CN104292163B - 具有抗多种肿瘤活性的格尔德霉素类似物及其制备方法和应用 - Google Patents
具有抗多种肿瘤活性的格尔德霉素类似物及其制备方法和应用 Download PDFInfo
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- CN104292163B CN104292163B CN201410440712.5A CN201410440712A CN104292163B CN 104292163 B CN104292163 B CN 104292163B CN 201410440712 A CN201410440712 A CN 201410440712A CN 104292163 B CN104292163 B CN 104292163B
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- geldanamycin
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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
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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Abstract
本发明公开了一组具有抗多种肿瘤活性的格尔德霉素类似物及其制备方法和应用。本发明利用半合成方法得到17及19位分别被修饰的格尔德霉素类似物，实验证明，这些化合物具有抗多种肿瘤的活性，且毒性比格尔德霉素明显降低，因此本发明的一组具有抗多种肿瘤活性的格尔德霉素类似物在作为抗肿瘤药物方面将具有广阔的应用前景。
Description
技术领域
本发明涉及格尔德霉素类似物及其在制备抗肿瘤药物中的用途，特别涉及一组17,19位分别被取代的格尔德霉素类似物及其在制备抗肿瘤药物中的用途。本发明属于医药技术领域。
背景技术
格尔德霉素(geldanamycin，GA)是一种从链霉菌中分离得到的天然的苯醌安莎类抗生素，具有抗肿瘤和抗病毒等多种生物活性[SasakiKetal,JAntibiot,1979,32,849-51]。GA可以通过改变热休克蛋白(heatshockprotein，HSP)90的构象，抑制其正常的分子伴侣功能，导致HSP90受体蛋白的降解[HahnJSetal,BMBRep,2009,42,623-30]，继而阻断肿瘤赖以生存的信号转导通路。由于GA具有水溶性低和肝毒性大的缺陷，诸多旨在改善其缺陷，提高抗肿瘤活性的研究被报道。Tian等曾经合成和评价了大量17-烷氨基-17脱甲氧基的GA衍生物、7位氨基甲酸酯类似物以及11位取代的GA类似物，17-烷氨基-17脱甲氧基的GA衍生物表现出了更明显的优势，其中17-AAG和17-DMAG已经进入临床试验阶段，但临床试验的结果不太乐观，这些肝毒性仍然较大[Tianetal,BMC,2004,12,5317-29；BMCL,2005,15,5016-21；JMC,2009,52,3265-73]；后来有研究显示GA衍生物的氢醌型化合物具有明显改善的水溶性，且毒性明显降低，代表化合物也已经处于临床研究阶段[GeJetal,JMC,2006,49,4606-15；SydorJRetal,ProcNatlAcadSciUSA2006；103:17408–13]。另外已有研究显示GA类似物的19位在体内能与含硫蛋白发生加和反应可能是其致毒的原因[Cysyk,RL,Chem.Res.Toxicol.,2006,19,376-81]，因而提示19位取代可能降低这类化合物的毒性，而且最新的一篇发表在Naturechemistry上的文章显示，19位取代的格尔德霉素具有明显的低毒性优势[KitsonRRetal,NatureChemistry,2013,5,307-14]，而且之前我们的同事也分离或合成得到了多种19-位硫醚取代的GA类似物，并且发现这些化合物具有明显的抗肿瘤活性，水溶性试验表明这些化合物还具有相比GA明显更高的溶解度[LiuXetal,JournalofAntibiotics,2011,64,519-22；NiSetal,JMicrobiolBiotechnol,2011,21,599-603]。但是这类19位取代GA类似物的抗肿瘤活性中等，没有GA的活性强，因此有必要对其进行相应的改造，在改善水溶性的同时提高其抗肿瘤活性。
本发明的目的，就是要以19位硫醚取代的GA类似物为原料，通过化学合成和活性测定筛选得到抗肿瘤活性更强，毒性降低的新型GA类似物。而且本发明涉及的这些化合物及其用于制备抗肿瘤药物的用途迄今均未见相关报道。
发明内容
本发明所要解决的技术问题在于提供一系列具有抗肿瘤活性强，且低毒的17-烷氨基取代-19-硫醚取代的格尔德霉素类似物及其制备方法和应用。
为了达到上述目的，本发明所采用的技术手段为：
本发明以天然分离或合成得到的19位硫醚取代GA类似物为原料，在极性非质子性溶剂中，将其与氨基化合物反应后，经过柱层析分离纯化从而得到一系列17-烷氨基取代-19-硫醚取代的新型格尔德霉素类似物。
本发明的格尔德霉素类似物或其药学上可接受的盐，其特征在于所述的格尔德霉素类似物的结构如式I所示：
其中，R1为取代的氨基，R2为烷基取代的巯基。
在本发明中，优选的，R1为-NH-(CH2)n-R，其中n＝1-6，R为饱和或不饱和的杂环基、经取代的饱和或不饱和的杂环基或磷酸酯基，R2为含1-5个碳原子的烷基取代的巯基。
其中，优选的，当R为饱和或不饱和的杂环基或经取代的饱和或不饱和的杂环基时，n＝1-3，其中杂环基为含N、O或S杂原子中至少一种的五元或六元饱和或不饱和的杂环烃，R2为含1-3个碳原子的烷基取代的巯基；当R为磷酸酯基时，n＝1-2，R2为含1-3个碳原子的烷基取代的巯基。
其中，所述的经取代的饱和或不饱和的杂环基中，取代基优选为含1-5个碳原子的烷基；所述的磷酸酯基优选为磷酸甲酯基、磷酸二甲酯基、磷酸乙酯基或磷酸二乙酯基。
更优选的，R1为 R2为甲硫基、乙硫基或丙硫基。
在本发明中，所述的药学上可接受的盐包括所述的格尔德霉素类似物的盐酸盐、硫酸盐、磺酸盐、苯甲酸盐、草酸盐或富马酸盐。
采用MTT法测定了上述化合物对多种肿瘤细胞的抑制活性，如人乳腺癌细胞(MCF7)、宫颈癌细胞系(HELA)或人结肠癌细胞系(HCT116)，结果表明本发明合成的这些化合物具有抗多种肿瘤的活性，且对正常细胞的毒性比格尔德霉素明显降低，因此本发明的化合物具有更高的选择性指数，这类17，19位被分别取代的格尔德霉素类似物也因此能够成为更安全的用于单一给药或联合治疗抗肿瘤药物的选择。
因此，进一步的，本发明还提出了所述的格尔德霉素类似物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
在本发明中，优选的，所述的抗肿瘤药物为抗胃癌、乳腺癌、宫颈癌、肠癌或肝癌的药物。
更进一步的本发明还提出了一种用于抗肿瘤的药物组合物，其特征在于由本发明所述的格尔德霉素类似物或其药学上可接受的盐为活性成分，与一种或多种药学上可接受的载体所组成。
有益效果：
本发明通过化学合成得到了一系列具有抗肿瘤活性强，且低毒的GA类似物，本发明的一组具有抗多种肿瘤活性的格尔德霉素类似物在作为抗肿瘤药物方面将具有广阔的应用前景。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是：在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例119-乙硫基-格尔德霉素的制备(化合物1)
将GA分散到PBS溶液中，加入3当量的乙硫醇，室温避光搅拌至GA上方出现明显红色斑点，用乙酸乙酯萃取PBS溶液，有机层浓缩后上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到红色固体纯品。分子式：C31H44N2O9S，ESI-MS:621(M+1)+
实施例219-丙硫基-格尔德霉素的制备(化合物2)
将GA分散到PBS溶液中，加入3当量的丙硫醇，室温避光搅拌至GA上方出现明显红色斑点，用乙酸乙酯萃取PBS溶液，有机层浓缩后上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到红色固体纯品。分子式：C32H46N2O9S，ESI-MS:635(M+1)+
实施例317-丙烯氨基-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物3)
将19-乙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的丙烯胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C33H47N3O8S,ESI-MS:646(M+1)+
实施例417-[2-(二甲氨基)乙氨基]-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物4)
将19-乙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的2-二甲氨基乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C34H52N4O8S，ESI-MS:677(M+1)+
实施例517-丙烯氨基-19-甲硫基-17-去甲氧基格尔德霉素的制备(化合物5)
将从链霉菌发酵液中分离得到的19-甲硫基格尔德霉素(100mg)溶于DCM，加入2当量的丙烯胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C32H45N3O8S,ESI-MS:632(M+1)+
实施例617-丙烯氨基-19-丙硫基-17-去甲氧基格尔德霉素的制备(化合物6)
将19-丙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的丙烯胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C34H49N3O8S,ESI-MS:660(M+1)+
实施例717-[2-(吡啶-4’-基)-乙氨基]-19-甲硫基-17-去甲氧基格尔德霉素的制备(化合物7)
将从链霉菌发酵液中分离得到的19-甲硫基格尔德霉素(100mg)溶于DCM，加入2当量的2-(吡啶-4’-基)-乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C36H54N4O8S；ESI-MS:703(M+1)+
实施例817-[2-(吡啶-4’-基)-乙氨基]-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物8)
将19-乙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的2-(吡啶-4’-基)-乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C37H56N4O8S，ESI-MS:717(M+1)+
实施例917-[2’-(2”-羟基乙氧基)乙氨基]-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物9)
将19-乙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的2-(2’-羟基乙氧基)乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C34H51N3O10S，ESI-MS:694(M+1)+
实施例1017-[2-(吡啶-4’-基)-乙氨基]-19-丙硫基-17-去甲氧基格尔德霉素的制备(化合物10)
将19-丙硫基-格尔德霉素(100mg)溶于DCM30ml，加入2当量的2-(吡啶-4’-基)-乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C38H58N4O8S，ESI-MS:731(M+1)+
实施例1117-(磷酸二乙酯基-甲氨基)-19-甲硫基-17-去甲氧基格尔德霉素的制备(化合物11)
将从链霉菌发酵液中分离得到的19-甲硫基格尔德霉素(100mg)溶于DCM，加入2当量的磷酸二酯基-甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C34H52N3O11PS,ESI-MS:742(M+1)+
实施例1217-(磷酸二乙酯基-甲氨基)-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物12)
将19-乙硫基格尔德霉素(100mg)溶于DCM，加入2当量的磷酸二酯基-甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C35H54N3O11PS,ESI-MS:756(M+1)+
实施例1317-(磷酸二乙酯基-甲氨基)-19-丙硫基-17-去甲氧基格尔德霉素的制备(化合物13)
将19-丙硫基格尔德霉素(100mg)溶于DCM，加入2当量的磷酸二酯基-甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C36H56N3O11PS,ESI-MS:770(M+1)+
实施例1417-(哌啶-4’-基)-甲氨基)-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物14)
将19-乙硫基格尔德霉素(100mg)溶于DCM，加入2当量的哌啶-4’-基-甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C36H54N4O8S，ESI-MS:703(M+1)+
实施例1517-(1’-乙基四氢吡咯-2’-基)-甲氨基-19-甲硫基-17-去甲氧基格尔德霉素的制备(化合物15)
将从链霉菌发酵液中分离得到的19-甲硫基格尔德霉素(100mg)溶于DCM，加入2当量的1’-乙基四氢吡咯-2’-基甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C36H54N4O8S，ESI-MS:703(M+1)+
实施例1617-[2-(噻吩-2’-基)-乙氨基]-19-甲硫基-17-去甲氧基格尔德霉素的制备(化合物16)
将从链霉菌发酵液中分离得到的19-甲硫基格尔德霉素(100mg)溶于DCM，加入2当量的2-(噻吩-2’-基)乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C35H47N3O8S2，ESI-MS:702(M+1)+
实施例1717-(四氢呋喃-2’-基)-甲氨基)-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物17)
将19-乙硫基格尔德霉素(100mg)溶于DCM，加入2当量的四氢呋喃-2’-基甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C35H51N3O9S，ESI-MS:690(M+1)+
实施例1817-(1’-乙基四氢吡咯-2’-基)-甲氨基-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物18)
将19-乙硫基格尔德霉素(100mg)溶于DCM，加入2当量的1’-乙基四氢吡咯-2’-基甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C37H56N4O8S，ESI-MS:717(M+1)+
实施例1917-(1’-乙基四氢吡咯-2’-基)-甲氨基-19-丙硫基-17-去甲氧基格尔德霉素的制备(化合物19)
将19-丙硫基格尔德霉素(100mg)溶于DCM，加入2当量的1’-乙基四氢吡咯-2’-基甲胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C38H58N4O8S，ESI-MS:731(M+1)+
实施例2017-[2-(噻吩-2’-基)-乙氨基]-19-乙硫基-17-去甲氧基格尔德霉素的制备(化合物20)
将19-乙硫基格尔德霉素(100mg)溶于DCM，加入2当量的2-(噻吩-2’-基)乙胺，室温密闭搅拌，4小时后，浓缩反应液，残余物上硅胶柱，洗脱剂为二氯甲烷/甲醇：20/1，分离得到灰黑色固体纯品。分子式：C36H49N3O8S2，ESI-MS:716(M+1)+
实施例21抗肿瘤活性测定
收集生长良好的肿瘤细胞，用含10％胎牛血清的MEM培养液配细胞悬液，接种于96孔板内，每孔190μl，6000细胞/孔，37℃，5％CO2孵箱培养24h后,加入20×药液10μl，每浓度设3个平行孔，设置空白对照。培养48h后弃上清,每孔加入MTT液20μl(5mg/ml)，继续培养4h，吸弃上清液，用Bio-Rad680型酶标仪在检测波长570nm下测吸光度(A)值，存活率(％)计算：A样品/A空白对照×100，采用GraphpadPrism5统计软件计算IC50，GA类似物的抗肿瘤活性见表1。
表1GA类似物的抗肿瘤活性及半数毒性浓度
实施例22细胞毒性测定
收集生长良好的正常人肝细胞L02，用含10％胎牛血清的DMEM培养液配成4×104/ml的细胞悬液，接种于96孔板内，每孔100μl。37℃，5％CO2孵箱培养24h后,分别加入含不同稀释度药物的培养液100μl，每浓度设3个平行孔，并设置空白对照。培养48h后吸弃上清，每孔加入MTT液20μl(5mg/ml)，继续培养4h，吸弃上清液，用Bio-Rad680型酶标仪在检测波长570nm下测吸光度(A)值，存活率(％)＝A样品/A空白对照×100，采用GraphpadPrism5统计软件计算IC50，结果如表1所示。
Claims (3)
1.格尔德霉素类似物或其药学上可接受的盐在制备抗肿瘤药物中的用途，所述的格尔德霉素类似物的结构如式I所示：
其中，R1为 R2为甲硫基、乙硫基或丙硫基。
2.如权利要求1所述的用途，其特征在于所述的药学上可接受的盐包括所述的格尔德霉素类似物的盐酸盐、硫酸盐、磺酸盐、苯甲酸盐、草酸盐或富马酸盐。
3.如权利要求1所述的用途，其特征在于所述的抗肿瘤药物为抗胃癌、乳腺癌、宫颈癌、肠癌或肝癌的药物。
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