CN108774223A - 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用 - Google Patents

一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用 Download PDF

Info

Publication number
CN108774223A
CN108774223A CN201810526502.6A CN201810526502A CN108774223A CN 108774223 A CN108774223 A CN 108774223A CN 201810526502 A CN201810526502 A CN 201810526502A CN 108774223 A CN108774223 A CN 108774223A
Authority
CN
China
Prior art keywords
pim1
vinylthiazole
inhibit
bases
chromene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810526502.6A
Other languages
English (en)
Inventor
俞军
杨翊柠
林森森
吴晓柳
朱明�
张元颖
李金田
张晓梅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Cancer Hospital
Original Assignee
Jiangsu Cancer Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Cancer Hospital filed Critical Jiangsu Cancer Hospital
Priority to CN201810526502.6A priority Critical patent/CN108774223A/zh
Publication of CN108774223A publication Critical patent/CN108774223A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于医药技术领域，公开了一类可抑制PIM1激酶活性的4‑(2H‑苯并吡喃‑3‑基)‑2‑乙烯基噻唑类化合物及其应用。该类化合物结构如通式(I)所示，其中R1代表C4‑C7的环烷基、苯基或取代苯基，R2代表C1‑C10的烷基、羟基、羟烷基、卤素、卤代烷基、氰基。该化合物可用于制备PIM1激酶抑制剂，为制备靶向抗肿瘤药提供了更多选择。

Description

一类可抑制PIM1激酶活性的4-(2H-苯并吡喃-3-基)-2-乙烯 基噻唑类化合物及其应用
技术领域
本发明属于医药技术领域，涉及一类可抑制PIM1激酶活性的4-(2H-苯并吡喃-3-基)-2-乙烯基噻唑类化合物及其应用。
背景技术
PIM1是一种癌基因，最早被发现为莫洛尼小鼠白血病病毒的前病毒插入点，在调控细胞凋亡、分化、增殖以及肿瘤形成等方面发挥非常重要的作用。PIM1蛋白激酶具有丝氨酸/苏氨酸蛋白激酶活性，引起许多细胞因子信号转导通路的下游效应子的启动。PIM1激酶可以下调丝氨酸/苏氨酸蛋白磷酸酶2A(protein phosphatase 2A，PP2A)水平，促进癌基因c-Myc的表达，导致肿瘤的发生。PIM1激酶还可以提高细胞周期素B1(cyclin B1)、cyclinB1-CDK1复合物的活性，延迟胞质分裂来加速产生多倍体，并在细胞周期中直接结合磷酸化磷酸酶cdc25A。目前已证实PIM1与白血病、淋巴瘤、肺癌、乳腺癌、前列腺癌等多种肿瘤的发生密切相关，在肿瘤的诊断、治疗、预后评价等方面具有重要的作用。PIM1已成为抗肿瘤治疗的重要靶点。目前，国外已有PIM1抑制剂进入临床试验，但尚未有选择性抑制PIM1激酶活性的分子靶向药物面世。
发明内容
本发明的目的是针对上述技术问题提供了一类可抑制PIM1激酶活性的4-(2H-苯并吡喃-3-基)-2-乙烯基噻唑类化合物。
本发明另一个目的是提供上述化合物在制药中的应用。
本发明通过建立PIM1高通量抑制剂筛选模型，在体外酶学水平上寻找先导化合物(化合物样品均购自Life Chemical公司筛选化合物库)，发现了一类结构新颖的PIM1激酶抑制剂，都是基于4-(2H-苯并吡喃-3-基)-2-乙烯基噻唑类的母核结构。本发明可以为靶向PIM1的抗肿瘤治疗提供结构新颖的先导化合物，为新型抗肿瘤分子靶向药物的研发提供依据。
本发明的目的是通过下列技术方案实现的：
一类可抑制PIM1激酶活性的4-(2H-苯并吡喃-3-基)-2-乙烯基噻唑类化合物，其结构如通式(I)所示：
其中：
R1代表C3-C7的环烷基、苯基或取代苯基，所述取代基为烷基、链烯基、烷氧基、亚甲二氧基、卤代烷基、卤代烷氧基、卤素、硝基、羟基、羟烷基、巯基、氰基、羧基、甲酰基、氨基、烷氨基或二烷基氨基；
R2代表C1-C10的烷基、羟基、羟烷基、卤素、卤代烷基、氰基。
所述的化合物在制备靶向抗肿瘤药中的应用，所述的靶向抗肿瘤药为PIM1激酶抑制剂。
具体地说，本发明建立了PIM1激酶抑制剂筛选模型；通过初筛与复筛，发现一类可抑制PIM1激酶活性活的化合物。步骤如下：
步骤一：建立PIM1激酶抑制剂高通量筛选模型；
步骤二：阳性药测试；
步骤三：样品初筛、复筛，获得先导化合物。
附图说明
图1：PIM1激酶筛选模型中，PIM1激酶浓度的优化(n＝3)；
图2：PIM1激酶筛选模型中，PIM1激酶反应时间的优化(n＝3)；
图3：PIM1激酶筛选模型中，PIM1激酶底物浓度的优化(n＝3)；
图4：PIM1激酶筛选模型中，ATP浓度的优化(n＝3)；
图5：PIM1激酶筛选模型中，阳性对照Staurosporine(STS)的抑制曲线(n＝3)；
图6：先导化合物活性列表
具体实施方式
以下结合附图对本发明作进一步的阐述。
1.检测方法
均相时间分辨荧光(HTRF)方法分为两个步骤：一是酶促反应，即当加入ATP后启动反应，激酶使底物发生磷酸化反应，将磷酸根连接在有生物素标记的底物上；二是终止及检测过程，在这个过程中EDTA终止了反应的进行，有铕元素标记抗磷酸化酪氨酸抗体靠近底物的磷酸根上，标记XL665的异藻蓝蛋白结合在底物的生物素标记上，两个荧光基团在互相靠近的过程中发生能量共振转移并在665nm处产生荧光，游离的TK antibody(标记铕离子)在620nm处发生荧光，此信号可作为背景信号，而游离的SA-XL665只产生短暂的荧光，通过延后检测时间(加入终止剂后1小时再进行检测)可将其忽略。最终仪器给出的信号值由下列公式进行计算：
Ratio＝(665nm/620nm)×104
2.模型建立与筛选
(1)以细胞培养基配制化合物溶液。在384孔板中每孔加入PIM1激酶溶液2μl，底物溶液2μl，缓冲液或待筛化合物4μl，ATP 2μl(n＝2)。室温反应1小时。(试剂盒KinEASETM，Cat.no 62TK0PEJ，厂家Cisbio Bioassays)
(2)每孔加入TK-Ab 5μl，SA-XL665 5μl，室温孵育1小时。
(3)利用Beckman Coulter检测平台HTRF模块进行检测。
(4)筛选模型的优化见图1～图4。
(5)阳性药结果见图5。
(6)先导化合物活性见图6。
3.实验结果
筛选得到的该类化合物结构通式与IC50值如下：

Claims (3)

1.一类可抑制PIM1激酶活性的4-(2H-苯并吡喃-3-基)-2-乙烯基噻唑类化合物，其结构如通式(I)所示：
其中：
R1代表C3-C7的环烷基、苯基或取代苯基，所述取代基为烷基、链烯基、烷氧基、亚甲二氧基、卤代烷基、卤代烷氧基、卤素、硝基、羟基、羟烷基、巯基、氰基、羧基、甲酰基、氨基、烷氨基或二烷基氨基；
R2代表C1-C10的烷基、羟基、羟烷基、卤素、卤代烷基、氰基。
2.权利要求1所述的化合物在制备靶向抗肿瘤药中的应用。
3.根据权利要求2所述的应用，其特征在于所述的靶向抗肿瘤药为PIM1激酶抑制剂。
CN201810526502.6A 2018-05-24 2018-05-24 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用 Pending CN108774223A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810526502.6A CN108774223A (zh) 2018-05-24 2018-05-24 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810526502.6A CN108774223A (zh) 2018-05-24 2018-05-24 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用

Publications (1)

Publication Number Publication Date
CN108774223A true CN108774223A (zh) 2018-11-09

Family

ID=64027918

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810526502.6A Pending CN108774223A (zh) 2018-05-24 2018-05-24 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用

Country Status (1)

Country Link
CN (1) CN108774223A (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020221334A1 (en) * 2019-04-30 2020-11-05 City University Of Hong Kong Pim1 inhibitors for use in treatment of viral infection and pharmaceutical compositions thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MASHRAQUI, SH ET AL.: "π-Aryl/Heteroaryl Conjugated Coumarin-Thiazoles: Synthesis, Optical Spectral and Nonlinear Optic Properties", 《J. HETEROCYCLIC CHEM》 *
STN检索报告: "CAS：308101-53-3", 《REGISTRY（在线）》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020221334A1 (en) * 2019-04-30 2020-11-05 City University Of Hong Kong Pim1 inhibitors for use in treatment of viral infection and pharmaceutical compositions thereof

Similar Documents

Publication Publication Date Title
Coussens et al. Small-molecule screens: A gateway to cancer therapeutic agents with case studies of food and drug administration–approved drugs
Vinet et al. Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers
Kay et al. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix
Zagorac et al. In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer
Chang et al. Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells
CN103435606A (zh) CDK2与GSK3β双重抑制剂及用途
Elia et al. Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1
Liu The ROCK signaling and breast cancer metastasis
CN110718268B (zh) 虚拟筛选在制备蛋白激酶抑制剂的应用和药物先导化合物
Matés et al. Metabolic reprogramming of cancer by chemicals that target glutaminase isoenzymes
CA2664114A1 (en) A method for profiling kinase inhibitors
Owusu et al. Mapping the human kinome in response to DNA damage
Esquer et al. Isolating and targeting the real-time plasticity and malignant properties of epithelial-mesenchymal transition in cancer
CN108774223A (zh) 一类可抑制pim1激酶活性的4－（2h－苯并吡喃－3－基）－2－乙烯基噻唑类化合物及其应用
Kim et al. c-Src-p38 mitogen-activated protein kinase signaling is required for Akt activation in response to ionizing radiation
Quintieri et al. Identification of molecular determinants of tumor sensitivity and resistance to anticancer drugs
Fan et al. The expression profile and prognostic value of APE/Ref‐1 and NPM 1 in high‐grade serous ovarian adenocarcinoma
Ahmad et al. Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors
Jin et al. Down‐regulation of MYH10 driven by chromosome 17p13. 1 deletion promotes hepatocellular carcinoma metastasis through activation of the EGFR pathway
Willers et al. Screening and validation of molecular targeted radiosensitizers
Petrovic et al. Virtual screening in the cloud identifies potent and selective ROS1 kinase inhibitors
Zou et al. Alpha-solanine anti-tumor effects in non-small cell lung cancer through regulating the energy metabolism pathway
Cho et al. Small interfering RNA-directed targeting of RON alters invasive and oncogenic phenotypes of human hepatocellular carcinoma cells
Marugán et al. Phenotypic screening approaches to develop aurora kinase inhibitors: drug discovery perspectives
CN107903256B (zh) 一种含取代噻唑的2,4-二氨基嘧啶及其应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20181109

WD01 Invention patent application deemed withdrawn after publication