CN107200771B - 多西紫杉醇与胞壁酰二肽简化物的共缀物的制备及抗肿瘤作用 - Google Patents
多西紫杉醇与胞壁酰二肽简化物的共缀物的制备及抗肿瘤作用 Download PDFInfo
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Abstract
本发明涉及了一类式(I)所示化合物,具有抑制肿瘤和抑制肿瘤转移双功能共缀物的化学合成制备及抗肿瘤作用。本发明合成了多个多西紫杉醇和胞壁酰二肽简化物的共缀物,并通过可靠的理化数据及药效学试验,发现该类共缀物具有良好的成药性,以及具有更好的抗肿瘤与抗肿瘤转移功效。
Description
技术领域
本发明主要涉及多西紫杉醇与胞壁酰二肽简化物形成的共缀物及其合成方法,以及在治疗癌症方面的应用,属于医药技术领域。
技术背景
恶性肿瘤是当今危害人类生命健康的重要杀手,肿瘤转移是恶性肿瘤的本质特征之一,也是肿瘤治疗失败的最根本原因,临床肿瘤患者约有80%以上死于恶性肿瘤转移,治疗肿瘤的转移是降低肿瘤死亡率的重要途径,控制转移是决定癌症患者预后的关键因素,已引起世界范围的重视,肿瘤转移不仅是肿瘤复杂发病学上的一环,更是临床医药工作者希望解决的治疗难题,因此寻求抑制肿瘤转移的药物就尤为紧迫和关键。
紫杉烷类药物包括紫杉醇、多西紫杉醇,具有口服生物利用度较低的特点,主要原因在于其易被胃肠道上皮的P-糖蛋白外排泵出,易被细胞色素P450代谢,且水溶性差。由于紫杉烷类药物目前依然是其治疗领域的一线药物,因此围绕该类化合物的各种研究是药物化学家的研究热点。自提出将天然抗肿瘤药物分子与免疫增强剂进行化学共缀以来,希望通过化学治疗与免疫治疗相结合,寻找具有抗肿瘤转移的药物分子的研究不断取得新的进展。
已申请的早期专利保护了主要两类共缀物,一类是通过将胞壁酰二肽连于紫杉醇的2′-位羟基形成的2'-O-MTC共缀物(见CN1712399A),但遗憾的是,2'-O-MTC类共缀物未能够在实验小鼠体内展示抗肿瘤转移的实验结果。
另外一类是将紫杉醇/多西紫杉醇与胞壁酰二肽衍生物相连形成的MTC/MDC系列共缀物(见WO2011147330A1),MTC/MDC系列共缀物在体外抑瘤和抑制肿瘤的转移实验中表现一定相应效果,但因其成药性问题使进一步的药物使用受到一定制约。
虽然上述系列化合物对本领域做出了很大贡献,但为改进抗癌药物,寻求具有更好抗肿瘤转移活性、成药性更好的化合物,本领域仍在继续进行研究。
发明内容
本发明要解决的技术问题是提供一种具有良好成药性的抗肿瘤及抑制肿瘤转移的化合物,以满足临床应用的需要。
本发明要解决的另一个技术问题是提供这种化合物的制备方法。
本发明要解决的再一个技术问题是提供这种化合物在制备抗肿瘤及抑制肿瘤转移药物中的应用。
为解决本发明的技术问题,采用如下技术方案:
其中,m选自0-1的自然数,即m=0或1;
n选自2-10的自然数,即n=2,3,4,5,6,7,8,9或10;
优选的n选自2-5的自然数,即n=2,3,4或5。
R1选自取代或非取代的五至十元芳基、取代或非取代的杂芳基和取代或非取代的亚甲氧基;所述取代的取代基选自羟基、巯基、卤素、氨基、硝基、氰基、醛基、C1-C6的烷基、羧基、羟氨基、C2-C6的烯烃基、C1-C4的酰氨基和苯甲酰胺基;
R2选自氢、取代或非取代的C1-C6的烷基、取代或非取代的C1-C6的烷氧基,所述取代的取代基选自卤素;
所述芳基优选为五-十元芳基,所述杂芳基优选为五-十元杂芳基。
所述的五-十元芳基,优选自五元芳基、六元芳基、十元稠环芳基;
所述的五元芳基选自
所述的六元芳基选自
所述的十元稠环芳基选自
所述的杂芳基表示一个或多个杂原子的芳族环系,优选含有1-4个杂原子,优选自含有N,O或S的杂原子的杂芳基;
优选的杂芳基选自含有1-4个选自N,O或S的杂原子的五-十元杂芳基;
更为优选的杂芳基选自含有1-4个选自N,O或S的杂原子的五元杂环基、含有1-4个选自N,O或S的杂原子的六元杂环基、含有1-4个选自N,O或S的杂原子的十元稠杂环基。
所述的含有1-4个选自N,O或S的杂原子的五元杂环基选自:
所述的含有1-4个选自N,O或S的杂原子的六元杂环基选自:
所述的含有1-4个选自N,O或S的杂原子的十元稠杂环基选自:
所述的C1-C6的烷基在本发明中表示具有1至6个碳原子的直链或支链烷烃基团,可选自甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、环戊基、正己基、环己基、二甲基丙基、2-甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基。
所述的C1-C6烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、正己氧基、异己氧基、甲氧基乙氧基、乙氧基甲氧基、丙氧基甲氧基和丙氧基乙氧基。
所述的卤素选自氟、氯、溴或碘,所述的C1-C4酰胺基选自乙酰氨基、丙酰氨基、丁酰氨基或异丁酰氨基;C2-C6的烯烃基选自乙烯基、丙烯基、丁烯基、异丁烯基、2-丁烯基、戊烯基、异戊烯基、2-戊烯基、己烯基和异己烯基。
所述R2为氢或者氢被金属或非金属阳离子所取代形成药学上可接受的盐,所述的金属或非金属阳离子选自Na+,K+,Ca2+,Mg2+,Zn2+,Al3+,NH4 +。
所述式I所示的化合物包括但不限定于式IA所示的化合物:
R1如上定义。
所述的化合物选自如下群组:
本发明提供了多西紫杉醇和胞壁酰二肽简化物的共缀物的合成通用方法如下:
1.液相合成多西紫杉醇2’-O-烷烃二酸单酯;
2.固相合成胞壁酰二肽简化物;
3.液相合成多西紫杉醇和胞壁酰二肽简化物的共缀物。
通用合成步骤1:多西紫杉醇2’-O-烷烃二酸单酯的合成
反应试剂与条件:succinic anhydride,TEA,THF,0℃-rt,4h
操作步骤:将多西紫杉醇溶解到四氢呋喃中,冰浴下向上述反应体系中先后滴加三乙胺和烷烃酸酐的四氢呋喃溶液。滴加完毕后在室温反应4小时,HPLC监控反应完毕,冰浴下用1.0M HCl缓慢中和反应体系中的三乙胺,并调节pH值至3~5,所得溶液在30℃下减压浓缩至1/3体积,之后将浓缩液慢慢滴加到10倍体积的冰水中析晶,减压过滤收集固体;所得固体在冰水中打浆、过滤;用水洗涤三次,30℃下真空干燥,得到目标产物白色固体。
通用合成步骤2:胞壁酰二肽简化物的合成
本法利用各种羟基树脂,如王树酯(负载量0.83mmol/g)作为固相载体,通过多肽固相合成策略先后向树脂引入Fmoc-L-Lys(Boc)-COOH、Fmoc-D-iso-Gln-COOH、Fmoc-L-Ala-COOH和各种有机羧酸。缩合反应完成后,经充分洗涤树脂、脱除Fmoc保护基、裂解树脂等步骤,得到各种胞壁酰二肽简化物。反应中各种酰化过程为常规酰胺缩合反应,通过加入过量的反应试剂(氨基酸或有机羧酸)以及强效缩合剂(如DIC、DCC、HATU、HBTU、BOP、PyBOP等),可以使各类缩合反应完全。
具体合成路线:
反应试剂与条件:(a)Fmoc-Lys(Boc)-OH,HOBt,DMAP,DIC,DCM,rt,12h;(b)Ac2O,pyridine,DMAP,DCM,rt,3h;(c)20%piperidine/DMF;rt,1h;(d)Fmoc-D-iso-Gln-OH,HOBt,DIC,DMF rt,12h;(e)Fmoc-Ala-OH,HOBt,DIC,DMF,rt,8h;(f)RCOOH,HOBt,DIC,DMF,rt,8h;(g)90%TFA/H2O,rt,2h.
操作步骤:
(a)将王树脂(负载量0.83mmol/g,1.0eq.),Fmoc-Lys(Boc)-OH(2.0eq.),HOBt(2.0eq.)和DMAP(0.05eq.)依次加入到固相反应器,减压抽真空1小时后,加入无水的二氯甲烷后搅拌0.5小时,之后加入活化剂DIC(2.0eq.),室温反应12小时,向树脂引入Fmoc-Lys(Boc)-OH。减压抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷充分洗涤树脂各3次,抽干,直接用于下一步;
(b)向反应器内依次加入DCM,乙酸酐(5.0eq.),吡啶(5.0eq.)和DMAP(0.05eq.);室温封端3小时,减压抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷(1.5L充分洗涤树脂6次,抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷充分洗涤树脂各3次,抽干,直接用于下一步;
(c)加入20%体积份数的哌啶/N,N-二甲基甲酰胺溶液,脱除氨基酸的Fmoc保护基,反应1小时后,抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷充分洗涤树脂6次,抽干,直接用于下一步;
(d)向反应器内加入Fmoc-D-iso-Gln-OH(2.0eq.),HOBt(2.0eq.)和N,N-二甲基甲酰胺,搅拌5min至体系均匀后再加入活化剂DIC(2.0eq.),室温反应向树脂引入Fmoc-D-iso-Gln-OH,反应12小时后,取少量树脂进行茚三酮法检测,树脂未呈现蓝色,阴性,说明反应完全,抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷充分洗涤树脂各3次,抽干,直接用于下一步;
(e)向反应器内加入Fmoc-Ala-OH(2.0eq.),HOBt(2.0eq.)和N,N-二甲基甲酰胺溶剂,搅拌5min至体系均匀后再加入活化剂DIC(2.0eq.),室温反应向树脂引入Fmoc-Ala-OH,反应8小时后,取少量树脂进行茚三酮法检测,树脂未呈现蓝色,阴性,说明反应完全,抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷充分洗涤树脂各3次,抽干,直接用于下一步;
(f)向反应器中依次加入有机酸RCOOH(1.5eq.)和HOBt(1.5eq.)和N,N-二甲基甲酰胺,搅拌均匀,之后加入DIC(1.5eq.),室温反应,向树脂引入有机酸,反应8小时后,取少量树脂进行茚三酮法检测,树脂未呈现蓝色,阴性,说明反应完全,抽干反应液,先后用N,N-二甲基甲酰胺和二氯甲烷洗涤树脂各3次,抽干;
(g)加入90%体积份数的三氟乙酸/水溶液,室温裂解2小时,过滤,用二氯甲烷洗涤树脂三次,滤液与裂解液合并,减压蒸干。冰浴条件下,向残余液中加入大量无水甲基叔丁基醚,搅拌、析出白色固体。过滤,将固体用无水甲基叔丁基醚洗涤3次,30℃下真空干燥,得到目标产物粗品。
通用合成步骤3:多西紫杉醇与胞壁酰二肽简化物的共缀物合成
反应试剂与条件:(a)HOSu,EDC·HCl,DMSO,rt,12h;(b)NMM,DMSO,rt,12h.
操作步骤:(a)向反应器中依次加入多西紫杉醇2’-O-烷基二酸单酯(1.0eq.)、HOSu(1.1eq.)、EDC·HCl(1.1eq.)和DMSO,室温搅拌反应12h。HPLC监控,结果显示多西紫杉醇纯度小于5%视为反应完全,直接用于下一步反应。
将胞壁酰二肽简化物寡肽(1.0eq.)加入到另外一个反应器中,加入DMSO,室温搅拌至溶解,然后加入N-甲基吗啡林(5.0eq.),室温搅拌5min,而后将上述已经制备好的N-羟基琥珀酰亚胺活性酯的反应液缓慢滴加到此反应体系中,室温反应12小时,HPLC监控,显示N-羟基琥珀酰亚胺活性酯中间体纯度小于5%视为反应完全。将反应体系冷却至0-4℃,先用1M盐酸水溶液中和反应体系中的N-甲基吗啡林,再用0.1M盐酸水溶液微调反应体系pH到3~5。然后将中和后的反应液慢慢滴加到10倍体积的0-4℃冰水中析晶;减压过滤得到目标粗产物;粗产物用冰水洗涤3次,30℃下真空干燥,得到目标粗品。粗产品经HPLC纯化即得到目标多西紫杉醇与胞壁酰二肽简化物的共缀物。
本发明所述的烷烃二酸酐选自C4-C12烷烃二酸酐。
本发明中的共缀物的制备方法条件比较温和,反应时间简短,收率稳定,有利于采用例如组合化学方法进行化合物库的合成,这种采用组合化学方法合成化合物库的方法亦属于本发明的范围。
其中,各缩写为如下定义,各试剂均可通过通过商业途径获得:
Fmoc | 9-芴甲氧羰基 |
Boc | 叔丁氧羰基 |
rt | 室温 |
eq. | 当量 |
succinic anhydride | 丁二酸酐 |
TEA | 三乙醇胺 |
THF | 四氢呋喃 |
DIC | N,N-二异丙基碳二亚胺 |
DCC | 二环己基碳二亚胺 |
HATU | 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 |
HBTU | O-苯并三氮唑-四甲基脲六氟磷酸盐 |
BOP | 苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐 |
PyBOP | 六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷 |
HOBt, | 1-羟基苯并三唑 |
DMAP | 4-二甲氨基吡啶 |
DCM | 二氯甲烷 |
Ac2O | 乙酸酐 |
pyridine | 吡啶 |
piperidine | 哌啶 |
DMF | N,N-二甲基甲酰胺 |
TFA | 三氟乙酸 |
HOSu | N-羟基丁二酰亚胺 |
EDC | 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐 |
DMSO | 二甲亚砜 |
NMM | N-甲基吗啉 |
本发明的另一目的在于涉及所述共缀物在治疗和预防各种肿瘤、以及由其引起的各种癌症的药物(剂)或者预防(剂)中的应用。所述的肿瘤选自黑色素瘤、胃癌、肺癌、优选非小细胞肺癌、乳腺癌、乳腺癌转移、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、结肠癌转移、脑癌、优选胶质细胞瘤引起的脑癌。
本发明的再一目的在于提供一种药物组合物,其特征在于,包含所述共缀物化合物或其药学上可接受的盐和一种以上药学上可接受的载体。所述载体包括但不限于各种适合药物制剂的赋形剂,可以通过胃肠道或者非胃肠道途径给予哺乳动物,特别是癌症患者。以胃肠道给药为例,赋形剂包括各种可以片剂或者颗粒剂的填充剂,如微晶纤维素等。
本发明化合物具有如下优势:
1、本发明的化合物具有明显更好的溶解性和亲水性,可大大减少或避免药物制剂研究中助溶辅料的使用,具有明显更好的成药性和药物抗过敏性。
2、本发明所述的化合物,对于治疗基因表达异常而引起的疾病,如:肿瘤,有很好的疗效。
3、本发明所述的化合物在抑制肿瘤的同时,具有优异的抑制肿瘤转移的功能。
附图说明
图1为本专利S-01、MDC-405及多西紫杉醇小鼠乳腺癌4T1肺转移模型试验对比结果,其中,1A为乳腺瘤重对比结果,1B为肺表面转移结节数对比结果,其中10mg S-01和10mgMDC-405,与5.7mg多西紫杉醇为等摩尔。
图2为本专利S-01、多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker小鼠乳腺癌4T1肺转移模型试验对比结果,其中,2A为乳腺瘤重对比结果,2B为肺表面转移结节数对比结果,其中10mg S-01与5.7mg多西紫杉醇为等摩尔。
图3:S-01、多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker对人乳腺癌MDA-MB-231裸鼠异种移植瘤的抑制作用,其中,3A为瘤体积对比结果,3B为瘤重对比结果,其中DTX代表多西紫杉醇,5mg S-01与2.85mg多西紫杉醇为等摩尔。
具体实施方式
以下通过多西紫杉醇(Docetaxel)与胞壁酰二肽(MDP)简化物的共缀物合成和生物学的优选实施例来具体说明本发明的各个方面和特征。本领域的技术人员应该理解,这些实施例只是用于说明目的,而不限制本发明的范围。本发明的保护范围只受权利要求书的限制。在不背离权利要求书范围的条件下,本领域的技术人员可以对本发明的各个方面进行各种修改和改进,这些修改和改进也属于本发明的保护范围。
另外,需要注意的是,除非特别指明,下面实施例中所用的各种材料和试剂都是本领域中常用的材料和试剂,可以通过常规的商业途径获得;所用的中间体可以通过常规的商业途径获得或通过公知的方法制备;所用方法均为本领域技术人员公知的常规方法。
化学实施例
实施列1:固相合成胞壁酰二肽简化物MDA-1(通用步骤2)
1H-NMR(500MHz,DMSO-d6):12.59(1H,br.s),8.47(1H,d,J=6.8Hz),8.24(1H,d,J=8.1Hz),8.11(1H,d,J=7.8Hz),7.76(1H,dd,J=8.8,6.2Hz),7.73-7.63(3H,m),7.55(1H,dd,J=8.8,2.6Hz),7.37-7.27(2H,m),7.13(1H,s),6.78(1H,d,J=15.7Hz),4.42(1H,q,J=6.9Hz),4.15(2H,m),2.77(2H,m),2.16(2H,t,J=8.0Hz),1.97(1H,m),1.71(2H,m),1.60-1.45(3H,m),1.40-1.20(6H,m).HR-MS(ESI-TOF)m/z:Calcd for C23H32N5O6FCl[M-CF3COO]+528.2020;Found 528.2023.
实施列2:固相合成胞壁酰二肽简化物MDA-2(通用步骤2)
1H-NMR(500MHz,DMSO-d6):12.58(1H,br.s),8.38(1H,d,J=6.8Hz),8.21(1H,d,J=8.1Hz),8.10(1H,d,J=7.8Hz),7.70(3H,s),7.59(2H,d,J=8.3Hz),7.48(2H,d,J=8.3Hz),7.40(1H,d,J=15.8Hz),7.31(1H,s),7.11(1H,s),6.77(1H,d,J=15.8Hz),4.40(1H,q,J=6.7Hz),4.15(2H,m),2.76(2H,m),2.16(2H,t,J=8.0Hz),1.96(1H,m),1.71(2H,m),1.60-1.45(3H,m),1.40-1.20(6H,m).HR-MS(ESI-TOF)m/z:Calcd for C23H33N5O6Cl[M-CF3COO]+510.2114;Found 510.2116.
实施列3:固相合成胞壁酰二肽简化物MDA-3(通用步骤2)
1H-NMR(500MHz,DMSO-d6):12.58(1H,br.s),8.54(1H,d,J=6.1Hz),8.25(1H,d,J=7.7Hz),8.12(1H,d,J=7.3Hz),7.96(1H,s),7.85-7.60(4H,m),7.53(1H,d,J=10.5Hz),7.44(1H,d,J=15.9Hz),7.40-7.30(2H,m),7.13(1H,s),6.87(1H,d,J=15.9Hz),4.40(1H,q,J=6.7Hz),4.15(2H,m),2.76(2H,m),2.16(2H,t,J=8.0Hz),1.96(1H,m),1.71(2H,m),1.60-1.45(3H,m),1.40-1.20(6H,m).HR-MS(ESI-TOF)m/z:Calcd for C23H32N5O6FCl[M-CF3COO]+528.2020;Found 528.1924.
实施列4:固相合成胞壁酰二肽简化物MDA-4(通用步骤2)
HR-MS(ESI-TOF)m/z:Calcd for C24H36N5O6[M-CF3COO]+490.2660;Found490.2666.
实施列5:固相合成胞壁酰二肽简化物MDA-5(通用步骤2)
HR-MS(ESI-TOF)m/z:Calcd for C24H33N6O6[M-CF3COO]+501.2456;Found501.2446.
实施列6:固相合成胞壁酰二肽简化物MDA-6(通用步骤2)
HR-MS(ESI-TOF)m/z:Calcd forC21H32N5O6S[M-CF3COO]+482.2068;Found482.2053.
实施例7:S-01的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.49(1H,br.s),8.45(1H,d,J=6.7Hz),8.25(1H,d,J=8.0Hz),8.09(1H,d,J=7.5Hz),7.99(2H,d,J=7.5Hz),7.90-7.80(2H,m),7.80-7.70(2H,m),7.70-7.60(3H,m),7.54(1H,dd,J=2.2,8.7Hz),7.45-7.30(6H,m),7.18(1H,t,J=6.7Hz),7.11(1H,s),6.79(1H,d,J=15.7Hz),5.79(1H,t,J=8.2Hz),5.41(1H,d,J=6.9Hz),5.15-4.85(6H,m),4.50-4.38(2H,m),4.20-4.10(2H,m),4.10-3.95(3H,m),3.64(1H,d,J=6.5Hz),3.02(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=6.9Hz),2.30-2.05(6H,m),1.98(1H,m),1.85(1H,m),1.78-1.60(6H,m),1.60-1.47(5H,m),1.45-1.20(16H,m),0.99(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H86N6O22FClNa[M+Na]+1439.5365;Found1439.5358.
实施例8:S-01-Na钠盐的合成
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将S-01(283mg,0.2mmol),溶于50mL乙腈/水=1/1(V/V)的混合溶剂中,之后将反应瓶放入-10℃的低温反应器中,搅拌5min,向上述溶液中滴加0.002mmol/mL的NaOH水溶液100mL,滴加完毕后快速将所得溶液于-20℃反应4小时;冻干,得到白色粉末固体290mg。1H-NMR(500MHz,DMSO-d6):8.45(1H,d,J=6.7Hz),8.25(1H,d,J=8.0Hz),8.09(1H,d,J=7.5Hz),7.99(2H,d,J=7.5Hz),7.90-7.80(2H,m),7.80-7.70(2H,m),7.70-7.60(3H,m),7.54(1H,dd,J=2.2,8.7Hz),7.45-7.30(6H,m),7.18(1H,t,J=6.7Hz),7.11(1H,s),6.79(1H,d,J=15.7Hz),5.79(1H,t,J=8.2Hz),5.41(1H,d,J=6.9Hz),5.15-4.85(6H,m),4.50-4.38(2H,m),4.20-4.10(2H,m),4.10-3.95(3H,m),3.64(1H,d,J=6.5Hz),3.02(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=6.9Hz),2.30-2.05(6H,m),1.98(1H,m),1.85(1H,m),1.78-1.60(6H,m),1.60-1.47(5H,m),1.45-1.20(16H,m),0.99(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H85N6O22FCl[M-Na]-1415.5395;Found 1415.5380.
实施例9:S-01-Ca钙盐的合成
将S-01(283mg,0.2mmol),溶于20mL乙腈/水=1/1(V/V)的混合溶剂中,之后将反应瓶放入0℃的低温反应器中,搅拌5min,向上述溶液中滴加0.01mmol/mL的Ca(OH)2水溶液20mL,滴加完毕后快速将所得溶液倒入到80mL冰水中,降温至-20℃反应4小时;冻干,得到白色粉末固体260mg。1H-NMR(500MHz,DMSO-d6):8.45(1H,d,J=6.7Hz),8.25(1H,d,J=8.0Hz),8.09(1H,d,J=7.5Hz),7.99(2H,d,J=7.5Hz),7.90-7.80(2H,m),7.80-7.70(2H,m),7.70-7.60(3H,m),7.54(1H,dd,J=2.2,8.7Hz),7.45-7.30(6H,m),7.18(1H,t,J=6.7Hz),7.11(1H,s),6.79(1H,d,J=15.7Hz),5.79(1H,t,J=8.2Hz),5.41(1H,d,J=6.9Hz),5.15-4.85(6H,m),4.50-4.38(2H,m),4.20-4.10(2H,m),4.10-3.95(3H,m),3.64(1H,d,J=6.5Hz),3.02(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=6.9Hz),2.30-2.05(6H,m),1.98(1H,m),1.85(1H,m),1.78-1.60(6H,m),1.60-1.47(5H,m),1.45-1.20(16H,m),0.99(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H85N6O22FCl[M-1/2Ca]-1415.5395;Found1415.5386.
实施例10:S-01-Me甲酯的合成
反应试剂与条件:(a)SOCl2,MeOH,0℃-rt,12h;(b)HOSu,EDC·HCl,DMSO,rt,12h;(c)NMM,DMSO,rt,12h.
反应操作:(a)冰浴下,将MDA-1(6.0g,9.4mmol)溶于80mL甲醇中,之搅拌5min,向上述反应器中缓慢滴加二氯亚砜(0.75mL,10.37mmol),滴加完毕,反应体系升至室温,反应12小时。则于30℃减压蒸干溶剂,用DCM溶解后再于30℃下减压蒸干DCM,所得固体产物在室温下用真空干燥24小时,直接用与下一步反应。(b)和(c)步骤参见通用合成步骤3,最后制备得到S-01-Me的纯品4.5g,产率34%(三步收率)。1H-NMR(500MHz,DMSO-d6):8.42(1H,d,J=6.8Hz),8.20(2H,t,J=7.8Hz),7.98(2H,d,J=7.5Hz),7.90-7.60(7H,m),7.53(1H,dd,J=2.6,8.8Hz),7.45-7.25(6H,m),7.18(1H,t,J=6.8Hz),7.09(1H,s),6.78(1H,d,J=15.7Hz),5.79(1H,t,J=8.3Hz),5.40(1H,d,J=7.1Hz),5.09(3H,s),4.98(1H,d,J=7.1Hz),4.90(2H,d,J=10.4Hz),4.50-4.35(2H,m),4.25-4.10(2H,m),4.10-3.95(3H,m),3.64(1H,d,J=7.0Hz),3.61(3H,s),3.01(2H,q,J=5.9Hz),2.70-2.55(2H,m),2.38(2H,t,J=7.1Hz),2.35-2.20(4H,m),2.17(2H,t,J=8.0Hz),1.98(1H,m),1.85(1H,m),1.78-1.60(6H,m),1.60-1.55(2H,m),1.52(3H,s),1.45-1.20(16H,m),0.99(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C71H87N6O22FCl[M-H]-1429.5551;Found 1429.5549.
实施例11:S-02的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.42(1H,br.s),8.48(1H,d,J=5.2Hz),8.21(1H,d,J=7.3Hz),8.06(1H,d,J=6.7Hz),7.96(2H,d,J=6.6Hz),7.90-7.75(2H,m),7.75-7.55(4H,m),7.51(1H,d,J=10.3Hz),7.45-7.20(6H,m),7.20-7.00(2H,m),6.83(1H,d,J=16.0Hz),5.76(1H,m),5.37(1H,d,J=6.0Hz),5.15-4.80(6H,m),4.50-4.30(2H,m),4.20-3.90(5H,m),3.61(1H,m),2.98(2H,m),2.70-2.55(2H,m),2.40-2.30(2H,m),2.30-2.05(6H,m),1.94(1H,m),1.80(1H,m),1.75-1.57(6H,m),1.57-1.43(5H,m),1.42-1.15(16H,m),0.95(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H86N6O22FClNa[M+Na]+1439.5365;Found1439.5360.
实施例12:S-03的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.45(1H,br.s),8.28(1H,d,J=6.6Hz),8.18(1H,d,J=7.8Hz),8.06(1H,d,J=7.6Hz),7.96(2H,d,J=7.5Hz),7.90-7.75(2H,m),7.70(1H,t,J=7.1Hz),7.63(2H,t,J=7.3Hz),7.45-7.25(8H,m),7.20(2H,d,J=7.6Hz),7.16(1H,t,J=6.6Hz),7.08(1H,s),6.67(1H,d,J=15.7Hz),5.76(1H,t,J=8.1Hz),5.38(1H,d,J=6.8Hz),5.06(3H,s),4.99(1H,d,J=6.8Hz),4.95-4.80(2H,m),4.45-4.30(2H,m),4.20-4.05(2H,m),4.05-3.90(3H,m),3.62(1H,d,J=6.3Hz),2.98(2H,m),2.70-2.55(2H,m),2.36(2H,t,J=6.7Hz),2.30(3H,s),2.26-2.05(6H,m),1.94(1H,m),1.82(1H,m),1.75-1.57(6H,m),1.57-1.43(5H,m),1.42-1.15(16H,m),0.95(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C71H91N6O22[M+H]+1379.6186;Found 1379.6180.
实施例13:S-04的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.54(1H,br.s),8.99(1H,d,J=5.2Hz),8.64(1H,d,J=6.9Hz),8.45(1H,d,J=5.2Hz),8.30-8.10(4H,m),8.03(2H,d,J=5.2Hz),7.98-7.85(3H,m),7.85-7.65(4H,m),5.84(1H,m),5.46(1H,d,J=6.0Hz),5.25-4.90(6H,m),4.70(1H,m),4.50(1H,s),4.30-4.00(5H,m),3.69(1H,d,J=6.8Hz),3.07(2H,m),2.80-2.65(2H,m),2.50-2.35(2H,m),2.35-2.15(6H,m),2.03(1H,m),1.90(1H,m),1.75-1.57(6H,m),1.57-1.43(5H,m),1.42-1.15(16H,m),1.03(6H,s).HR-MS(ESI-TOF)m/z:Calcd forC71H87N7O22Na[M+Na]+1412.5802;Found 1412.5794.
实施例14:S-05的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.47(1H,br.s),8.35(1H,d,J=5.1Hz),8.19(1H,d,J=7.1Hz),8.07(1H,d,J=6.8Hz),7.99(2H,d,J=6.6Hz),7.90-7.80(1H,m),7.78-7.50(5H,m),7.50-7.33(5H,m),7.30(1H,s),7.20-7.05(3H,m),6.50(1H,d,J=15.6Hz),5.79(1H,t,J=8.1Hz),5.40(1H,d,J=6.8Hz),5.06(3H,s),4.99(1H,d,J=6.8Hz),4.95-4.80(2H,m),4.50-4.30(2H,m),4.20-4.10(2H,m),4.10-3.90(3H,m),3.63(1H,d,J=6.3Hz),3.01(2H,s),2.70-2.55(2H,m),2.38(2H,t,J=6.7Hz),2.30-2.05(6H,m),1.96(1H,m),1.84(1H,m),1.75-1.57(6H,m),1.57-1.43(5H,m),1.42-1.15(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C68H85N6O22S[M-H]-1369.5443;Found 1369.5445.
实施例15:S-06的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.48(1H,br.s),8.98(1H,d,J=7.0Hz),8.25-8.15(2H,m),8.10(1H,d,J=7.4Hz),7.98(2H,d,J=7.3Hz),7.93-7.80(3H,m),7.75-7.60(4H,m),7.45-7.30(4H,m),7.27(1H,s),7.18(1H,t,J=4.8Hz),7.11(1H,s),5.78(1H,t,J=8.1Hz),5.40(1H,d,J=7.0Hz),5.08(3H,s),5.01(1H,d,J=6.4Hz),4.95-4.80(2H,m),4.50-4.30(2H,m),4.19(1H,q,J=5.4Hz),4.11(1H,q,J=5.4Hz),4.08-3.95(3H,m),3.63(1H,d,J=6.6Hz),3.01(2H,s),2.70-2.55(2H,m),2.38(2H,t,J=6.8Hz),2.30-2.05(6H,m),1.95(1H,m),1.83(1H,m),1.78-1.60(6H,m),1.60-1.43(5H,m),1.42-1.15(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C68H83ClN7O24[M-H]-1416.5183;Found1416.5167.
实施例16:S-07的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.49(1H,br.s),8.48(1H,d,J=6.7Hz),8.24(1H,d,J=8.1Hz),8.09(1H,d,J=7.6Hz),7.99(2H,d,J=7.4Hz),7.93-7.80(2H,m),7.77-7.60(4H,m),7.50-7.30(7H,m),7.18(2H,t,J=7.2Hz),7.12(1H,s),6.82(1H,d,J=16.0Hz),5.78(1H,t,J=8.6Hz),5.40(1H,d,J=7.0Hz),5.15-4.80(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=6.7Hz),3.01(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=7.0Hz),2.30-2.05(6H,m),1.98(1H,m),1.84(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H85N6O22F2[M-H]-1399.5690;Found 1399.5688.
实施例17:S-08的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.49(1H,br.s),8.34(1H,d,J=6.8Hz),8.23(1H,d,J=8.1Hz),8.09(1H,d,J=7.5Hz),7.98(2H,d,J=7.4Hz),7.91-7.80(2H,m),7.75-7.60(4H,m),7.55-7.28(8H,m),7.18(1H,t,J=7.1Hz),7.11(1H,s),6.75(1H,d,J=15.8Hz),5.78(1H,t,J=8.6Hz),5.40(1H,d,J=7.1Hz),5.15-4.85(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=7.0Hz),3.00(2H,m),2.70-2.55(2H,m),2.37(2H,t,J=7.0Hz),2.30-2.05(6H,m),1.98(1H,m),1.83(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).
HR-MS(ESI-TOF)m/z:Calcd for C70H85N6O22F2[M-H]-1399.5690;Found1399.5692.
实施例18:S-09的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.49(1H,br.s),8.35(1H,d,J=6.8Hz),8.24(1H,d,J=8.0Hz),8.10-7.95(3H,m),7.90-7.80(2H,m),7.78-7.60(4H,m),7.60-7.30(9H,m),7.17(1H,t,J=7.1Hz),7.10(1H,s),6.83(1H,d,J=15.9Hz),5.78(1H,t,J=8.6Hz),5.40(1H,d,J=7.0Hz),5.15-4.85(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=7.0Hz),3.00(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=7.1Hz),2.30-2.05(6H,m),1.98(1H,m),1.82(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H87N6O22FK[M+K]+1421.5495;Found 1421.5627.
实施例19:S-10的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.48(1H,br.s),9.85(1H,s),8.20(2H,dd,J=11.3,7.6Hz),8.08(1H,d,J=7.8Hz),7.98(2H,d,J=7.4Hz),7.90-7.80(2H,m),7.72(1H,t,J=7.2Hz),7.65(2H,t,J=7.4Hz),7.45-7.25(8H,m),7.18(1H,t,J=7.0Hz),7.10(1H,s),6.79(2H,d,J=8.5Hz),6.52(1H,d,J=15.8Hz),5.78(1H,t,J=8.6Hz),5.40(1H,d,J=7.1Hz),5.15-4.85(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=6.8Hz),3.01(2H,m),2.70-2.55(2H,m),2.37(2H,t,J=7.1Hz),2.30-2.05(6H,m),1.99(1H,m),1.82(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C70H88N6O23Na[M+Na]+1403.5799;Found 1403.5795.
实施例20:S-11的合成(通用合成步骤3)
1H-NMR(500MHz,DMSO-d6):12.49(1H,br.s),8.75(1H,s),8.56(1H,d,J=4.1Hz),8.42(1H,d,J=6.8Hz),8.25(1H,d,J=8.0Hz),8.09(1H,d,J=6.9Hz),7.98(3H,d,J=7.7Hz),7.93-7.80(2H,m),7.80-7.60(3H,m),7.50-7.30(7H,m),7.18(1H,d,J=6.6Hz),7.12(1H,s),6.87(1H,d,J=16.0Hz),5.78(1H,t,J=8.6Hz),5.40(1H,d,J=6.9Hz),5.15-4.85(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=6.8Hz),3.01(2H,m),2.70-2.55(2H,m),2.37(2H,t,J=6.8Hz),2.30-2.05(6H,m),1.96(1H,m),1.81(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C69H86N7O22[M-H]-1364.5831;Found 1364.5820.
实施例21:S-12的合成(通用合成步骤3)
1H-NMR(300MHz,DMSO-d6):12.44(1H,br.s),8.62(1H,d,J=4.0Hz),8.57(1H,d,J=6.7Hz),8.21(1H,d,J=8.2Hz),8.09(1H,d,J=7.7Hz),7.99(2H,d,J=7.1Hz),7.93-7.80(3H,m),7.78-7.62(3H,m),7.58(1H,d,J=7.8Hz),7.50-7.28(7H,m),7.16(3H,m),5.78(1H,t,J=8.5Hz),5.40(1H,d,J=7.1Hz),5.15-4.85(6H,m),4.50-4.35(2H,m),4.20-3.95(5H,m),3.63(1H,d,J=7.1Hz),3.01(2H,m),2.70-2.55(2H,m),2.38(2H,t,J=7.0Hz),2.30-2.05(6H,m),1.98(1H,m),1.82(1H,m),1.78-1.60(6H,m),1.60-1.45(5H,m),1.40-1.20(16H,m),0.98(6H,s).HR-MS(ESI-TOF)m/z:Calcd for C69H86N7O22[M-H]-1364.5831;Found 1364.5826.
本发明所公布的化合物S-01及文献报道的MDC-405按照药典溶解度标准操作,试验结果表明:随着缓冲液的pH值的增大,其溶解度逐渐增加,当达到pH值6.5以上,S-01的溶解度达到溶解级别,表现出更好的亲水性,从而表现出明显优异的成药性。试验结果参见附表一。
备注:
极易溶解:1g溶质在不到1ml溶剂中溶解;
易溶:1g溶质在1~10ml溶剂中溶解;
溶解:1g溶质在10~30ml溶剂中溶解;
略溶:1g溶质在30~100ml溶剂中溶解;
微溶:1g溶质在100~1000ml溶剂中溶解;
极微溶解:1g溶质在1000~10000ml溶剂中溶解;
几乎不溶或不溶指1g溶质在10000ml溶剂中不能完全溶解。
生物学实施例
体外活性测试部分
实施例22:
一、实验细胞:
NCI-H460,人大细胞肺癌细胞;A549,人非小细胞肺癌细胞
二、实验材料
2.1 细胞培养相关材料及试剂
2.2 96孔板
2.3 分液器
2.4 SRB试剂盒
2.4.1 三羟甲基氨基甲烷(Trizma base):V900483-500G,Lot#WXBB4482V,PCode:101421913
2.4.2 三氯乙酸Trichloroacetic acid(TCA):T9159-500G,Lot#BCBL5964V,PCode:10146647
2.4.3 磺酰罗丹明B Sulforhodamine B(SRB):341738-1G,Lot#20223EAV,PCode:1001890567
2.5 吸水纸
2.6 排枪及枪头
2.7 灭菌水
2.8二甲亚砜DIMETHYL SULPHOXIDE(DMSO):D2438,Lot RNBD1974,Exp:04/2016
2.9 乙酸Acetic acid:338826-500ML,Lot#SHBD0354V,PCode:1001616171
三、实验方法
3.1 细胞复苏
①水浴锅升温至37℃,10%FBS及1%青霉素-链霉素的RPMI-1640培养基37℃预热;开启离心机,使温度降至4℃;
②在安全柜内取约5ml10%FBS及1%青霉素-链霉素的RPMI-1640培养基至15ml离心管中,待用;
③从液氮罐内取出冻存细胞至盛有37℃水的量杯中,37℃水浴锅内振摇冻存管,至约90%-95%冻存液溶化;
④将含细胞的冻存液移至②的离心管中,1000rpm/min,离心5min;
⑤弃上清,加入约1ml10%FBS及1%青霉素-链霉素的RPMI-1640培养基重悬混匀细胞,移至含4ml10%FBS及1%青霉素-链霉素的RPMI-1640培养基的25cm2培养瓶中;
⑥置于37℃,5%CO2,相对湿度100%的培养箱中培养。
3.2 细胞传代
①开启离心机,使温度降至4℃;安全柜内弃去培养瓶中的培养基,PBS冲洗培养瓶1-2次;
②加入0.25%胰酶-EDTA 1ml,37℃消化;
③消化至可见少部分细胞脱落,约2.5min,加入10ml 10%FBS及1%青霉素-链霉素的RPMI-1640培养基终止消化,吹散细胞,移至15ml离心管中;
④1000rpm/min,4℃,离心5min;
⑤弃上清,加入1ml 10%FBS及1%青霉素-链霉素的RPMI-1640培养基重悬,按1:3传代至75cm2中;
⑥置于37℃,5%CO2,相对湿度100%的培养箱中培养。
3.3 SRB试剂盒及试剂的准备
10mM Tris base配制(ddH2O):精密称取0.1211g三羟甲基氨基甲烷,加入ddH2O定容至100ml。
0.4%SRB的配制(1%醋酸):精密称取0.4g SRB,加入1%醋酸定容至100ml。
1%醋酸:精密量取5ml冰醋酸,加入ddH2O定容至500ml。
TCA(50%)(ddH2O):精密称取50gTCA,加入ddH2O定容至100ml。
3.4 细胞接种(收集细胞,铺板)
H460细胞或A549培养于含10%FBS及1%青霉素-链霉素的RPMI-1640培养基中。取对数生长期细胞,用5%-1640完全培养基重悬,将细胞密度调整为7.5*104个/mL,100μL/孔,接种于96孔板,将培养板放入培养箱中培养24h。
3.5 药物(化合物)的配制
3.5.1 待测化合物贮存液的配制方法
3.5.2 待测化合物贮存液的配制方法:
将20mM贮存液进行十倍稀释,得2*10-3M稀释液,同理,依次稀释得2*10-4M,2*10- 5M,2*10-6M,2*10-7M,2*10-8M,2*10-9M稀释液,避光,4℃保存
3.6 平行对照组细胞固定
3.6.1 50%TCA 4℃放置1h
3.6.2 向平行对照组板内加入25μL/well TCA,4℃放置1h
3.6.3 去离子水洗板5次,自然晾干
3.7 细胞给药
3.7.1 溶媒对照组:取DMSO 4μL,加入796μL的5%-1640培养基,100μL/孔/板
3.7.2 受试给药组:取各浓度贮存液2μL加398μL 5%-1640完全培养基,即得10- 4M,10-5M,10-6M,10-7M,10-8M,10-9M,10-10M,10-11M,100μL/孔/板,按布局加样37℃,5%CO2,相对湿度100%的培养箱中培养48h
3.8 给药组细胞固定(药物处理48h后)
3.8.1 50%TCA 4℃放置1h
3.8.2 向受试药组板内加入50μL/well TCA,4℃放置1h
3.8.3 去离子水洗板5次,自然晾干
3.9 细胞染色
3.9.1 向板内加入100μL/well 0.4%SRB,室温静置10min
3.9.2 1%醋酸洗板5次,自然晾干(去掉未结合的SRB)
3.10 检测
向板内加入150μL/well 10mM Tris碱液,震荡5min,与515nm处检测OD值
3.11 数据处理方法
将平行对照组OD值记为Tz,溶媒对照组OD值记为C,受试给药组OD值记为Ti:
1)若Ti≥Tz,说明细胞加药后仍然生长
生长率%(Percentage growth)=[(Ti-Tz)/(C-Tz)]×100
2)若Ti<Tz,说明加药后细胞被杀死
生长率%(Percentage growth)=[(Ti-Tz)/Tz]×100
用软件GraphPad拟合曲线,并计算GI50。
本发明的公布的优选化合物,针对A549和H460人源肿瘤细胞株的实验结果表明,该类型共缀物的生长抑制50%值(GI50值)与相对于MDC-405有更小的GI50值,预测有更好的抗肿瘤效果,实验结果参见附表二。
表二:GI50体外试验结果
注:E表示×10n,例如5.06E-08表示5.06×10-8。
体内活性测试部分
实施例23,采用小鼠乳腺癌4T1肺转移模型:
(1)细胞培养与肿瘤接种:4T1细胞培养在含有10%胎牛血清(Hyclone Corp,USA)、1%谷氨酰胺与1%青-链霉素的1640培养基(Gibco)中。收集对数生长期的4T1细胞,调节细胞浓度为1.5×106/mL。取雌性BALB/c小鼠,于第4乳腺脂肪垫内接种4T1细胞,接种体积为0.1mL,即1.5×105/只。
分组与给药:BALB/c小鼠乳腺脂肪垫内接种4T1乳腺癌细胞,设接种当天为D0,接种后第4天分组给药,试验设四组:
①溶媒对照组(空白对照组),
②S-01 10mg/kg组,
③DTX(多西紫杉醇)5.7mg/kg组,
④MDC-405 10mg/kg组。
③和④为阳性对照组。
每组10只动物。小鼠每周一次尾静脉注射给药,连续4周。给药过程中监测动物体重及瘤体积。每2-3天称量动物体重,游标卡尺测量乳腺肿瘤的长、短径,以公式:(1/2)×长径×(短径)2计算肿瘤大小。接瘤后第28天(D28)结束实验,眼球采血后颈椎脱臼法处死小鼠,称乳腺瘤重、肺重,计数肺表面转移结节数。瘤重实验结果如图1A所示,肺表面转移结节数实验结果如图1B所示。
如图1A和1B所示,S-01、MDC-405及多西紫杉醇相对于空白对照组显著抑制乳腺瘤重和肺表面转移结节数,更为重要的是,S-01相对于阳性对照组多西紫杉醇的抑制具有显著差异,而MDC-405相对于多西紫杉醇的抑制未表现显著差异,由此可见S-01相对于MDC-405及多西紫杉醇均具有更好的抑制瘤和癌转移作用。
(2)细胞培养与肿瘤接种:4T1细胞培养在含有10%胎牛血清(Hyclone Corp,USA)、1%谷氨酰胺与1%青-链霉素的1640培养基(Gibco)中。收集对数生长期的4T1细胞,调节细胞浓度为1.5×106/mL。取雌性BALB/c小鼠,于第4乳腺脂肪垫内接种4T1细胞,接种体积为0.1mL,即1.5×105/只。
分组与给药:BALB/c小鼠乳腺脂肪垫内接种4T1乳腺癌细胞,设接种当天为D0,接种后第4天分组给药,试验设五组:
①溶媒对照组(空白对照组),
②S-01 10mg/kg组,
③DTX(多西紫杉醇)5.7mg/kg组,
④DTX(5.7mg/kg)+MDA-1(4.53mg/kg)组,
⑤DTX(5.7mg/kg)+MDA-1-linker(4.43mg/kg)组。
③、④和⑤为阳性对照组。
每组10只动物。小鼠每周一次尾静脉注射给药,连续4周。给药过程中监测动物体重及瘤体积。每2-3天称量动物体重,游标卡尺测量乳腺肿瘤的长、短径,以公式:(1/2)×长径×(短径)2计算肿瘤大小。接瘤后第28天(D28)结束实验,眼球采血后颈椎脱臼法处死小鼠,称乳腺瘤重、肺重,计数肺表面转移结节数。瘤重实验结果如图2A所示,肺表面转移结节数实验结果如图2B所示。
如图2A所示,S-01、多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker相对于空白对照组显著抑制乳腺瘤重增加,更为重要的是,S-01相对于阳性对照组多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker的抑制均具有显著差异,说明S-01相对于阳性对照组均具有更好的抑瘤作用。
如图2B所示,S-01、多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker相对于空白对照组显著抑制肺表面转移结节数增加,更为重要的是,S-01相对于阳性对照组多西紫杉醇的抑制具有显著差异,相对于多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker抑制效果分别增加了27.9%和18.6%,说明S-01相对于阳性对照组均具有更好的抑制癌转移作用。
(3)细胞培养与肿瘤接种:BALB/c(nu/nu)小鼠,雌性,SPF级,4~5周龄,购自广东实验动物中心,合格证编号:NO.44007200013511,小鼠饲养于深圳信立泰药业股份有限公司技术中心创新药物研究中心SPF级动物实验室。试验所用瘤株由中国医学科学院刘刚教授馈赠,该瘤株为MDA-MB-231乳腺癌,在本实验室复苏传代后的第三代。
分组与给药:选择肿瘤生长及全身状况良好的荷瘤动物,颈椎脱臼处死。无菌条件下取出瘤块,用手术刀切割成直径为2-3mm的瘤块,套管针接种于裸小鼠腋后皮下。肿瘤自然生长,待瘤体积长至100mm3后随机分组。设分组给药日为D0。
试验共设六组,分别为:
①溶媒对照组,
②SAL-0101 5mg/kg组,
③SAL-0101 10mg/kg组,
④DTX 2.85mg/kg组,
⑤DTX(2.85mg/kg)+MDA-1(2.26mg/kg)组,
⑥DTX(2.85mg/kg)+MDA-1-linker(2.21mg/kg)组。
每组8只动物,即日起分别按动物体重开始给药。各组动物每周静脉注射给药1次,共3次。
给药过程中每2-3天测量动物肿瘤长、短径及体重,以公式:(1/2)×长径×(短径)2计算肿瘤体积,分组后第18天(D18)结束试验。实验结束时将动物颈椎脱臼处死,剥离肿瘤,称瘤重,计算药物对肿瘤生长抑制率。计算肿瘤体积(TV)及相对肿瘤体积(RTV)。用t检验法比较各组动物肿瘤重量、肿瘤体积、RTV等指标差别的统计学意义。
计算公式如下:
肿瘤体积(TV)=(长×宽2)/2。
相对肿瘤体积(RTV)=Vt/Vo
(其中Vo为分笼给药时测量所得TV,Vt为以后每次测量时的TV。)
抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(%),
疗效评价标准:T/C(%)>40为无效;
T/C(%)≤40,并经统计学处理P<0.05为有效。
瘤体积实验结果如图3A所示,瘤重实验结果如图3B所示。
如图3A和3B所示,S-01、多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker相对于空白对照组显著抑制瘤体积和瘤重增加,更为重要的是,S-01相对于阳性对照组多西紫杉醇、多西紫杉醇+MDA-1及多西紫杉醇+MDA-1-linker的抑制均具有显著差异,说明S-01相对于阳性对照组均具有更好的抑制瘤作用。
通过同样的实验发现,本发明其他优选的化合物具有S-01类似的抑瘤效果和抑瘤转移效果,但以S-01最为优异,从而可以推论,本发明优选的化合物均相对于MDC-405及多西紫杉醇、有更好的抑瘤效果和抑瘤转移效果。
注,上述实验中,MDA-1-linker的结构如下:
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Claims (5)
1.如下所示的化合物及其药学上可接受的盐
2.根据权利要求1的化合物及其药学上可接受的盐,其特征在于,所述的药学上可接受的盐选自如下化合物
3.权利要求1-2中任一项所述的化合物或其药学上可接受的盐在制备治疗各种肿瘤的药物中的应用。
4.根据权利要求3的应用,其特征在于,所述的肿瘤选自黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌。
5.一种药物组合物,其特征在于,包含权利要求1-2中任一项所述的化合物或其药学上可接受的盐和一种以上药学上可接受的载体。
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