CN109400597B - A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and its preparation method and application - Google Patents
A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and its preparation method and application Download PDFInfo
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Abstract
一种基于VEGFR‑2抑制剂ABT‑869的蛋白降解靶向嵌合体及制备方法和应用,烷基二羧酸与1‑(4‑(3‑氨基‑1H‑吲唑‑4‑基)苯基)‑3‑(2‑氟‑5‑甲基苯基)脲在PyBop的缩合作用下,得到带有单羧酸的中间产物;2)带有单羧酸的中间产物与(2S,4R)‑1‑((S)‑2‑氨基‑3,3‑二甲基丁酰基)‑4‑羟基‑N‑(4‑(4‑甲基噻唑‑5‑基)苄基)吡咯烷‑2‑甲酰胺在HATU的缩合作用下,得到蛋白降解靶向嵌合体,本发明的蛋白降解靶向嵌合体制备方法简单,易于实现,并且收率较高,可应用于抗肿瘤药物的制备,尤其是用于制备以VEGFR‑2激酶为靶点的抗肿瘤药物。A kind of protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and preparation method and application, alkyl dicarboxylic acid and 1-(4-(3-amino-1H-indazol-4-yl)benzene base)-3-(2-fluoro-5-methylphenyl) urea under the condensation of PyBop, obtains the intermediate product with monocarboxylic acid; 2) the intermediate product with monocarboxylic acid and (2S, 4R )-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- Under the condensation effect of HATU, 2-formamide obtains a protein degradation targeting chimera, the preparation method of the protein degradation targeting chimera of the present invention is simple, easy to realize, and has a high yield, and can be applied to the preparation of antitumor drugs, Especially for the preparation of anti-tumor drugs targeting VEGFR-2 kinase.
Description
技术领域technical field
本发明涉及一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体及制备方法和应用。The present invention relates to a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and a preparation method and application thereof.
背景技术Background technique
蛋白降解靶向嵌合体(PROTACs),对相应的靶标蛋白(如VEGFR-2蛋白)和多肽具有泛素化和降解的功能。靶蛋白配体部分与目标蛋白质结合,E3泛素连接酶配体部分与E3泛素连接酶结合,两部分由linker连接,通过E3泛素连接酶将活化的泛素转移至目标蛋白上,实现了对目标蛋白的选择性泛素化,最终泛素化的目标蛋白被蛋白酶体识别并降解。Protein degradation targeting chimeras (PROTACs) have the functions of ubiquitination and degradation of corresponding target proteins (such as VEGFR-2 protein) and polypeptides. The ligand part of the target protein binds to the target protein, the ligand part of the E3 ubiquitin ligase binds to the E3 ubiquitin ligase, and the two parts are connected by the linker, and the activated ubiquitin is transferred to the target protein through the E3 ubiquitin ligase to achieve After selective ubiquitination of target proteins, the final ubiquitinated target proteins are recognized and degraded by the proteasome.
具体来说,蛋白降解靶向嵌合体(PROTACs)泛素化并降解靶标蛋白和多肽涉及到一种生物体内的蛋白质降解途径,即泛素-蛋白酶体系统。泛素-蛋白酶体系统是细胞内蛋白质降解的主要途径,参与细胞内80%以上蛋白质的降解。泛素-蛋白酶体系统降解蛋白过程是:有三个酶参与了靶蛋白的泛素化。即E1:泛素激活酶;E2:泛素结合酶;E3:泛素连接酶。首先E1将泛素活化,而后将泛素传递给E2,在E3的作用下,泛素分子被转移到靶标蛋白上,实现了蛋白的泛素化。最终被蛋白酶体识别并降解为长度一定的肽段。Specifically, protein degradation-targeted chimeras (PROTACs) ubiquitinate and degrade target proteins and polypeptides involving a protein degradation pathway in organisms, the ubiquitin-proteasome system. The ubiquitin-proteasome system is the main pathway of intracellular protein degradation, and is involved in the degradation of more than 80% of intracellular proteins. The protein degradation process of the ubiquitin-proteasome system is as follows: three enzymes are involved in the ubiquitination of target proteins. Namely E1: ubiquitin activating enzyme; E2: ubiquitin conjugating enzyme; E3: ubiquitin ligase. First, E1 activates ubiquitin, and then transmits ubiquitin to E2. Under the action of E3, the ubiquitin molecule is transferred to the target protein to achieve protein ubiquitination. It is finally recognized by the proteasome and degraded into peptides of a certain length.
利用蛋白降解靶向嵌合体可以治疗各种疾病,其方式与传统小分子化合物完全不同。蛋白降解靶向嵌合体通过识别并泛素化靶标蛋白,随后通过蛋白酶体降解,从而能够选择性的降低患者细胞中靶标蛋白的水平,以治疗一些疾病。Targeting chimeras for protein degradation can treat a variety of diseases in a completely different way than traditional small-molecule compounds. Protein degradation targeting chimeras can selectively reduce the level of target proteins in patient cells to treat some diseases by recognizing and ubiquitinating target proteins, followed by proteasomal degradation.
血管内皮生长因子受体(vascular endothelial growth factor receptor)是由VEGF基因表达的膜蛋白,属于酪氨酸家族蛋白,是与恶性肿瘤密切相关的大分子蛋白。血管内皮生长因子及其受体在一系列肿瘤细胞中都有过表达,该受体家族包括三个亚型:VEGFR-1、VEGFR-2、VEGFR-3。其中VEGFR-2主要参与血管内皮细胞的增殖,在癌细胞中分布也最广泛。一系列的研究证实它可以作为有效的药物靶标。Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor) is a membrane protein expressed by the VEGF gene, belonging to the tyrosine family of proteins, and is a macromolecular protein closely related to malignant tumors. Vascular endothelial growth factor and its receptors are overexpressed in a series of tumor cells, and the receptor family includes three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is mainly involved in the proliferation of vascular endothelial cells and is most widely distributed in cancer cells. A series of studies have confirmed that it can be an effective drug target.
从2008年开始,相继报道了E3泛素连接酶MDM2(mouse double minute2homologue),clAP1(cellulr inhibitor of apoptosis),CRBN(cereblon)和VHL(vonHippel-Lindau)的配体与蛋白配体所构成的小分子PROTACs,其中一个效果比较优秀的E3泛素连接酶配体是VHL(von Hippel-Lindau)配体。Since 2008, E3 ubiquitin ligases MDM2 (mouse double minute2homologue), clAP1 (cellulr inhibitor of apoptosis), CRBN (cereblon) and VHL (von Hippel-Lindau) ligands and protein ligands have been reported successively. Molecular PROTACs, one of the more effective E3 ubiquitin ligase ligands is the VHL (von Hippel-Lindau) ligand.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体及制备方法和应用。The purpose of the present invention is to provide a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 and its preparation method and application.
为达到上述目的,本发明采用以下技术方案:To achieve the above object, the present invention adopts the following technical solutions:
一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体,结构式如下:A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, the structural formula is as follows:
其中,n为1-20之间的整数。Among them, n is an integer between 1-20.
本发明进一步的改进在于,n为3、8或12。A further improvement of the present invention is that n is 3, 8 or 12.
一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体的制备方法,包括以下步骤:A preparation method of protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, comprising the following steps:
1)烷基二羧酸与1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲在PyBop的缩合作用下,得到带有单羧酸的中间产物;1) Condensation of alkyldicarboxylic acid with 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea in PyBop Under the action, an intermediate product with a monocarboxylic acid is obtained;
2)带有单羧酸的中间产物与(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺在HATU的缩合作用下,得到基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体,结构式如下:2) Intermediate product with monocarboxylic acid with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4 -Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide under the condensation of HATU, obtains a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, the structural formula is as follows:
其中,n为1-20之间的整数。Among them, n is an integer between 1-20.
本发明进一步的改进在于,所述步骤1)的具体过程为:将烷基二羧酸与PyBop溶于二氯甲烷中,滴加三乙胺,搅拌均匀后,加入1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲,室温搅拌12h后进行处理,得到带有单羧酸的中间产物。A further improvement of the present invention is that the specific process of the step 1) is: dissolving the alkyl dicarboxylic acid and PyBop in dichloromethane, adding triethylamine dropwise, stirring evenly, adding 1-(4-(3 -Amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea, stirred at room temperature for 12 h and then worked up to give an intermediate product with a monocarboxylic acid.
本发明进一步的改进在于,将庚二酸3.99mmol与PyBop 3.19mmol溶于20mL二氯甲烷中,滴加三乙胺4.79mmol,搅拌均匀后,加入1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲0.799mmol,室温搅拌12h后进行处理,得到带有单羧酸的中间产物。A further improvement of the present invention is that 3.99 mmol of pimelic acid and 3.19 mmol of PyBop are dissolved in 20 mL of dichloromethane, 4.79 mmol of triethylamine is added dropwise, and after stirring uniformly, 1-(4-(3-amino-1H- Indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea 0.799 mmol, stirred at room temperature for 12 h, and then treated to obtain an intermediate product with a monocarboxylic acid.
本发明进一步的改进在于,所述步骤2)的具体过程为:将步骤1)得到的带有单羧酸的中间产物溶于二氯甲烷中,加入(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺,冰浴下搅拌均匀,然后逐滴加入DIPEA,搅拌均匀,加入HATU,25℃下搅拌12h,反应结束后进行处理,得到基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体。A further improvement of the present invention is that the specific process of the step 2) is as follows: the intermediate product with the monocarboxylic acid obtained in the step 1) is dissolved in dichloromethane, and (2S, 4R)-1-(((S) is added. )-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, ice bath Stir well, then add DIPEA dropwise, stir well, add HATU, stir at 25 °C for 12 h, and process after the reaction to obtain a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869.
本发明进一步的改进在于,将7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酸0.193mmol溶于20mL二氯甲烷中,加入(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺0.193mmol,冰浴下搅拌均匀,然后逐滴加入DIPEA0.773mmol,搅拌均匀,加入HATU0.29mmol,25℃下搅拌12h后进行处理,得到基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体。A further improvement of the present invention is that 7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl )-7-oxoheptanoic acid 0.193 mmol was dissolved in 20 mL of dichloromethane, and (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl was added -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 0.193mmol, stir well under ice bath, then add DIPEA 0.773mmol dropwise, stir well, add HATU0. 29 mmol, stirred at 25 °C for 12 h, and then processed to obtain a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869.
一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体在制备治疗或预防癌症的药物中的应用。Application of a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 in the preparation of a drug for treating or preventing cancer.
本发明进一步的改进在于,基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体在制备以VEGFR-2激酶为靶点的抗肿瘤药物中的应用。A further improvement of the present invention lies in the application of the protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 in the preparation of antitumor drugs targeting VEGFR-2 kinase.
与现有技术相比,本发明具有以下有益效果:Compared with the prior art, the present invention has the following beneficial effects:
本发明通过使用烷基二羧酸将联苯脲类VEGFR-2蛋白抑制剂和E3泛素连接酶复合体中von Rippel-Lindau(VHL)蛋白配体连接获得蛋白降解靶向嵌合体。该蛋白降解靶向嵌合体(PROTACs)能够选择性诱导VEGFR-2蛋白的降解。本发明的蛋白降解靶向嵌合体制备方法简单,易于实现,并且收率较高。In the present invention, a protein degradation targeting chimera is obtained by linking a biphenylurea VEGFR-2 protein inhibitor and a von Rippel-Lindau (VHL) protein ligand in an E3 ubiquitin ligase complex using an alkyl dicarboxylic acid. The protein degradation targeting chimeras (PROTACs) can selectively induce the degradation of VEGFR-2 protein. The preparation method of the protein degradation targeting chimera of the present invention is simple, easy to realize, and has a high yield.
本发明中的小分子蛋白降解靶向嵌合体可以对VEGFR-2蛋白进行泛素化标记,诱导蛋白降解,抗肿瘤效果优于VEGFR-2蛋白抑制剂。抑制VEGFR-2蛋白往往需要将药物长期维持在较高的浓度,有可能造成严重的副作用;而诱导蛋白降解只需要少量的化合物,这个过程类似于催化反应,并不需要等摩尔量的药物,所以使用小分子蛋白降解靶向嵌合体可以降低药物使用剂量,减轻毒副作用。本发明的蛋白降解靶向嵌合体在体外具有抗肿瘤活性,可应用于抗肿瘤药物的制备,尤其用于制备以VEGFR-2激酶为靶点的抗肿瘤药物。The small molecule protein degradation targeting chimera in the present invention can carry out ubiquitination labeling on VEGFR-2 protein, induce protein degradation, and the anti-tumor effect is better than that of VEGFR-2 protein inhibitor. Inhibition of VEGFR-2 protein often requires the drug to be maintained at a high concentration for a long time, which may cause serious side effects; while inducing protein degradation requires only a small amount of compound, this process is similar to catalytic reaction, and does not require equimolar amount of drug, Therefore, the use of small-molecule protein degradation targeting chimeras can reduce the dosage of drugs and reduce toxic and side effects. The protein degradation targeting chimera of the present invention has anti-tumor activity in vitro, and can be applied to the preparation of anti-tumor drugs, especially for the preparation of anti-tumor drugs targeting VEGFR-2 kinase.
附图说明Description of drawings
图1为本发明提供的具有抗肿瘤活性的小分子蛋白降解靶向嵌合体的合成路线图;Fig. 1 is the synthetic route diagram of the small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention;
其中,化合物1为1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲,化合物2为烷基二羧酸,化合物3为带有单羧酸的中间产物,化合物4为(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺,化合物(X)为具有抗肿瘤活性的小分子蛋白降解靶向嵌合体。Wherein, compound 1 is 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea, and compound 2 is alkyldi Carboxylic acid, compound 3 is an intermediate product with a monocarboxylic acid, compound 4 is (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, compound (X) is a small molecule protein degradation targeting chimera with antitumor activity.
图中标注的具体为:Specifically marked in the figure are:
a.PyBop,TEA,CH2Cl2,rt;b.HATU,DIPEA,CH2Cl2,rt。a. PyBop , TEA, CH2Cl2 , rt ; b. HATU, DIPEA, CH2Cl2 , rt.
具体实施方式Detailed ways
下面结合附图和具体的实施例对本发明做进一步的详细说明,所述是对本发明的解释而不是限定。The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, which are to explain rather than limit the present invention.
本发明涉及的蛋白降解靶向嵌合体(PROTACs)能够选择性诱导VEGFR-2蛋白的降解。本发明通过使用烷基二羧酸将联苯脲类VEGFR-2蛋白抑制剂和E3泛素连接酶复合体中von Rippel-Lindau(VHL)蛋白配体连接获得蛋白降解靶向嵌合体。这些化合物有诱导VEGFR-2蛋白降解的功能,可用于制备新型抗肿瘤药物。The protein degradation targeting chimeras (PROTACs) involved in the present invention can selectively induce the degradation of VEGFR-2 protein. In the present invention, a protein degradation targeting chimera is obtained by linking a biphenylurea VEGFR-2 protein inhibitor and a von Rippel-Lindau (VHL) protein ligand in an E3 ubiquitin ligase complex using an alkyl dicarboxylic acid. These compounds have the function of inducing the degradation of VEGFR-2 protein and can be used to prepare novel antitumor drugs.
本发明提供了一种具有抗肿瘤活性的小分子蛋白降解靶向嵌合体,该蛋白降解靶向嵌合体在体外具有抗肿瘤活性,可应用于抗肿瘤药物的制备。The present invention provides a small molecule protein degradation targeting chimera with antitumor activity, the protein degradation targeting chimera has antitumor activity in vitro, and can be applied to the preparation of antitumor drugs.
本发明提供的具有抗肿瘤活性的小分子蛋白降解靶向嵌合体的化学结构式具体如下:The chemical structural formula of the small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention is as follows:
其中,n选自1-20之间的整数;优选的,n为3、8或12。Wherein, n is selected from an integer between 1-20; preferably, n is 3, 8 or 12.
本发明所述的蛋白降解靶向嵌合体,其包括:The protein degradation targeting chimera of the present invention comprises:
(2S,4R)-1-((S)-2-(7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;(2S,4R)-1-((S)-2-(7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-7-oxoheptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;
(2S,4R)-1-((S)-2-(12-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-12-氧代十二烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;(2S,4R)-1-((S)-2-(12-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-12-oxododecanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- yl)benzyl)pyrrolidine-2-carboxamide;
(2S,4R)-1-((S)-2-(16-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-16-氧代十六烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;(2S,4R)-1-((S)-2-(16-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-16-oxohexadecylamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- yl)benzyl)pyrrolidine-2-carboxamide;
下面结合图1中所示的合成路线和具体的合成实施例来详细说明本发明提供的具有抗肿瘤活性的候选药物小分子蛋白降解靶向嵌合体的制备和活性筛选方法。The preparation and activity screening method of the candidate drug small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention will be described in detail below in conjunction with the synthetic route shown in FIG. 1 and specific synthetic examples.
参见图1,一种基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体的制备方法,包括以下步骤:Referring to Figure 1, a method for preparing a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, comprising the following steps:
1)烷基二羧酸与联苯脲类VEGFR-2蛋白配体1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲在PyBop缩合剂的缩合作用下得到带有单羧酸的中间产物;1) Alkyl dicarboxylic acid and biphenylurea VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5- Methyl phenyl) urea obtains the intermediate product with monocarboxylic acid under the condensation action of PyBop condensing agent;
2)此带有单羧酸的中间产物与E3泛素连接酶配体(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺在HATU缩合剂的缩合作用下得到通式(X)表示的化合物;2) This intermediate product with monocarboxylic acid interacts with E3 ubiquitin ligase ligand (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide obtains the compound represented by general formula (X) under the condensation of HATU condensing agent;
所述步骤1)的具体操作为:将烷基二羧酸,PyBop溶于二氯甲烷中,缓慢滴加三乙胺,搅拌3min后,取样。加入VEGFR-2蛋白配体1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲,室温搅拌过夜,反应结束后,低压旋除有机溶剂,加入适量水,用乙酸乙酯萃取,萃取的有机相经洗涤、干燥后减压蒸去溶剂,得粗品,用层析柱分离粗品,得到带有单羧酸的中间产物。The specific operation of the step 1) is: dissolving the alkyl dicarboxylic acid and PyBop in dichloromethane, slowly adding triethylamine dropwise, stirring for 3 min, and sampling. VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea was added, stirred at room temperature overnight, After the reaction, the organic solvent was spun off under low pressure, an appropriate amount of water was added, and extracted with ethyl acetate. The extracted organic phase was washed and dried, and then the solvent was evaporated under reduced pressure to obtain a crude product. Acid intermediates.
所述步骤2)的具体操作为:将步骤1)得到的带有单羧酸的中间产物溶于二氯甲烷中,加入(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺,冰浴下搅拌5min,然后逐滴加入DIPEA,搅拌5min,加入HATU,25℃下搅拌12h,反应结束后,低压旋除有机溶剂,加入适量水,用乙酸乙酯萃取,萃取的有机相经洗涤、干燥后减压蒸去溶剂,得粗品,用层析柱分离粗品,得到通式(X)表示的化合物。The specific operation of the step 2) is: dissolving the intermediate product with the monocarboxylic acid obtained in the step 1) in dichloromethane, adding (2S, 4R)-1-((S)-2-amino-3 ,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, stirred under ice bath for 5min, then dropwise Add DIPEA, stir for 5 min, add HATU, and stir at 25°C for 12 h. After the reaction is completed, the organic solvent is spun off under low pressure, an appropriate amount of water is added, and extracted with ethyl acetate. The extracted organic phase is washed and dried, and then the solvent is evaporated under reduced pressure. The crude product was obtained, and the crude product was separated by chromatography to obtain the compound represented by the general formula (X).
所述的具有抗肿瘤活性的小分子蛋白降解靶向嵌合体在制备以VEGFR-2激酶为靶点的抗肿瘤药物中的应用。The application of the small-molecule protein degradation targeting chimera with anti-tumor activity in the preparation of anti-tumor drugs targeting VEGFR-2 kinase.
实施例1Example 1
该具有抗肿瘤活性的小分子蛋白降解靶向嵌合体的结构式中,n为3,通过以下步骤制备(参见图1):In the structural formula of the small molecule protein degradation targeting chimera with anti-tumor activity, n is 3, and is prepared by the following steps (see Figure 1):
1)庚二酸(化合物2)与VEGFR-2蛋白配体1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲(化合物1)在PyBop缩合剂的缩合作用下得到7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酸(化合物3);具体过程如下:1) Pimelic acid (compound 2) and VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methyl) Phenyl)urea (compound 1) under condensation with PyBop condensing agent gives 7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl) -1H-indazol-1-yl)-7-oxoheptanoic acid (compound 3); the specific process is as follows:
将庚二酸(0.64g,3.99mmol),PyBop(1.66g,3.19mmol)溶于20mL二氯甲烷中,缓慢滴加三乙胺(665μL,4.79mmol),搅拌3min后,取样。加入1-(4-(3-氨基-1H-吲唑-4-基)苯基)-3-(2-氟-5-甲基苯基)脲(0.3g,0.799mmol),室温搅拌过夜,然后低压旋除有机溶剂,加入适量水,用乙酸乙酯萃取,无水硫酸钠干燥,减压旋除有机溶剂,残留物通过硅胶柱色谱层析纯化,使用石油醚/乙酸乙酯(V/V=6/1-3/1)洗脱得到白色固体,重0.28g,收率67.7%。Pimelic acid (0.64 g, 3.99 mmol) and PyBop (1.66 g, 3.19 mmol) were dissolved in 20 mL of dichloromethane, and triethylamine (665 μL, 4.79 mmol) was slowly added dropwise, stirred for 3 min, and then sampled. Add 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea (0.3 g, 0.799 mmol) and stir at room temperature overnight , then the organic solvent was removed under low pressure, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (V /V=6/1-3/1) eluted to obtain a white solid, weighing 0.28 g, with a yield of 67.7%.
LCMS(ESI,m/z):518.20[M-H]- LCMS(ESI,m/z):518.20[MH] -
2)7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酸(化合物3)与E3泛素连接酶配体(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(化合物4)在HATU缩合剂的缩合作用下得到(2S,4R)-1-((S)-2-(7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(化合物X);具体过程如下:2) 7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxo Heptanoic acid (compound 3) with E3 ubiquitin ligase ligand (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4 -(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (compound 4) under the condensation of HATU condensing agent to give (2S,4R)-1-((S)-2- (7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxoheptyl amido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound X); The specific process is as follows:
将7-(3-氨基-4-(4-(3-(2-氟-5-甲基苯基)脲基)苯基)-1H-吲唑-1-基)-7-氧代庚酸(0.1g,0.193mmol)溶于20mL二氯甲烷中,加入(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(0.084g,0.193mmol),冰浴下搅拌5min,然后逐滴加入DIPEA(132μL,0.773mmol),搅拌5min,加入HATU(0.11g,0.29mmol),25℃下搅拌12h,然后低压旋除有机溶剂,加入适量水,用乙酸乙酯萃取,无水硫酸钠干燥,减压旋除有机溶剂,残留物通过硅胶柱色谱层析纯化,使用石油醚/乙酸乙酯(V/V=1/1-0/1)洗脱得到目标化合物,重0.11g,收率61.22%。7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxoheptane The acid (0.1 g, 0.193 mmol) was dissolved in 20 mL of dichloromethane, and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N was added -(4-(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.084 g, 0.193 mmol), stirred under ice bath for 5 min, then DIPEA (132 μL, 0.773 mmol) was added dropwise , stir for 5min, add HATU (0.11g, 0.29mmol), stir at 25°C for 12h, then spin off the organic solvent under low pressure, add an appropriate amount of water, extract with ethyl acetate, dry over anhydrous sodium sulfate, spin off the organic solvent under reduced pressure, The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (V/V=1/1-0/1) to obtain the title compound, weighing 0.11 g, and yield 61.22%.
所得目标化合物的结构如下:The structure of the obtained target compound is as follows:
氢谱核磁共振数据为:1H NMR(400MHz,DMSO-D6)δ9.28(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.31-8.33(d,1H),δ8.00-8.02(d,1H),δ7.87-7.89(d,1H),δ7.58-7.64(m,3H),δ7.37-7.43(m,6H),δ7.10-7.19(m,2H),δ6.81-6.84(m,1H),δ5.21(s,2H),δ5.14(d,1H),δ4.53-4.56(d,1H),δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H),δ2.29(s,3H),δ2.12-2.19(m,1H),δ2.02-2.06(m,1H),δ1.87-1.94(m,1H),δ1.67-1.75(m,3H),δ1.50-1.61(m,2H),δ1.34-1.39(m,2H),δ1.24(m,2H),δ0.91(s,9H).The hydrogen spectrum nuclear magnetic resonance data are: 1 H NMR (400MHz, DMSO-D6)δ9.28(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.31-8.33( d,1H),δ8.00-8.02(d,1H),δ7.87-7.89(d,1H),δ7.58-7.64(m,3H),δ7.37-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.81-6.84(m,1H),δ5.21(s,2H),δ5.14(d,1H),δ4.53-4.56(d,1H), δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H) ,δ2.29(s,3H),δ2.12-2.19(m,1H),δ2.02-2.06(m,1H),δ1.87-1.94(m,1H),δ1.67-1.75(m ,3H),δ1.50-1.61(m,2H),δ1.34-1.39(m,2H),δ1.24(m,2H),δ0.91(s,9H).
LCMS(ESI,m/z):930.45[M-H]- LCMS(ESI,m/z):930.45[MH] -
实施例2Example 2
该具有抗肿瘤活性的小分子蛋白降解靶向嵌合体的结构式中,n为8。In the structural formula of the small molecule protein degradation targeting chimera with antitumor activity, n is 8.
合成步骤同实施例1。The synthesis steps are the same as those in Example 1.
所得目标化合物的结构如下:The structure of the obtained target compound is as follows:
氢谱核磁共振数据为:1H NMR(400MHz,DMSO-D6)δ9.28(s,1H),δ8.99(s,1H),δ8.58(s,2H),δ8.31-8.33(d,1H),δ8.01-8.03(d,1H),δ7.85-7.87(d,1H),δ7.58-7.64(m,3H),δ7.40-7.43(m,6H),δ7.10-7.19(m,2H),δ6.83(m,1H),δ5.21(s,2H),δ5.14(s,1H),δ4.54-4.56(d,1H),δ4.43-4.45(t,2H),δ4.36(s,1H),δ4.21-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H),δ2.29(s,3H),δ2.00-2.12(m,3H),δ1.91-1.92(m,1H),δ1.66-1.71(m,2H),δ1.43-1.55(m,2H),δ1.17-1.36(m,14H),δ0.93(s,9H).LCMS(ESI,m/z):1000.55[M-H]- The hydrogen spectrum nuclear magnetic resonance data are: 1 H NMR (400MHz, DMSO-D6)δ9.28(s,1H),δ8.99(s,1H),δ8.58(s,2H),δ8.31-8.33( d,1H),δ8.01-8.03(d,1H),δ7.85-7.87(d,1H),δ7.58-7.64(m,3H),δ7.40-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.83(m,1H),δ5.21(s,2H),δ5.14(s,1H),δ4.54-4.56(d,1H),δ4. 43-4.45(t,2H),δ4.36(s,1H),δ4.21-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H),δ2 .29(s,3H),δ2.00-2.12(m,3H),δ1.91-1.92(m,1H),δ1.66-1.71(m,2H),δ1.43-1.55(m,2H) ),δ1.17-1.36(m,14H),δ0.93(s,9H).LCMS(ESI,m/z):1000.55[MH] -
实施例3Example 3
该具有抗肿瘤活性的小分子蛋白降解靶向嵌合体的结构式中,n为12。In the structural formula of the small molecule protein degradation targeting chimera with antitumor activity, n is 12.
合成步骤同实施例1Synthesis steps are the same as in Example 1
所得目标化合物的结构如下:The structure of the obtained target compound is as follows:
氢谱核磁共振数据为:1H NMR(400MHz,DMSO-D6)δ9.27(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.30-8.32(d,1H),δ8.00-8.02(d,1H),δ7.83-7.86(d,1H),δ7.57-7.64(m,3H),δ7.37-7.43(m,6H),δ7.10-7.19(m,2H),δ6.82(m,1H),δ5.19(s,2H),δ5.13-5.14(d,1H),δ4.53-4.56(d,1H),δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.24(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H),δ2.29(s,3H),δ1.99-2.12(m,2H),δ1.87-1.94(m,1H),δ1.67-1.71(m,2H),δ1.23-1.49(m,25H),δ0.94(s,9H).The hydrogen spectrum nuclear magnetic resonance data are: 1 H NMR (400MHz, DMSO-D6)δ9.27(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.30-8.32( d,1H),δ8.00-8.02(d,1H),δ7.83-7.86(d,1H),δ7.57-7.64(m,3H),δ7.37-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.82(m,1H),δ5.19(s,2H),δ5.13-5.14(d,1H),δ4.53-4.56(d,1H), δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.24(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H) ,δ2.29(s,3H),δ1.99-2.12(m,2H),δ1.87-1.94(m,1H),δ1.67-1.71(m,2H),δ1.23-1.49(m ,25H),δ0.94(s,9H).
LCMS(ESI,m/z):1056.60[M-H]- LCMS(ESI,m/z):1056.60[MH] -
实施例4Example 4
蛋白降解靶向嵌合体对VEGFR-2激酶的抑制活性筛选。Screening for inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase.
采用的是ADP-Glo发光方法测定蛋白降解靶向嵌合体对VEGFR-2激酶的抑制活性。The ADP-Glo luminescence method was used to determine the inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase.
用Buffer(Tris 80mM,MgCl2 20mM,BSA 0.2mg/mL,DTT 2mM)稀释ATP(10mM)为250μM;将ATP和底物Poly(4:1Glu,Tyr)Peptide按体积1:1配成ATP(125μM)-Poly(4:1Glu,Tyr)Peptide(0.5μg/μL)混合溶液;用Buffer稀释激酶为1.5ng/μL。将待测化合物配成6个浓度梯度的溶液,于384孔板上依次加入2μL ATP-Poly(4:1Glu,Tyr)Peptide溶液、1μL样品溶液、2μL酶溶液启动反应。30℃孵育60min后,加入ADP-Glo试剂5μL终止反应。再加入KinaseDetection试剂10μL将ADP转化为ATP,在25℃孵育30min,使用PerkinElmer多功能酶标仪的化学发光模块测定发光值,计算抑制率。Dilute ATP (10 mM) to 250 μM with Buffer (Tris 80 mM, MgCl 2 20 mM, BSA 0.2 mg/mL, DTT 2 mM); ATP and substrate Poly (4:1 Glu, Tyr) Peptide are prepared by volume 1:1 to prepare ATP (125 μM )-Poly(4:1Glu,Tyr)Peptide(0.5μg/μL) mixed solution; dilute the kinase with Buffer to 1.5ng/μL. The compounds to be tested were prepared into 6 concentration gradient solutions, and 2 μL of ATP-Poly (4:1Glu,Tyr) Peptide solution, 1 μL of sample solution and 2 μL of enzyme solution were sequentially added to the 384-well plate to initiate the reaction. After incubation at 30°C for 60 min, 5 μL of ADP-Glo reagent was added to stop the reaction. Then add 10 μL of KinaseDetection reagent to convert ADP into ATP, incubate at 25°C for 30min, use the chemiluminescence module of PerkinElmer multi-function microplate reader to measure the luminescence value and calculate the inhibition rate.
数值处理:抑制率=(阳性值-给药组值)/(阳性值-阴性值)×100%;Numerical processing: inhibition rate=(positive value-administration group value)/(positive value-negative value)×100%;
化合物的实验结果见表1:The experimental results of the compounds are shown in Table 1:
表1蛋白降解靶向嵌合体对VEGFR-2激酶的抑制活性结果。(60nM)Table 1 Results of inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase. (60nM)
从表1可以看出,本发明制备的基于VEGFR-2抑制剂ABT-869的蛋白降解靶向嵌合体具有较好的抑制活性。It can be seen from Table 1 that the protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 prepared by the present invention has good inhibitory activity.
实施例5Example 5
蛋白降解靶向嵌合体细胞水平活性测定。Protein degradation targeting chimeric cellular level activity assay.
蛋白降解靶向嵌合体细胞水平的活性检测采用MTT检测法。将处于对数增长期的EA.hy926细胞或SMMC-7721细胞,用0.25%胰蛋白酶消化,制成单细胞悬液,接种于96孔板(2×104个/孔),每孔180μL。放入37℃,5%CO2恒温培养箱中培养,24h后待细胞贴壁后加药。每组设置3个复孔,阴性对照组加入20μL/孔无血清培养基,实验组加入不同浓度的药物20μL/孔(以无血清培养基稀释药物),放入37℃,5%CO2恒温培养箱中继续培养。药物作用72h后,小心吸弃上清液,加入无血清培养基稀释10倍的MTT溶液(终浓度为0.5mg/mL)200μL/孔,37℃孵育4-6h后,小心吸弃上清液,加入DMSO 150μL/孔,脱色摇床上充分振摇15min。用酶联免疫检测仪于490nm波长下测定各孔吸光度(OD)值。The activity of protein degradation targeting chimera cells was detected by MTT assay. The EA.hy926 cells or SMMC-7721 cells in the logarithmic growth phase were digested with 0.25% trypsin to prepare a single cell suspension, which was inoculated in a 96-well plate (2×10 4 cells/well), 180 μL per well. Incubate in a 37°C, 5% CO 2 constant temperature incubator, and add drugs after 24 h after the cells adhere to the wall. Three duplicate wells were set in each group. The negative control group was added with 20 μL/well of serum-free medium, and the experimental group was added with 20 μL/well of different concentrations of drugs (diluted with serum-free medium), and placed in a constant temperature of 37°C, 5% CO 2 Continue to cultivate in the incubator. After 72 hours of drug action, carefully aspirate and discard the supernatant, add 200 μL/well of MTT solution (final concentration 0.5 mg/mL) diluted 10 times in serum-free medium, and incubate at 37°C for 4-6 hours, then carefully aspirate the supernatant. , add 150 μL/well of DMSO, and shake well on a destaining shaker for 15 min. The absorbance (OD) value of each well was measured at a wavelength of 490 nm with an enzyme-linked immunosorbent assay.
数值处理:抑制率=(OD阴性组-OD给药组)/(OD阴性组-OD空白组)×100%;Numerical processing: inhibition rate=(OD negative group- OD administration group )/(OD negative group- OD blank group )×100%;
部分化合物的实验结果见表2:The experimental results of some compounds are shown in Table 2:
表2优选化合物对EA.hy926细胞和SMMC-7721细胞的抑制活性(100nM,72h)Table 2 Inhibitory activity of preferred compounds on EA.hy926 cells and SMMC-7721 cells (100nM, 72h)
从表2可以看出,本发明制备的嵌合体对EA.hy926细胞和SMMC-7721细胞具有较好的抑制活性。It can be seen from Table 2 that the chimera prepared by the present invention has better inhibitory activity on EA.hy926 cells and SMMC-7721 cells.
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