具有良好的临床应用前景。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
试验材料:核磁共振由Varian EM-360A,EM-390或BrukerAMX-300型仪器测定。质谱由Finnigan 4021,HP5989A,FinniganFTMS-2000型仪器测定。快速柱层析在硅胶(300-400目)上进行。薄层层析(TLC)用HSGF254高效板,用UV灯254和365nm波长或5%磷钼酸乙醇溶液检测。反应的完成终点由TLC检测确定。实验使用的试剂都是商品化试剂,未经过纯化直接使用。
为了与进入临床研究的17位修饰的格尔德霉素衍生物进行平行比较,申请人合成了表1所示的两个用做比较对象的比较例化合物1和2:17-DMAG(17-N,N-二甲胺基乙胺基-17-去甲氧基格尔德霉素)和17-AAG(17-丙烯胺基-17-去甲氧基格尔德霉素)。合成方法参考文献(Shen,Y.,Xie,Q.,Norberg,M.,et al.Bioorg.Med.Chem.2005,13,4960.)。
表2
中间体式III所示的乙二胺衍生物的制备:
中间体9:(S)-3-(2-胺乙基、)-5-苄基咪唑烷-2,4-二酮
具体步骤如下:
(1)合成化合物N-叔丁基氧羰基苯丙氨酸(化合物9-2)
称取原料化合物苯丙氨酸(化合物9-1)(2.0g,12.1mmol),溶于1,4-二氧六环/水(12/12mL)混合溶剂中,滴加三乙胺(2.9mL,20.58mmol),冰浴降温至0℃,随后加入二碳酸二叔丁酯(4.50g,20.58mmol),室温反应过夜。除去大部分溶剂,用1N HCl酸化反应体系,用乙酸乙酯萃取水相三次,饱和食盐水洗有机相,无水硫酸钠干燥,浓缩得到粘稠液体,即化合物9-2。
(2)合成化合物N-苄氧羰基乙二胺(化合物9-3)
取液体乙二胺(147mL,2.2mol),溶于500mL二氯甲烷中。冰浴降温至0℃,将溶于1.5L二氯甲烷的苄氧酰氯(30mL,219mmol)溶于慢慢滴加到反应瓶内。体系恢复至室温,反应过夜。反应体系过滤,浓缩除去部分溶剂后,水洗。最后浓缩得到浅黄色粘稠液体。柱层析后得到澄清的油状液体(23g),即化合物9-3。
(3)合成化合物(S)-3-(2-胺乙基)-5-苄基咪唑烷-2,4-二酮(中间体9)
称取化合物9-2(3.20g,12.1mmol)和1-羟基苯并三唑(1.80g,13.3mmol),置于100mL茄形瓶中,加入二甲基甲酰胺(25mL)。0℃下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.55g,13.3mmol),保持低温搅拌30min。随后,再向体系中滴加氮甲基吗啡啉(2.94mL,26.6mmol),以及化合物9-3(2.59g,13.3mmol)的二甲基甲酰胺溶液(10mL)。加料完毕,体系逐渐恢复至室温,反应过夜。加入水淬灭反应,乙酸乙酯萃取水相三次,饱和食盐水洗有机相,无水硫酸钠干燥,浓缩得到淡黄色固体(化合物9-4)(4.59g)。化合物9-4(4.59g)溶于40mL二氯甲烷中,冰浴下滴加13mL三氟醋酸,随后室温反应过夜。浓缩除去溶剂,1N氢氧化钠溶液碱化反应体系。乙酸乙酯萃取水相,合并有机相,饱和食盐水洗,无水硫酸钠干燥。最后浓缩得到浅黄色固体(化合物9-5)(3.49g)。取产物9-5(3.1g)溶于1,4-二氧六环/水(45/5mL)混合溶剂中,滴加二异丙基乙基胺(3.9mL,24.0mmol)。随后体系冰浴降温至0℃,再滴加苯氧酰氯(2.3mL,18.0mmol)。体系恢复至室温,搅拌过夜。直接浓缩体系,乙酸乙酯萃取水相,合并有机相,饱和食盐水洗,无水硫酸钠干燥。再度浓缩,得到黄色固体(化合物9-6)(5.0g)。粗产品化合物9-6(5.0g,12.0mmol)溶于50mL二甲基甲酰胺中,滴加二异丙基乙基胺(4.2mL,24mmol),室温搅拌24小时。加入水淬灭反应,乙酸乙酯萃取水相三次,饱和食盐水洗有机相,无水硫酸钠干燥,浓缩。柱层析得到淡白色固体(化合物9-7)(2.43g)。化合物9-7(2.43g,6.6mmol)溶于50mL甲醇中,加入钯碳(500mg),室温常压氢化反应24 小时。过滤除去钯碳,浓缩得到浅黄色稠液1g,冷却后为固体,得到中间体9。
在本发明的具体实施方式中,采用上述相同的合成路线,选用不同的氨基酸为原料,合成了以下各中间体。
实施例1:RZ854的制备
取式II所示的格尔德霉素化合物(135mg),加入合成的乙二胺衍生物(中间体1,100mg),加二氯甲烷(20mL),室温搅拌反应。体系颜色呈橙红色。反应2days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=500∶7),得到紫色固体(164mg,93%)。
1H NMR(CDCl3,400MHz)δ0.90-1.01(m,12H);1.50-1.60(m,1H);1.65-1.88(m,6H);2.02(s,2H);2.09(s,2H);2.32-2.42(m,1H);2.62-2.80(m,2H);3.26(s,3H);3.36(s,3H);3.42-3.47(m,1H);3.53-3.62(m,1H);3.65-3.77(m,1H);3.77-3.88(m,3H);4.09-4.16(m,1H);4.17-4.26(m,1H);4.31(d,J=9.6Hz,1H);5.14-5.23(m,3H);5.81-5.91(m,2H);6.58(t,J=11.4Hz,1H);6.70-6.80(m,1H);6.85-7.00(m,2H);7.20-7.24(m,1H);9.13 (s,1H)
13C NMR(d6-acetone,100MHz)δ12.30,12.47,12.68,21.62,22.64,22.91,24.94,28.59,32.21,34.05,34.86,37.71,40.69,45.06,56.07,56.61,56.98,72.54,81.16,81.35,81.50,108.97,109.69,126.41,126.94,132.82,133.54,134.83,135.78,140.71,145.36,156.42,157.55,168.30,174.67,180.83,183.78
ESI:726.5[M-H]-
证明得到了分子式如式I-1所示的产物RZ854:
式I-1
实施例2:RZ855的制备
取式II所示的格尔德霉素化合物(150mg),加入合成的乙二胺衍生物(中间体2,148mg),加二氯甲烷(20mL),室温搅拌反应。体系颜色呈橙红色。反应7days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=500∶7),得到紫色固体(120mg,58%)。
1H NMR(CDCl3,400MHz)δ0.78-1.51(m,14H);1.65-1.87(m,6H);1.96-2.09(m,4H);2.26-2.49(m,1H);2.61-2.84(m,2H);3.26(s,3H);3.36(s,3H);3.39-3.49(m,1H);3.51-3.62(m,1H);3.64-3.75(m,1H);3.76-3.95(m,3H);4.05(d,J=3.6Hz,1H);4.16-4.27(m,1H);4.31(d,J=10.0Hz,1H);5.11(s,2H);5.17(s,1H);5.81-5.99(m,2H);6.58(t,J=11.4Hz,1H);6.68-6.86(m,2H);6.95(d,J=11.6Hz,1H);7.24(s,1H);9.12(s,1H)
13C NMR(d6-acetone,100MHz)δ11.48,12.30,12.48,12.69,14.86,22.63,23.75,28.59,30.80,32.24,34.89,36.96,37.53, 45.23,56.63,57.00,62.07,72.57,81.17,81.38,81.54,109.00,109.67,126.43,126.92,132.81,133.59,134.86,135.80,140.72,145.36,156.38,157.80,168.31,173.63,180.87,183.72
ESI:726.6[M-H]-
证明得到了分子式如式I-2所示的产物RZ855:
式I-2
实施例3:RZ856的制备
取式II所示的格尔德霉素化合物(270mg),加入合成的乙二胺衍生物(中间体3,267mg),加二氯甲烷(20mL),室温搅拌反应。体系颜色呈橙红色。反应7days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=50∶1),得到紫色固体(134mg,39%)。
1H NMR(CDCl3,400MHz)δ0.89(d,J=6.8Hz,3H);0.95(d,J=6.4Hz,3H);0.99(d,J=7.2Hz,3H);1.40(d,J=6.8Hz,3H);1.65-1.94(m,6H);2.02(s,3H);2.20-2.30(m,1H);2.33-2.43(m,1H);2.63-2.80(m,2H);3.27(s,3H);3.36(s,3H);3.42-3.46(m,1H);3.53-3.60(m,1H);3.65-3.76(m,1H);3.77-3.88(m,3H);4.01(d,J=3.6Hz,1H);4.19(s,br,1H);4.28(d,J=10.0Hz,1H);5.12(s,2H);5.17(s,1H);5.82-5.91(m,2H);6.58(t,J=11.4Hz,1H);6.68-6.78(m,2H);6.95(d,J=11.6Hz,1H);7.24(s,1H);9.13(s,1H).
13C NMR(d6-acetone,100MHz)δ12.32,12.49,12.71,15.97,18.45,22.63,28.62,30.23,32.24,34.07,34.90,37.54,45.23,56.63,57.01,72.57,81.36,81.55,109.02,109.69,126.42,126.94, 132.81,133.60,134.86,135.81,140.72,145.34,156.37,157.90,168.32,173.64,180.89,183.74
ESI:736.5[M+Na]+
证明得到了分子式如式I-3所示的产物RZ856:
式I-3
实施例4:RZ857的制备
取式II所示的格尔德霉素化合物(300mg),加入合成的乙二胺衍生物(中间体4,500mg),加二氯甲烷和甲醇混合溶剂(50/10mL),室温搅拌反应。体系颜色呈橙红色。反应4days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=50∶1),得到紫色固体(320mg,78%)。
1H NMR(CDCl3,400MHz)δ0.92(d,J=6.4Hz,3H);1.00(d,J=6.8Hz,3H);1.65-1.88(m,6H);2.02(s,3H);2.30(t,J=12.4Hz,1H);2.65(d,J=14.0Hz,1H);2.70-2.80(m,1H);2.95-3.08(m,1H);3.15-3.30(m,4H);3.36(s,4H);3.42-3.48(m,1H);3.53-3.86(m,4H);4.07-4.55(m,3H);4.90-5.28(m,3H);5.81-5.97(m,2H);6.48-6.81(m,3H);6.96(d,J=11.2Hz,1H);7.04-7.39(m,6H);9.13(s,1H)
13C NMR(CDCl3,100MHz)δ12.49,12.66,12.88,22.85,28.65,32.41,34.26,35.13,37.38,37.49,45.33,56.80,57.17,58.51,72.76,81.32,81.54,81.72,109.10,109.58,126.62,127.06,127.59,128.58,128.70,129.71,132.96,133.77,134.47,135.05,135.94,140.97,145.44,156.57,157.53,168.47,173.27,180.96,183.80
ESI:784.2[M+Na]+
证明得到了分子式如式I-4所示的产物RZ857:
式I-4
实施例5:RZ858的制备
取式II所示的格尔德霉素化合物(280mg),加入合成的乙二胺衍生物(中间体5,145mg),加二氯甲烷和甲醇混合溶剂(30/10mL),室温搅拌反应。体系颜色呈橙红色。反应5days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=50∶1),得到紫色固体(50mg,15%)。
1H NMR(CDCl3,400MHz)δ0.95(d,J=6.4Hz,3H);0.98(d,J=6.8Hz,3H);1.52-1.98(m,6H);2.02(s,3H);2.37(t,J=12.2Hz,1H);2.65(d,J=14.0Hz,1H);2.69-2.81(m,1H);3.26(s,3H);3.35(s,3H);3.39-3.49(m,1H);3.51-3.62(m,1H);3.65-3.92(m,4H);3.98-4.12(m,2H);4.16(s,br,1H);4.30(d,J=9.6Hz,1H);4.97-5.16(m,2H);5.17(s,1H);5.78-5.92(m,2H);6.58(t,J=11.4Hz,1H);6.69-6.85(m,2H);6.94(d,J=11.6Hz,1H);7.20(s,1H);9.12(s,1H)
13C NMR(CDCl3,100MHz)δ12.52,12.67,12.88,22.83,28.81,32.41,34.22,35.07,37.94,45.30,46.92,56.80,57.20,72.73,81.35,81.51,81.72,109.11,109.94,126.65,127.19,133.00,133.76,135.01,135.98,140.96,145.54,156.56,158.66,168.51,171.74,180.99,184.09
ESI:694.2[M+Na]+
证明得到了分子式如式I-5所示的产物RZ858:
式I-5
实施例6:RZ859的制备
取式II所示的格尔德霉素化合物(280mg),加入合成的乙二胺衍生物(中间体6,393mg),加二氯甲烷和甲醇混合溶剂(30/10mL),室温搅拌反应。体系颜色呈橙红色。反应6days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=500∶8),得到紫色固体(170mg,49%)。
1H NMR(CDCl3,400MHz)δ0.95(d,J=6.4Hz,3H);0.98(d,J=6.8Hz,3H);1.47(d,J=6.8Hz,3H);1.61-1.93(m,6H);2.02(s,3H);2.28-2.43(m,1H);2.66(d,J=13.6Hz,1H);2.69-2.79(m,1H);3.26(s,3H);3.36(s,3H);3.40-3.49(m,1H);3.51-3.62(m,1H);3.63-3.78(m,1H);3.78-3.94(m,3H);4.09-4.24(m,2H);4.30(d,J=9.6Hz,1H);4.91-5.15(m,2H);5.17(s,1H);5.80-5.92(m,2H);6.58(t,J=11.4Hz,1H);6.69-6.86(m,2H);6.94(d,J=11.2Hz,1H);7.21(s,1H);9.12(s,1H)
13C NMR(CDCl3,100MHz)δ12.46,12.64,12.84,17.47,22.78,28.77,32.35,34.18,35.02,37.84,45.37,53.47,56.77,57.14,72.68,81.32,81.46,81.64,109.07,109.81,126.61,127.15,132.97,133.72,134.96,135.92,140.93,145.52,156.60,157.81,168.49,175.07,180.95,183.99
ESI:708.2[M+Na]+
证明得到了分子式如式I-6所示的产物RZ859:
式I-6
实施例7:RZ860的制备
取式II所示的格尔德霉素化合物(280mg),加入合成的乙二胺衍生物(中间体7,393mg),加二氯甲烷和甲醇混合溶剂(30/10mL),室温搅拌反应。体系颜色呈橙红色。反应6days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=500∶8),得到紫色固体(230mg,67%)。
1H NMR(CDCl3,400MHz)δ0.96(d,J=6.8Hz,3H);0.99(d,J=6.8Hz,3H);1.47(d,J=7.2Hz,3H);1.62-1.94(m,6H);2.02(s,3H);2.28-2.48(m,1H);2.67(d,J=13.6Hz,1H);2.71-2.81(m,1H);3.27(s,3H);3.36(s,3H);3.41-3.48(m,4H);3.52-3.63(m,1H);3.65-3.95(m,4H);4.09-4.23(m,2H);4.31(d,J=10.0Hz,1H);5.07(s,br,2H);5.18(s,1H);5.79-5.99(m,2H);6.51-6.71(m,2H);6.72-6.82(m,1H);6.95(d,J=11.6Hz,1H);7.24(s,1H);9.13(s,1H)
13C NMR(CDCl3,100MHz)δ12.46,12.63,12.86,17.48,22.80,28.72,32.34,34.18,34.98,37.87,45.24,53.40,56.75,57.12,72.68,81.32,81.46,81.61,109.10,109.81,126.59,127.08,132.95,133.65,134.97,135.91,140.88,145.52,156.61,157.63,168.46,175.03,180.92,184.01
ESI:708.3[M+Na]+
证明得到了分子式如式I-7所示的产物RZ860:
式I-7
实施例8:RZ861的制备
取式II所示的格尔德霉素化合物(257mg),加入合成的乙二胺衍生物(中间体8,300mg),加二氯甲烷(50mL),室温搅拌反应。体系颜色呈橙红色。反应2days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=500∶7),得到紫色固体(230mg,69%)。
1H NMR(CDCl3,400MHz)δ0.81-1.08(m,12H);1.64-1.89(m,6H);2.02(s,3H);2.14-2.31(m,1H);2.32-2.42(m,1H);2.62(s,1H);2.63-2.81(m,2H);3.27(s,3H);3.36(s,3H);3.41-3.51(m,1H);3.52-3.62(m,1H);3.63-3.78(m,1H);3.79-3.95(m,3H);3.96-4.08(m,1H);4.14(s,br,1H);4.30(d,J=10.0Hz,1H);4.82(s,br,2H);5.18(s,1H);5.61-6.05(m,3H);6.45-6.75(m,2H);6.95(d,J=11.6Hz,1H);7.26(s,3H);9.11(s,1H)
13C NMR(CDCl3,100MHz)δ12.35,12.49,12.71,15.99,18.44,22.6,28.58,30.23,32.19,34.03,34.85,37.43,40.63,45.22,56.61,56.93,62.67,72.52,81.15,81.34,81.40,108.89,109.51,126.41,126.97,132.85,134.76,135.82,140.71,140.74,145.34,156.72,158.09,168.31,173.79,180.76,183.69
ESI:750.4[M+Na]+
证明得到了分子式如式I-8所示的产物RZ861:
式I-8
实施例9:RZ862的制备
取式II所示的格尔德霉素化合物(387mg),加入合成的乙二胺衍生物(中间体9,800mg),加二氯甲烷和甲醇混合溶剂(50/2mL),室温搅拌反应。体系颜色呈橙红色。反应4days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=50∶1),得到紫色固体(100mg,19%)
1H NMR(CDCl3,400MHz)δ0.94(t,J=6.6Hz,3H);1.00(d,J=6.8Hz,3H);1.65-1.88(m,6H);2.02(s,3H);2.18-2.38(m,1H);2.62-2.82(m,2H);2.85-3.08(m,1H);3.18-3.32(m,4H);3.33-3.39(m,3H);3.41-3.82(m,6H);4.05-4.28(m,1H);4.29-4.39(m,2H);4.65-4.99(s,br,2H);5.19(s,1H);5.74(d,J=20.0Hz,1H);5.81-5.98(m,2H);6.45-6.65(m,2H);6.95(d,J=6.8Hz,1H);7.14-7.38(m,8H);9.13(d,J=5.6Hz,1H)
13C NMR(d6-acetone,100MHz)δ12.44,12.55,12.86,22.86,28.58,32.37,34.25,35.10,37.32,37.44,45.10,56.77,57.16,58.53,72.72,81.33,81.50,81.69,109.08,109.53,126.60,127.04,127.47,128.51,128.67,129.66,132.95,133.70,134.48,135.00,135.94,140.94,145.42,156.59,157.60,168.43,173.25,180.92,183.95
ESI:784.5[M+Na]+
证明得到了分子式如式I-9所示的产物RZ862:
式I-9
实施例10:RZ863的制备
取式II所示的格尔德霉素化合物(210mg),加入合成的乙二胺衍生物(中间体10,300mg),加二氯甲烷(50mL),室温搅拌反应。体系颜色呈橙红色。反应4days,体系颜色呈紫色。停止反应,减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=50∶1),得到紫色固体(80mg,30%)。
1H NMR(CDCl3,400MHz)δ0.91-1.05(m,12H);1.65-1.87(m,7H);2.02(s,3H);2.37(t,J=12.8Hz,1H);2.62-2.89(m,2H);3.27(s,3H);3.36(s,3H);3.41-3.50(m,1H);3.51-3.64(m,1H);3.65-3.77(m,1H);3.78-3.92(m,3H);4.07-4.21(m,2H);4.31(d,J=9.6Hz,1H);4.51-4.85(s,br,2H);5.19(s,1H);5.51(d,J=11.6Hz,1H);5.73-6.04(m,2H);6.51-6.73(m,2H);6.95(d,J=11.6Hz,1H)
13C NMR(d6-acetone,75MHz)δ12.40,13.50,14.20,21.99,22.61,23.55,25.84,31.29,33.50,34.43,35.53,39.13,42.04,45.03,56.87,57.04,57.52,74.32,82.07,82.94,109.64,111.33,127.13,129.60,132.81,134.44,135.38,137.90,142.31,147.26,159.07,170.71,177.09,181.22,185.93
ESI:736.3[M+Na]+
证明得到了分子式如式I-10所示的产物RZ863:
式I-10
实验例1格尔德霉素衍生物的10μM生长抑制率检测
为了对前述实施例1-10中合成的各格尔德霉素衍生物(式I-1至式I-10化合物)进行生物活性验证,本发明采用6种细胞株对各衍生物的10μM生长抑制率进行了检测。具体地,采用细胞株:A549,AGS,Hela229,Bel7402、SMMC7721和K562(上述细胞株均购自中国科学院上海生命科学研究院细胞资源中心)。
培养基:F12K+10%FBS培养基(A549细胞株);RPMI 1640+10%FBS培养基(AGS,Hela229,Bel7402、SMMC7721和K562细胞株)。
药物稀释:所有衍生物均溶解于DMSO中,配成5mg/ml的贮存溶液,给药前用培养基稀释新鲜配制。阳性对照药物为17-AAG(RZC02)和17-DMAG(RZC03)。空白对照组只加培养基不加药物,其它与给药组相同。
10μM生长抑制率的检测方法:
培养细胞接种于96孔板上(1×104/孔),37℃培养24h后加入终浓度为10μM的药物,继续培养48h,每孔加入20μl浓度为5mg/ml的MTT溶液(溶解于PBS中,过滤除菌,避光4℃保存);37℃孵育4h;吸出孔中液体,注意不要碰到细胞;每孔加入100μl100%DMSO;室温震荡15min;490nm波长读数(酶标仪ThermoMultiskan Spectrum)。抑制率结果按照公式[(ODc(空白对照组)-ODt(给药组))]/ODc(空白对照组)×100%进行计算,具体抑制结果如 表3所示。
表3格尔德霉素衍生物对不同细胞系的10μM生长抑制率(%)
上述结果表明本发明化合物具有很好的细胞杀伤活性和细胞生长抑制活性,并且普遍具有很好的体外抗癌活性,尤其是对于肺癌(A549)、胃癌(AGS)、宫颈癌(Hela229)、肝癌(Bel7402,SMMC7721)和白血病(K562),其活性普遍与对照药物相当甚至优于对照药物。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (11)
1.一种如式I所示的格尔德霉素衍生物,
其中,
R为H、C1~C6直链或支链烷基、C2~C6直链或支链烯基、或C3~C6环烷基,所述的烷基、烯基或环烷基可以任选被选自以下的取代基单或多取代:卤素、腈基、任选被卤素取代的C1~C6直链、支链烷基、任选被卤素取代的C2~C6直链、支链烯基、甲氧基、三氟甲基、三氟甲氧基、羟基、羟甲基、硝基、脒基、氰基、氨基、酰胺基、苯基、苯氧基、苄基、苄氧基;
GA如式(i)所示,
或其光学异构体、或其药学上可接受的盐。
2.权利要求1所述的衍生物或其光学异构体或其药学可接受的盐,其中R为H、任选被苯基取代的C1~C6直链或支链烷基。
3.权利要求1所述的衍生物或其光学异构体或其药学可接受的盐,其中R为H、甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁 基、叔丁基、苄基。
4.权利要求1所述的衍生物或其光学异构体或其药学上可接受的盐,所述的式I化合物为选自下列结构所示的化合物I-1至化合物I-10:
5.权利要求1至4任一项所述的化合物的制备方法,其包括以下步骤:
(1)式III所示的乙二胺衍生物的合成:
从式IX所示的Boc保护氨基酸出发,通过下述合成步骤合成得到式III所示的乙二胺衍生物;
(2)式I所示化合物的合成:
将步骤(1)制备的式III所示的乙二胺衍生物与式II所示的格尔德霉素化合物进行反应,制备得到式I化合物
。
6.药物组合物,其中至少含有权利要求1至4任一项所述衍生物、或其光学异构体、或者其药学上可接受的盐中的一种作为有效成分。
7.权利要求6所述的药物组合物,其中还含有药学上允许的赋形剂和/或其它肿瘤治疗药物。
8.权利要求1至4任一项所述的衍生物或权利要求6至7任一项 所述的药物组合物在制备治疗肿瘤的药物、作为细胞生长抑制剂的药物、作为细胞增殖抑制剂的药物、或作为细胞杀伤剂的药物中的用途,或在制备用于抑制细胞周期的生物探针中的用途。
9.权利要求1至4任一项所述的衍生物或权利要求6至7任一项所述的药物组合物在制备治疗癌症的药物中的用途。
10.权利要求9的用途,其中所述的癌症为肺癌、胃癌、乳腺癌、肝癌或卵巢癌。
11.权利要求9的用途,其中所述的癌症为肺腺癌。
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