CN102115460A - 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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- CN102115460A CN102115460A CN2010100001383A CN201010000138A CN102115460A CN 102115460 A CN102115460 A CN 102115460A CN 2010100001383 A CN2010100001383 A CN 2010100001383A CN 201010000138 A CN201010000138 A CN 201010000138A CN 102115460 A CN102115460 A CN 102115460A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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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。
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 product p185erbB-2 in vitro andin vivo by geldanamycin and dihydrogeldanamycin derivatives:J.Med.Chem.,1995,38,3806-3812]、文献[M.Bendin,et al.;Geldanamycin,aninhibitor of the chaperone activity of HS90,inducesMAPK-independent cell cycle arrest:Int.J.Cancer,2004,109,643-652]、文献[Z.-Q.Tian et al.;Synthesis and biological activities ofnovel 17-aminogeldanamycin derivatives:Bioorg.Med.Chem.,2004,12,5317-5329]以及文献[J.-Y.L.Brazidec,et al.; Synthesis and biologicalevaluation of a new class of geldanamycin derivatives as potentinhibitors of
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,从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。
本发明人通过刻苦的努力,发现了选自下述式(1)-(14)所示的一类具有细胞杀伤活性、细胞增殖抑制活性及抗肿瘤活性的格尔德霉素衍生物:
式(1)
式(2)
式(3)
式(4)
式(5)
式(6)
式(7)
式(8)
式(9)
式(10)
式(11)
式(12)
式(13)
式(14)
在本发明中,为了描述简便,将下述分子式(15)所述结构定义为GA,即
(式15)
在本发明中所述的修饰都是在式(15)中的17位进行的。
本发明还提供了合成式(1)-(14)所示格尔德霉素衍生物的方法。
所述分离纯化包括利用本领域技术人员熟知的天然产物分离纯化的常规方法,如液液萃取、柱层析、薄层层析及重结晶等。
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。本发明式I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。本发明式I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。
本发明的式I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。
本发明的式(1)-(14)所示的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。当把式(1)-(14)所示的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。
具体实施方式:
下列实施例将进一步说明本发明,但并不对本发明构成限制。
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。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。实验使用的胺类片段部分通过商品化购买得到,不能购买得到的通过以下两种合成路线合成得到。
比较例1
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:RZC01和RZC02。合成方法参考文献(Shen,Y.,Xie,Q.,Norberg,M.,et al.Bioorg.Med.Chem.2005,73,4960.)。
表1
实施例1
向格尔德霉素(2g)中加入多巴胺盐酸盐(1.35g),然后加入二氯甲烷(100mL),三乙胺(1.5mL),甲醇(33mL),于室温下搅拌反应。反应式如下:
反应体系初呈桔红色,颜色逐渐加深至黑色。反应2.5天,反应完成。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:二氯甲烷/甲醇=20∶1),得到紫色固体,命名为RZ801(732mg,30%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.94(d,J=5.7Hz,3H);1.00(d,J=6.6Hz,3H);1.62-1.84(obscure,m,8H);2.02(s,3H);2.32-2.48(m,1H);2.58-2.90(m,4H);3.28(s,3H);3.37(s,3H);3.35-3.47(m,2H),3.48-3.82(m,3H);4.33(d,br,1H);4.54(s,br,1H);4.90(s,br,2H);5.19(s,1H);5.82-5.98(m,2H);6.16(br,s,1H);6.38-6.47(m,1H);6.52-6.64(m,2H);6.68-6.75(m,2H);6.83(br,d,J=8.1Hz,1H);6.95(br,d,J=11.7Hz,1H);7.22(s,1H);9.17(s,1H)。
13C NMR(acetone,75MHz)δ12.46,12.90,13.14,23.22,29.07,33.13,34.70,35.95,47.77,56.68,56.74,73.20,81.59,82.20,82.27,108.46,109.26,116.26,116.60,120.97,126.91,128.80,130.64,133.44,134.27,134.87,137.71,138.69,144.70,145.96,146.11,157.12,169.39,180.79,184.82。
ESI(m/z):704.2(M+Na+)。
证明得到了分子式如式(1)所示的产物:
实施例2
格尔德霉素(562mg),加对羟基苯乙胺盐酸盐(348mg),加二氯甲烷(50mL),加甲醇(12mL),加三乙胺(0.5mL),室温搅拌反应,10分钟后体系呈暗红色。反应式如下:
反应2天,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=40∶1),再经过制备TLC分离到紫色固体,命名为RZ802(123mg,18%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.95(d,J=6.6Hz,3H);1.00(d,J=6.9Hz,3H);1.61-1.83(obscure,m,6H);2.02(s,3H);2.36-2.48(m,1H);2.62-2.81(m,2H);2.82-2.93(m,2H);3.27(s,3H);3.36(s,3H);3.40-3.50(m,1H);3.54-3.83(m,3H);4.32(d,J=9.9Hz,1H);4.42(br,s,1H);4.90(br,s,2H);5.19(s,1H);5.81-5.94(m,2H);6.13(s,1H);6.31-6.39(m,1H);6.58(t,J=11.7Hz,1H);6.81(d,J=8.4Hz,2H);6.94(d,br,J=11.4Hz,1H);7.07(d,J=8.1Hz,2H);7.25(d,J=8.7Hz,1H);9.17(s,1H)。
13C NMR(CDCl3,75MHz)δ12.37;12.61;12.78;22.86;28.47;28.50;32.28;34.39;35.02;47.09;56.69;57.10;72.66;81.14;81.39;81.71;108.52;108.69;115.83;126.60;126.88;128.78;129.79;132.72;133.68;134.95;135.72;141.27;144.73;155.06;156.16;168.43;180.58;183.76。
ESI(m/z):688.3(M+Na+)。
证明得到了分子式如式(2)所示的产物:
式(2)
实施例3
取格尔德霉素(1g),加入[(2-氨基)-乙硫基]-甲基呋喃(0.5mL),加入二氯甲烷(100mL),室温搅拌反应,体系呈橙红色悬浊液,反应式如下:
反应8天,停止反应。减压蒸除溶剂,柱层析提纯(洗脱剂:二氯甲烷/甲醇=40∶1),再经过制备TLC分离得到紫色固体,命名为RZ803(150mg,12%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.90-1.10(m,6H);1.62-1.90(obscure,m,3H);1.80(s,3H);2.03(s,3H);2.26-2.37(m,1H);2.62-2.87(m,4H);3.72(d,J=2.1Hz,3H);3.37(d,J=0.9Hz,3H);3.42-3.70(m,4H);3.74(s,3H);4.26-4.40(m,1H);4.94(br,s,2H);5.19(br,s,1H);5.81-5.96(m,2H);6.22(br,s,1H);6.50-6.65(m,2H);6.94(br,d,J=11.4Hz,1H);7.29(d,J=2.4Hz,1H);7.38(s,1H);9.14(s,1H)。
13C NMR(CDCl3,75MHz)δ12.34;12.60;12.78;22.95;27.86;28.55;31.10;32.26;34.41;35.00;43.92;56.71;57.10;72.55;81.14;81.37;81.61;107.94;108.90;109.09;110.61;126.55;126.90;132.76;133.69;134.94;135.79;141.03;142.45;144.68;150.86;156.03;168.38;180.78;183.80。
ESI(m/z):708.1(M+Na+)。
证明得到了分子式如式(3)所示的产物:
实施例4
格尔德霉素(567mg),加2,2-二苯基-1-丙胺(496mg),加二氯甲烷(50mL),加甲醇(12mL),加三乙胺(0.45mL),室温搅拌反应,反应式如下:
反应6天,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=20∶1),再经过制备TLC分离得到紫色固体,命名为RZ805(136mg,18%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.96(d,J=6.3Hz,3H);1.01(d,J=6.9Hz,3H);1.62-1.95(m,9H);2.02(s,3H);2.32-2.48(m,1H);2.63-2.80(m,2H);3.26(s,3H);3.37(s,3H);3.42-3.64(m,2H);3.96-4.05(m,1H);4.21-4.46(m,3H);4.90(s,br,2H);5.19(s,1H);5.81-5.94(m,2H);6.19(s,br,1H);6.58(t,J=11.4Hz,1H);6.94(d,br,J=11.7Hz,1H);7.15-7.41(m,11H);9.14(s,1H)。
13C NMR(CDCl3,75MHz)δ12.41;12.59;12.79;23.07;27.03;28.47;32.27;34.67;35.07;47.55;55.37;56.69;57.11;72.54;81.12;81.41;81.60;108.78;126.55;126.87;126.99;127.01;127.23;127.24;128.75;132.71;133.67;134.93;135.76;141.10;145.18;145.34;145.35;156.01;168.38;180.54;183.65。
ESI(m/z):726.3(M+Na+)。
证明得到了分子式如式(4)所示的产物:
实施例5
格尔德霉素(561mg),加3-(二乙氧基甲基硅烷基)-1-丙胺(840mg),加二氯甲烷(50mL),室温搅拌反应,反应式如下:
反应3天,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=1∶1),得到紫色固体,命名为RZ811(590mg,80%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.15(s,3H);0.63-0.74(m,2H);0.97(d,J=4.8Hz,3H);1.00(d,J=5.1Hz,3H);1.23(t,J=5.3Hz,6H);1.67-1.84(m,8H);2.03(s,3H),2.37-2.48(m,1H);2.62-2.80(m,2H);3.27(s,3H);3.37(s,3H);3.42-3.62(m,4H);3,78(q,J=5.4Hz,4H);4.28-4.34(br,d,J=4.3Hz,1H);4.39(br,s,1H);4.89(s,br,1H);5.19(s,1H);5.82-5.95(m,2H);6.34-6.42(m,1H);6.59(t,J=8.7Hz,1H);6.96(d,br,J=8.7Hz,1H);7.28(s,1H);9.20(s,1H)。
13C NMR(CDCl3,75MHz)δ-4.99;11.19;12.30;12.60;12.74;18.39;22.85;23.52;28.44;32.25;34.38;35.01;48.30;56.69;57.07;58.25;72.56;81.19;81.45;81.63;108.24;108.62;126.56;126.85;132.68;133.79;134.96;135.73;141.43;144.84;156.06;168.39;180.49;183.88。
ESI(m/z):742.3(M+Na+)。
证明得到了分子式如式(5)所示的产物:
实施例6
格尔德霉素(561mg),加2-(二烯丙基氨基)乙胺(200mg),加二氯甲烷(100mL),室温搅拌反应,反应式如下:
反应2天,停止反应。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:丙酮/石油醚=1∶3),得到紫色固体,命名为RZ813(566mg,95%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.93-1.05(m,6H);1.66-1.92(obscure,m,6H);2.03(s,3H);2.35-2.47(m,1H);2.62-2.82(m,4H);3.15(d,J=6.6Hz,4H);3.27(s,3H);3.37(s,3H);3.40-3.45(m,2H);3.46-3.68(m,2H);4.32(d,J=9.9Hz,1H);4.53(br,s,1H);4.98(s,br,2H);5.15-5.21(m,4H);5.24(s,1H);5.78-5.96(m,4H);6.59(t,J=11.3Hz,1H);6.96(d,J=11.1Hz,1H);7.16(s,br,1H);7.27(s,br,1H);9.21(s,1H)。
13C NMR(CDCl3,75MHz)δ12.57;12.62,12.71,22.95,28.39,32.28,34.44,35.12,42.66,50.75,56.53,56.70,57.08,72.54,81.24,81.52,81.70,108.40,108.83,118.22,126.60,126.81,132.67,133.88,134.91,135.03,135.65,141.27,145.37,156.03,168.40,180.13,184.03。
ESI(m/z):668.9(M+H+)。
证明得到了分子式如式(6)所示的产物:
实施例7
格尔德霉素(561mg),加2-氨基茚满(340mg),加二氯甲烷(50mL),加甲醇(12mL),加三乙胺(0.5mL),反应式如下:
室温搅拌反应5.5天,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=40∶1)得到较纯产物。再经过乙酸乙酯溶解,石油醚滴加重结晶得到纯紫色固体,命名为RZ816(180mg,27%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.92-1.06(m,6H);1.57-1.67(m,3H);1.74-1.86(obsure,m,4H);2.03(s,3H);2.33-2.46(m,1H);2.68-2.82(m,2H);2.86-3.04(m,2H);3.20-3.30(m,4H);3.38(s,3H);3.42-3.54(m,2H);3.55-3.64(m,1H);4.26-4.38(m,2H);4.85(br,s,2H);5.20(s,1H);5.81-5.97(m,2H);6.47-6.64(m,2H);6.69(d,J=11.7Hz,1H);7.18-7.32(m,5H);9.17(s,1H)。
13C NMR(CDCl3,75MHz)δ12.30;12.57;12.74;22.86;28.72;32.24;34.52;34.93;40.82;41.32;54.95;56.67;57.03;72.56;81.15;81.36;81.54;108.61;108.81;124.77;124.95;126.50;126.88;127.15;127.23;132.77;133.67;134.90;135.78;139.56;139.66;141.18;144.17;156.15;168.32;180.66;183.69。
ESI(m/z):684.4(M+Na+)。
证明得到了分子式如式(7)所示的产物:
实施例8
格尔德霉素(561mg),加2-(2-萘氧基)乙胺(700mg),加二氯甲烷(50mL),室温搅拌反应,反应式如下:
反应4天,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=20∶1),得到紫色固体,命名为RZ818(380mg,53%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.94-1.08(m,6H);1.66-1.88(obscure,m,6H);2.03(s,3H);2.35-2.52(m,1H);2.68-2.82(m,2H);3.27(s,3H);3.37(s,3H);3.42-3.50(m,1H);3.54-3.64(m,1H);3.90-4.14(m,2H);4.21-4.38(m,4H);4.91(s,br,2H);5.20(s,1H);5.81-5.95(m,2H);6.59(t,J=11.6Hz,1H);6.62-6.71(m,1H);6.95(d,J=11.1Hz,1H);7.14-7.22(m,2H);7.29(s,1H);7.32-7.42(m,1H);7.41-7.50(m,1H);7.70-7.82(m,3H);9.13(s,1H)。
13C NMR(CDCl3,75MHz)δ12.35;12.57;12.76;22.98;28.56;32.25;34.36;35.01;45.01;56.69;57.05;65.84;72.53;81.13;81.56;106.97;108.91;109.22;118.53;124.05;126.51;126.56;126.74;126.88;127.66;129.26;129.71;132.79;133.63;134.25;134.91;135.77;140.92;144.94;155.90;156.12;168.32;180.76;183.83。
ESI(m/z):738.4(M+Na+)。
证明得到了分子式如式(8)所示的产物:
实施例9
格尔德霉素(561mg),加2-(2,4-二氯苯氧基)乙胺(900mg),加二氯甲烷(50mL),室温搅拌反应。反应式如下:
体系颜色呈红色。反应7天,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=30∶1),得到紫色固体,命名为RZ819(300mg,41%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.94-1.06(m,6H);1.66-1.86(obscure,m,6H);2.30-2.44(m,1H);2.68-2.82(m,2H);3.28(s,3H);3.37(s,3H);3.40-3.50(m,1H);3.52-3.64(m,1H);3.92-4.10(m,2H);4.16-4.26(m,3H);4.32(d,J=9.6Hz,1H);4.86(s,br,2H);5.20(s,br,1H);5.81-5.94(m,2H);6.53-6.64(m,2H);6.85-7.00(m,2H);7.17-7.42(m,3H);9.13(s,1H)。
13C NMR(CDCl3,75MHz)δ12.36;12.56;12.77;22.96;28.63;32.26;34.33;35.00;44.73;56.69;57.07;67.89;72.54;81.11;81.32;81.56;109.03;109.68;115.13;124.49;126.51;126.92;127.16;127.70;130.26;132.82;133.58;134.92;135.81;140.77;145.02;152.40;156.10;168.33;180.85;183.87。
ESI(m/z):756.4(M+Na+)。
证明得到了分子式如式(9)所示的产物:
实施例10
格尔德霉素(0.56g).加2-{[4-(1,2,3-三唑)丁基]苯氧基}乙胺(0.42g),加二氯甲烷(50mL),室温搅拌反应。反应式如下:
反应7天,停止反应。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1∶1→二氯甲烷/甲醇=30∶1),得到紫色固体,命名为RZ820(350mg,44%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ1.01(d,J=6.6Hz,6H);1.55-1.68(m,2H);1.70-1.84(m,obscure,4H);1.86-2.00(m,4H);2.03(s,3H);2.34-2.47(m,1H);2.60(t,J=7.4Hz,2H);2.66-2.80(m,2H);3.27(s,3H);3.37(s,3H);3.42-3.50(m,1H);3.54-3.64(m,1H);3.80-4.05(m,2H);4.10-4.21(m,2H);4.25-4.35(m,2H);4.40(t,J=7.1Hz,2H);4.97(s,br,2H);5.19(s,1H);5.81-5.94(m,2H);6.53-6.66(m,2H);6.84(d,J=8.4Hz,2H);6.96(d,J=8.7Hz,1H);7.08(d,J=8.7Hz,2H);7.27-7.32(m,1H);7.52(s,1H);7.70(s,1H);9.16(s,1H)。
13C NMR(CDCl3,75MHz)δ12.39,12.52,12.74,22.95,28.24,28.64,29.65,32.33,34.19,34.34,35.10,45.07,49.94,56.69,57.07,66.09,72.63,81.16,81.43,81.59,108.91,109.31,114.75,123.09,126.46,126.98,129.42,132.83,113.62,133.75,134.65,134.93,135.86,141.01,145.09,156.07,156.38,168.33,180.84,183,85。
ESI(m/z):789.6(M+H+);811.5(M+Na+)。
证明得到了分子式如式(10)所示的产物:
实施例11
格尔德霉素(1g),加1-叔丁氧羰基-3-(2-氨基甲基)哌啶(0.57g),加二氯甲烷(89mL),室温搅拌反应。反应式如下:
体系颜色呈橙红色。反应1.5天,体系颜色呈深褐色。补加1-叔丁氧羰基-3-(2-氨基甲基)哌啶(0.20g)加热回流,反应5天,停止反应。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1∶1),得到紫色固体,命名为RZ821(997mg,73%)。产物为两差向异构体的混合物,比例为1.5∶1(HPLC鉴定)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.92-1.05(m,6H);1.20-1.60(m,obscure,13H);1.62-2.10(m,obscure,10H);2.30-2.46(m,1H);2.62-2.80(m,2H);2.81-2.95(m,1H);3.00-3.14(m,1H);3.27(s,3H);3.37(s,3H);3.40-3.52(m,2H);3.54-3.63(m,1H);4.31(d,J=9.6Hz,2H);5.05(s,br,2H);5.18(s,1H);5.81-5.94(m,2H);6.38(s,br,1H);6.59(t,J=11.4Hz,1H);6.96(d,J=11.7Hz,1H);7.29(s,1H);9.17(s,1H)。
ESI(m/z):765.7(M+Na+)。
证明得到了分子式如式(11)所示的产物:
实施例12
格尔德霉素(1g),加1-(2-甲氧基)-4-(2-氨基乙基)哌嗪(628mg),加二氯甲烷(100mL),室温搅拌反应。反应式如下:
反应3天,停止反应。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1∶1),得到紫色固体,命名为RZ822(1.73g,86%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ)0.95-1.05(m,6H);1.68-1.86(m,6H);2.03(s,3H);2.37-2.50(m,1H);2.65-2.82(m,8H);3.13(br,s,4H);3.27(s,3H);3.37(s,3H);3.42-3.65(m,3H);3.68-3.82(m,1H);3.87(s,3H);4.32(d,J=10.2Hz,1H);4.50(s,br,1H);4.87(s,br,2H);5.19(s,1H);5.81-5.96(m,2H);6.59(t,J=11.3Hz,1H);6.85-7.06(m,5H);7.19(s,br,1H);7.27(s,1H);9.21(s,1H)。
13C NMR(CDCl3,75MHz)δ12.27;12.57;12.72;23.07;28.41;32.25;34.41;35.08;41.75;50.58;52.66;55.30;55.81;56.68;57.04;72.50;81.19;81.44;81.62;108.67;108.84;111.09;118.29;120.97;123.04;126.56;126.81;132.68;133.78;134.97;135.65;141.02;141.15;145.44;152.16;156.09;168.38;180.11;184.10。
ESI(m/z):764.6(M+H+);786.6(M+Na+)。
证明得到了分子式如式(12)所示的产物:
实施例13
格尔德霉素(1g),加2-[二(2-甲氧基)氨基]乙胺(472mg),加二氯甲烷(100mL),室温搅拌反应。反应式如下:
反应5天,停止反应。减压蒸除溶剂,柱层析提纯(洗脱剂:丙酮/石油醚=1∶2.5),得到紫色固体(931mg,79%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.92-1.04(m,6H);1.62-1.84(m,6H);2.03(s,3H);2.36-2.50(m,1H);2.62-2.82(m,6H);2.85-2.94(m,2H);3.27(s,3H);3.34(s,6H);3.37(s,3H);3.40-3.53(m,6H);3.54-3.73(m,2H);4.32(d,J=10.2Hz,1H);4.58(s,br,1H);4.83(s,br,2H);5.19(s,1H);5.80-5.98(m,2H);6.59(t,J=11.3Hz,1H);6.96(d,J=11.4Hz,1H);7.20(s,br,1H);7.25(s,1H);9.22(s,1H)。
13C NMR(CDCl3,75MHz)δ12.25;12.59;12.72;22.93;28.37;32.26;34.35;35.08;43.09;53.27;53.68;56.69;57.06;58.86;71.45;72.50;81.24;81.52;81.68;108.50;108.83;126.61;126.76;132.63;133.90;135.02;135.59;141.21;145.69;156.08;168.41;179.83;184.11。
ESI(m/z):705.4(M+H+);727.5(M+Na+)。
证明得到了分子式如式(13)所示的产物:
式(13)
实施例14
格尔德霉素(1g),加[1-甲基-2-(3,4-二甲氧基)苯基]氨基乙胺(638mg),加二氯甲烷(100mL),室温搅拌反应。反应式如下:
反应2天,停止反应。减压蒸除溶剂,硅胶柱层析提纯(洗脱剂:丙酮/石油醚=1∶1.5),得到紫色固体(1300mg,95%)。将该产物进行分析测试,得到如下的波谱数据:
1H NMR(CDCl3,300MHz)δ0.96(d,J=6.0Hz,3H);1.00(d,J=6.9Hz,3H);1.72(s,3H);1.75-1.88(m,4H);2.03(s,3H);2.33(s,3H);2.35-2.44(m,1H);2.61-2.82(m,6H);3.27(s,3H);3.37(s,3H);3.48-3.51(m,2H);3.53-3.56(m,2H);3.85(s,3H);3.87(s,3H);4.32(d,J=9.9Hz,1H);4.50(s,br,1H);4.87(s,br,2H);5.19(s,1H);5.80-5.88(m,2H);6.59(t,J=11.3Hz,1H);6.64-6.81(m,3H);6.97(d,J=11.4Hz,1H);7.08(s,br,1H);7.27(s,1H);9.20(s,1H)。
13C NMR(CDCl3,75MHz)δ12.27;12.57;12.72;22.94;28.38;32.25;33.53;34.35;35.05;41.32;42.55;55.28;55.79;55.86;56.66;57.04;59.32;72.51;81.20;81.47;81.62;108.49;108.80;111.25;111.88;120.49;126.56;126.79;132.51;132.67;133.80;134.98;135.64;141.17;145.35;147.34;148.81;156.10;168.39;180.04;183.96。
ESI(m/z):767.5(M+H+);789.5(M+Na+)。
证明得到了分子式如式(14)所示的产物:
式(14)
实施例15:格尔德衍生物的生物活性的检测
为了对前述实施例1-14中合成的各衍生物进行生物活性验证,申请人采用5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,MCF-7,AGS,HepG2和A2780培养基:HG-DMEM+10%NBS培养基(MCF-7 HCT116和HepG2细胞株);RPMI+10%FBS培养基(A2780,A549和AGS细胞株)药物稀释:所有药物均溶解于DMSO中,配成10mg/ml的贮存溶液,给药前用培养基稀释新鲜配制。
10μM生长抑制率的检测方法
在平底96孔板上培养细胞;24h后加入终浓度为10μM的复合物;72h后每孔加入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;用排枪将MTT从孔中吸出,注意不要碰到细胞;每孔加入100μl 100%DMSO;室温震荡15min;570nm波长读数(酶标仪Thermo Multiskan Spectrum)。结果按照公式(ODc-ODt)/ODc x 100%进行计算,具体抑制结果如表1所示。
表1:格尔德霉素衍生物对5种不同的细胞系的生长抑制检测结果
化合物 | 命名 | A549 | MCF-7 | AGS | A2780 | HEPG-2 |
比较例1 | RZC02 | -0.16 | 65.02 | 76.99 | 50.81 | 65.76 |
比较例2 | RZC03 | 38.10 | 23.01 | 77.77 | 19.90 | 49.25 |
式(1)化合物 | RZ801 | 36.17 | 22.47 | 62.42 | 61.36 | 59.87 |
式(2)化合物 | RZ802 | 28.19 | 22.74 | 77.16 | 35.87 | 46.95 |
式(3)化合物 | RZ803 | 30.32 | 24.53 | 58.78 | 8.19 | 43.28 |
式(4)化合物 | RZ805 | 71.37 | -4.21 | 74.29 | 29.37 | 55.51 |
式(5)化合物 | RZ811 | 15.54 | 23.40 | 78.02 | 30.26 | 50.88 |
式(6)化合物 | RZ813 | 43.64 | 35.81 | 68.68 | 19.71 | 46.93 |
式(7)化合物 | RZ816 | 15.45 | 15.91 | 64.75 | 10.01 | 44.59 |
式(8)化合物 | RZ818 | 39.44 | 28.09 | 45.77 | 41.79 | 54.30 |
式(9)化合物 | RZ819 | 35.91 | 40.86 | 51.46 | 51.88 | 64.68 |
式(10)化合物 | RZ820 | 36.01 | 48.18 | 59.65 | 51.20 | 59.12 |
式(11)化合物 | RZ821 | 39.19 | 44.18 | 39.81 | 57.34 | 58.23 |
式(12)化合物 | RZ822 | 31.43 | 43.04 | 43.93 | 58.67 | 53.56 |
式(13)化合物 | RZ823 | 42.71 | 53.02 | 50.13 | 56.85 | 61.12 |
式(14)化合物 | RZ824 | 49.12 | 73.36 | 84.18 | 73.19 | 64.09 |
表中A549、MCF-7、AGS、A2780和HEPG-2分别代表肺腺癌、乳腺癌、胃癌、卵巢癌和肝癌细胞系,纵向表示化学式(1)-(14)所示的格尔德霉素衍生物。表中稍大的加黑斜体为阳性结果。
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,尤其是对于胃癌(AGS)、卵巢癌(A2780)和肝癌(HEPG-2)。与进入临床的药物分子RZC02与RZC03相比,化合物RZ823与RZ824体现出了更高的抗癌活性,且具有广谱抗癌活性的特点,能同时抑制多种肿瘤细胞。
Claims (9)
2.药物组合物,其中至少含有化学式(1)-(14)所示的化合物或者其盐中的一种作为有效成分。
3.权利要求2的药物组合物,其中还含有药学上允许的赋形剂。
4.权利要求2的药物组合物,其中还含有其它肿瘤治疗药物。
5.细胞生长抑制剂,其中至少含有化学式(1)-(14)所示的化合物或者其盐中的一种作为有效成分。
6.细胞增殖抑制剂,其中至少含有化学式(1)-(14)所示的化合物或者其盐中的一种作为有效成分。
7.化学式(1)-(14)所示的任一种格尔德霉素衍生物或者其盐在制备用于治疗肿瘤的药物中的用途。
8.化学式(1)-(14)所示的任一种格尔德霉素衍生物或者其盐在制备用于细胞杀伤的杀伤剂中的用途。
9.化学式(1)-(14)所示的任一种格尔德霉素衍生物或者其盐在制备用于细胞增殖抑制剂中的用途。
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CN102603635A (zh) * | 2011-01-21 | 2012-07-25 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN103360312A (zh) * | 2013-07-22 | 2013-10-23 | 山东大学 | 一组格尔德霉素衍生物及其应用 |
CN103450164A (zh) * | 2012-05-31 | 2013-12-18 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN103819457A (zh) * | 2014-02-12 | 2014-05-28 | 复旦大学附属上海市第五人民医院 | 一类能够抑制去势抵抗性前列腺癌和成骨转移的格尔德霉素衍生物及其应用 |
CN103819456A (zh) * | 2014-02-12 | 2014-05-28 | 复旦大学附属上海市第五人民医院 | 一组格尔德霉素衍生物及其应用 |
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CN102603635B (zh) * | 2011-01-21 | 2016-08-03 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN103450164A (zh) * | 2012-05-31 | 2013-12-18 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
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CN103360312A (zh) * | 2013-07-22 | 2013-10-23 | 山东大学 | 一组格尔德霉素衍生物及其应用 |
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CN103819456A (zh) * | 2014-02-12 | 2014-05-28 | 复旦大学附属上海市第五人民医院 | 一组格尔德霉素衍生物及其应用 |
CN103819456B (zh) * | 2014-02-12 | 2015-10-28 | 复旦大学附属上海市第五人民医院 | 一组格尔德霉素衍生物及其应用 |
CN103819457B (zh) * | 2014-02-12 | 2016-08-31 | 复旦大学附属上海市第五人民医院 | 一类能够抑制去势抵抗性前列腺癌和成骨转移的格尔德霉素衍生物及其应用 |
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