CN117903232A - 一种双芳基桥连环肽的合成方法 - Google Patents
一种双芳基桥连环肽的合成方法 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1019—Tetrapeptides with the first amino acid being basic
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明公开了一种双芳基桥连环肽的合成方法,合成通式如下,包括以下步骤:S1:选择树脂为原料,将其依次偶联氨基酸合成直链多肽M‑II,肽链上有两个侧链或末端由芳基卤代物进行修饰;S2:在过渡金属催化剂作用下,S1中所得产物侧链上的两个芳基卤化物在一定温度下发生偶联反应,所得中间产物经过酸切割和脱保护基,得到双芳基桥连环肽M‑I。该方法以树脂为原料,具有原料易得、合成方法简便、反应时间短,条件温和、副反应少等优点。
Description
技术领域
本发明涉及多肽合成技术领域,具体涉及一种双芳基桥连环肽的合成方法。
背景技术
近几十年来,随着具有不同生物活性的天然环肽被发现,环肽合成与应用引起了人们的广泛关注。与线性肽相比,环状肽具有更刚性的构象,对酶促蛋白水解更有抵抗力,因此代谢更稳定。环肽的受限的结构还可增加对受体和蛋白质靶标的结合亲和力和特异性,是一类有潜力开发成治疗剂的对象。在研究环状肽的结构-活性关系时,环状肽的化学合成是必不可少的。
环肽一般依赖于内酰胺、内酯,硫醚和二硫键等环化方式进行合成。随着钌催化的闭环复分解和铜催化的炔烃-叠氮化物环加成的出现,利用过渡金属催化构建环肽的桥连方式作为一种强大的大环化工具,在化学生物和肽药物发现中有着相关的应用。双芳基桥连环肽常见于一些生物活性分子结构中,如:BiphenomycinB(双酚酶素B),Vancomycin(万古霉素)和ArylomycinA2(芳桥霉素A2)。双芳基桥连环肽的合成一般选用Suzuki-Miyaura偶联作为主要合成方法。此类方法需要先分步合成具有芳基卤化物和芳基硼酸修饰的多肽前体,然后在液相条件下进行双芳基的偶联,反应一般需要在高温或者微波条件,并且需要到贵金属钯催化剂与膦配体的参与,成本高,工艺流程复杂且反应条件苛刻。
发明内容
为了克服现有技术中合成环肽上存在的缺点与不足,本发明的目的在于提供一种双芳基桥连环肽的合成方法,该方法具有原料易得、合成方法简便、反应时间短,条件温和、副反应少等优点,为环肽合成领域提供一种新的技术路线和思路。
本发明解决其技术问题所采用的技术方案是:提供一种双芳基桥连环肽的合成方法,合成通式如下,
包括以下步骤:
S1:选择树脂为原料,将其依次偶联氨基酸合成直链多肽M-II,肽链上有两个侧链或末端由芳基卤代物进行修饰;
S2:在过渡金属催化剂作用下,S1中所得产物侧链上的两个芳基卤化物在设定温度下发生偶联反应,所得中间产物经过酸切割和脱保护基,得到双芳基桥连环肽M-I。
进一步地,合成通式中所述直链多肽M-II中的PGa选用N-H保护基团、Trt(三苯基甲基)、Boc(叔丁氧羰基)、Fmoc((9H-芴-9-基甲氧基)羰基)、Cbz(苄氧羰基)、1-2个氨基酸或芳基卤代物对所述直链肽进行封端。
进一步地,合成通式中Ar-X与羧基通过酰胺键偶联;Ar-X的Ar为芳基或芳杂环;Ar-X的X为氯、溴或碘。
进一步地,S1中所述氨基树脂为固相多肽合成树脂。
进一步地,S1中所述合成直链多肽M-II所用的氨基酸选自可在固相上酰胺缩合的天然氨基酸或非天然氨基酸。优选的,合成通式中的n的数值范围为0-20的自然数。
进一步地,S1中所述由芳基卤代物修饰的两个侧链上的氨基酸选自赖氨酸、鸟氨酸、谷氨酸、天冬氨酸或者其对应的D-构型氨基酸。
进一步地,S2中所述金属催化剂为亚铜类催化剂;所述金属催化剂为底物的0.1~5eq。所选用的亚铜类催化剂为碘化亚铜、溴化亚铜、氯化亚铜、三氟甲烷磺酸亚铜、醋酸亚铜、2-噻吩甲酸亚铜、六氟磷酸四乙腈铜或氰化亚铜。
进一步地,S2中选用的环化溶剂为DMF、NMP、甲苯或DCE;环化溶剂浓度为0.001~0.05mol/L。
进一步地,S2中所述环化反应温度为0~50℃,环化反应时间为0.5-5h。
本发明的有益效果是:
本发明选用廉价金属铜作为催化剂,两个芳基卤化物可高效实现偶联反应,直接在固相上合成成环前体,成本低、选择性高、条件温和,适合工业化生产;并且本发明原料易得,可以氨基树脂和CTC树脂作为原料。
附图说明
图1为本发明的合成通式;
图2为本发明实施例1环肽M-I-A的结构图;
图3为本发明实施例2环肽M-I-B的结构图;
图4为本发明环肽M-I-A的LCMS色谱图;
图5为本发明环肽M-I-A的HPLC色谱图;
图6为本发明环肽M-I-B的LCMS色谱图;
图7为本发明环肽M-I-B的HPLC色谱图。
具体实施方式
本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。下面通过具体实施例,对本发明的技术方案作进一步的具体说明。
本发明中,若非特指,所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法,如无特别说明,均为本领域的常规方法。
实施例1:(M-I-A)
步骤一:Boc-Lys(2-iodobenzoyl)-Pro-His(Trt)-Lys(2-iodobenzoyl)-CTC(M-II-A)的合成
取2-CTC Resin(2.04g,2mmol)于多肽合成管中,室温条件下用二氯甲烷(DCM,15mL)溶胀15分钟,排干溶剂。向多肽合成管依次加入首氨Fmoc-Lys(Alloc)-OH(0.54g,1.2mmol)、DCM(15mL)和二异丙基乙胺(DIEA,0.31g,2.4mmol),室温下用氮气鼓吹反应2小时(中间补加DCM,冲洗挂壁树脂),排干溶剂。用DCM洗涤树脂三遍,加入MeOH/DIEA/DCM的混合溶液(VDCM:VMeOH:VDIEA=75:20:5,20mL)封闭30分钟后排干反应液,用DCM洗涤三次,最后用N,N-二甲基甲酰胺(DMF)洗涤3次,排干溶剂,直接用于下一步反应。
脱Fmoc保护基团:往上述树脂中加入哌啶/DMF(体积比1/4,20mL),25℃±5℃下反应5分钟,抽干,再次加入哌啶/DMF(体积比1/4,20mL)25℃±5℃下反应10分钟。反应完成排干反应液,并用DMF(20mL)洗涤6次,排干等待下一步反应。
偶联氨基酸:将HOBT(0.40g,3mmol)、TBTU(0.96g,3mmol)和DIEA(0.78g,6mmol)依次加入Fmoc-His(Trt)-OH(1.86g,3mmol)的DMF(20mL)溶液中,冰浴下活化反应10分钟;活化完成后将活化液加入上述制备的树脂中,室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂6次,直接用于下一步反应。
重复以上操作逐个依次偶联氨基酸Fmoc-Pro-OH、Fmoc-Lys(Alloc)-OH得到Fmoc-Lys(Alloc)-Pro-His(Trt)-Lys(Alloc)-CTC。
脱Fmoc保护基:向上述制备的树脂中加入哌啶/DMF(体积比1/4,20mL),25℃±5℃下反应5分钟,抽干,再次加入哌啶/DMF(体积比1/4,20mL)25℃±5℃下反应5分钟。反应完成排干反应液,并用DMF(20mL)洗涤6次,直接用于下一步。
Boc保护:向上述制备的树脂中依次加入DMF(20mL),Boc2O(0.65g,3mmol)和DIEA(0.78g,6mmol)。室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂6次,直接用于下一步。
Alloc脱保护
向上述制备的树脂中依次加入DCM(25mL),三苯基膦(0.26g,1mmol),苯硅烷(1.6g,15mmol)和四三苯基膦钯(58mg,0.05mmol)。室温条件下反应2小时;排干反应液,用DMF(20mL)和DCM(20mL)交替洗涤树脂3次,直接用于下一步反应。
2-I苯甲酰化
将TBTU(1.93g,6mmol)和DIEA(1.55g,12mmol)依次加入2-碘苯甲酸中(1.49g,6mmol)的DMF(20mL)溶液中,冰浴下活化反应10分钟;活化完成后将活化液加入上述制备的树脂中,室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂3次,再用DCM(20mL)和EtOH(20mL)交替洗涤2次,最后用EtOH(5mL)洗涤两次;将得到的树脂在真空干燥箱中30℃下干燥3h,得到Boc-Lys(2-iodobenzoyl)-Pro-His(Trt)-Lys(2-iodobenzoyl)-CTC(M-II-A)3.01g。
步骤二:Boc-Lys(2-iodobenzoyl)-Pro-His(Trt)-Lys(2-iodobenzoyl)-CTC的双芳基桥连环化
取树脂(0.15mmol,0.45g)于史莱克管中,依次加入加入NMP(8mL),铜催化剂(2.5eq,72mg),反应5小时后,过滤,用DMF和二乙基二硫代氨基甲酸钠,鼓泡5分钟后,抽干,用DMF洗涤6遍,再用DCM(20mL)和EtOH(20mL)交替洗涤2次,最后用EtOH(5mL)洗涤两次;将得到的树脂在真空干燥箱中30℃下干燥3h,得到联苯桥连的环肽树脂,直接用于下一步反应。
裂解:取上述树脂和TFA:TIS:H2O(体积比95:2.5:2.5,5mL)混合溶液分别加入25mL反应瓶中,25℃±5℃室温条件下反应2h;反应结束后过滤,加入40mL的甲基叔丁基醚中,在冰浴下沉降30分钟,离心,并用甲基叔丁基醚(10mL)洗涤3次,将固体放入真空干燥箱中干燥过夜,溶解,直接通过Pre-HPLC纯化得到纯化液,浓缩并冻干,得到白色固体20mg,HPLC纯度98.4%,收率:18.7%。LCMS(2.74min):M+H+=715.5,1/2(M+2H+)=358.3
利用高效液相色谱对实施例1中得到的分子M-I-A进行分析,得到其HPLC谱图如图2所示,色谱条件如下:仪器型号为Agilent 1260,色谱柱为Sepax HP-C18,4.6*50mm*3umflow:1mL/min,bufferA:0.1%TFA-H2O,buffer B:ACN,B%:5%(4min)→90%→(5min)90%→(5.01)5%→7min→5%,220nm,T Oven 40℃。
实施例2(M-I-B)
步骤一:
Boc-Lys(2-iodobenzoyl)-Pro-Ala-Lys(2-iodobenzoyl)-MBHA的合成
脱Fmoc保护基团:将RinkAmide MBHAResin(0.28mmol/g,3.6g)用DCM(20mL)在多肽合成管中25℃±5℃条件下溶胀15分钟,排干溶剂,加入哌啶/DMF(体积比1/4,20mL),25℃±5℃下反应5分钟,抽干,再次加入哌啶/DMF(体积比1/4,20mL)25℃±5℃下反应10分钟。反应完成排干反应液,并用DMF(20mL)洗涤6次,排干等待下一步反应。
偶联氨基酸:将HOBT(0.40g,3mmol)、TBTU(0.96g,3mmol)和DIEA(0.78g,6mmol)依次加入Fmoc-Lys(Alloc)-OH(1.36g,3mmol)的DMF(20mL)溶液中,冰浴下活化反应10分钟;活化完成后将活化液加入上述制备的树脂中,室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂6次,得到Fmoc-Lys(Alloc)-MBHA。
重复以上操作逐个依次偶联氨基酸Fmoc-Ala-OH、Fmoc-Pro-OH、Fmoc-Lys(Alloc)-OH得到Fmoc-Lys(Alloc)-Pro-Ala-Lys(Alloc)-MBHA。
脱Fmoc保护基:向上述制备的树脂中加入哌啶/DMF(体积比1/4,20mL),25℃±5℃下反应5分钟,抽干,再次加入哌啶/DMF(体积比1/4,20mL)25℃±5℃下反应5分钟。反应完成排干反应液,并用DMF(20mL)洗涤6次,得到H-Lys(Alloc)-Pro-Ala-Lys(Alloc)-MBHA。
Boc保护:向上述制备的树脂中依次加入DMF(20mL),Boc2O(0.65g,3mmol)和DIEA(0.78g,6mmol)。室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂6次,得到Boc-Lys(Alloc)-Pro-Ala-Lys(Alloc)-MBHA。
Alloc脱保护
向上述制备的树脂中依次加入DCM(25mL),三苯基膦(0.26g,1mmol)苯硅烷(1.6g,15mmol)和四三苯基膦钯(58mg,0.05mmol)。室温条件下反应2小时;排干反应液,用DMF(20mL)和DCM(20mL)交替洗涤树脂3次,直接用于下一步反应。
2-I苯甲酰化
将TBTU(1.93g,6mmol)和DIEA(1.55g,12mmol)依次加入2-碘苯甲酸中(1.49g,6mmol)的DMF(20mL)溶液中,冰浴下活化反应10分钟;活化完成后将活化液加入上述制备的树脂中,室温条件下反应1小时;排干反应液,用DMF(20mL)洗涤树脂3次,再用DCM(20mL)和EtOH(20mL)交替洗涤2次,最后用EtOH(5mL)洗涤两次;将得到的树脂在真空干燥箱中30℃下干燥3h,得到Boc-Lys(2-iodobenzoyl)-Pro-Ala-Lys(2-iodobenzoyl)-MBHA4.75 g。
步骤二:
Boc-Lys(2-iodobenzoyl)-Pro-Ala-Lys(2-iodobenzoyl)-MBHA的双芳基桥连环化
取树脂(0.15mmol,0.71g)于史莱克管中,依次加入加入NMP(8mL),铜催化剂(2.5eq,72mg),反应5小时后,过滤,用DMF洗涤3次,加入DMF和二乙基二硫代氨基甲酸钠,鼓泡5分钟后,抽干,用DMF洗涤6遍,再用DCM(20mL)和EtOH(20mL)交替洗涤2次,最后用EtOH(5mL)洗涤两次;将得到的树脂在真空干燥箱中30℃下干燥3h,得到联苯桥连的环肽树脂,直接用于下一步反应。
裂解:取上述树脂和TFA:TIS:H2O(体积比95:2.5:2.5,5mL)混合溶液分别加入25mL反应瓶中,25℃±5℃室温条件下反应2h;反应结束后过滤,加入40mL的甲基叔丁基醚中,在冰浴下沉降30分钟,离心,并用甲基叔丁基醚(10mL)洗涤3次,将固体放入真空干燥箱中干燥过夜,溶解,直接通过Pre-HPLC纯化得到纯化液,浓缩并冻干,得到白色固体35mg,HPLC纯度96.1%,收率:36.1%。LCMS(2.96min):M+H+=648.5,1/2(M+2H+)=324.9。
利用高效液相色谱对实施例2中得到的分子M-I-B进行分析,得到其HPLC谱图如图4所示,色谱条件如下:仪器型号为Agilent 1260,色谱柱为Sepax HP-C18,4.6*50mm*3umflow:1mL/min,bufferA:0.1%TFA-H2O,buffer B:ACN,B%:5%(4min)→90%→(5min)90%→(5.01)5%→7min→5%,220nm。
以上所述的实施例只是本发明的一种较佳的方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (10)
1.一种双芳基桥连环肽的合成方法,其特征在于,合成通式如下,
2.根据权利要求1所述的双芳基桥连环肽的合成方法,其特征在于,包括以下步骤:
S1:选择树脂为原料,将其依次偶联氨基酸合成直链多肽M-II,肽链上有两个侧链或末端由芳基卤代物进行修饰;
S2:在过渡金属催化剂作用下,S1中所得产物侧链上的两个芳基卤化物在设定温度下发生偶联反应,所得中间产物经过酸切割和脱保护基,得到双芳基桥连环肽M-I。
3.根据权利要求1所述的双芳基桥连环肽的合成方法,其特征在于:合成通式中所述直链肽M-II中的PGa选用N-H保护基团、Trt(三苯基甲基)、Boc(叔丁氧羰基)、Fmoc((9H-芴-9-基甲氧基)羰基)、Cbz(苄氧羰基)、1-2个氨基酸或芳基卤代物对所述直链肽进行封端。
4.根据权利要求1所述的双芳基桥连环肽的合成方法,其特征在于:合成通式中Ar-X与羧基通过酰胺键偶联;Ar-X的Ar为芳基或芳杂环;Ar-X的X为氯、溴或碘。
5.根据权利要求2所述的双芳基桥连环肽的合成方法,其特征在于:S1中所述氨基树脂为固相多肽合成树脂。
6.根据权利要求2所述的双芳基桥连环肽的合成方法,其特征在于:S1中所述合成直链多肽M-II所用的氨基酸选自可在固相上酰胺缩合的天然氨基酸或非天然氨基酸。
7.根据权利要求2所述的双芳基桥连环肽的合成方法,其特征在于:S1中所述由芳基卤代物修饰的两个侧链上的氨基酸选自赖氨酸、鸟氨酸、谷氨酸、天冬氨酸或者其对应的D-构型氨基酸。
8.根据权利要求2所述的双芳基桥连环肽的合成方法,其特征在于:S2中所述金属催化剂为亚铜类催化剂;所述金属催化剂为底物的0.1~5eq。
9.根据权利要求2所述的双芳基桥连环肽的合成方法,其特征在于:S2中选用的环化溶剂为DMF、NMP、甲苯或DCE;环化溶剂浓度为0.001~0.05mol/L。
10.根据权利要求8-9任一项所述的双芳基桥连环肽的合成方法,其特征在于:S2中所述环化反应温度为0~50℃,环化反应时间为0.5-5h。
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CN108148115A (zh) * | 2018-01-30 | 2018-06-12 | 中国药科大学 | 一种环肽合成新方法及其在药物开发中的应用 |
CN110698538A (zh) * | 2019-08-30 | 2020-01-17 | 浙江工业大学 | 一种基于酪氨酸偶联的环肽化合物及其制备与应用 |
CN113583088A (zh) * | 2020-04-30 | 2021-11-02 | 中国科学院分子细胞科学卓越创新中心 | 用于治疗胃癌的环肽及其药物组合物 |
CN116178503A (zh) * | 2021-07-27 | 2023-05-30 | 杭州彗搏科技有限公司 | 一种多肽环肽的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN108148115A (zh) * | 2018-01-30 | 2018-06-12 | 中国药科大学 | 一种环肽合成新方法及其在药物开发中的应用 |
CN110698538A (zh) * | 2019-08-30 | 2020-01-17 | 浙江工业大学 | 一种基于酪氨酸偶联的环肽化合物及其制备与应用 |
CN113583088A (zh) * | 2020-04-30 | 2021-11-02 | 中国科学院分子细胞科学卓越创新中心 | 用于治疗胃癌的环肽及其药物组合物 |
CN116178503A (zh) * | 2021-07-27 | 2023-05-30 | 杭州彗搏科技有限公司 | 一种多肽环肽的制备方法 |
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