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WO2021114864A1 - DÉRIVÉ DE β-CARBOLINE CYCLOCÉTÈNE BASÉ SUR UNE RÉPONSE DOUBLE AU PH ET GSH ET UTILISATION ASSOCIÉE - Google Patents

DÉRIVÉ DE β-CARBOLINE CYCLOCÉTÈNE BASÉ SUR UNE RÉPONSE DOUBLE AU PH ET GSH ET UTILISATION ASSOCIÉE Download PDF

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Publication number
WO2021114864A1
WO2021114864A1 PCT/CN2020/121436 CN2020121436W WO2021114864A1 WO 2021114864 A1 WO2021114864 A1 WO 2021114864A1 CN 2020121436 W CN2020121436 W CN 2020121436W WO 2021114864 A1 WO2021114864 A1 WO 2021114864A1
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WIPO (PCT)
Prior art keywords
methyl
pyrido
carbamate
indole
oxocyclohex
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Ceased
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PCT/CN2020/121436
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English (en)
Chinese (zh)
Inventor
凌勇
刘季
刘昕
凌长春
张延安
钱建强
孟迟
杭佳颖
陈苏蒙
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Nantong University
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Nantong University
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • 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
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms

Definitions

  • human cytoplasmic GSTs can be divided into 7 subtypes, namely: ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ .
  • GST ⁇ is related to human tissue cell canceration, Tumor formation and the generation of tumor drug resistance are closely related.
  • Studies have shown that in a variety of tumor cells (such as breast cancer, colon cancer tumor cells) and drug-resistant tumors, GST ⁇ is overexpressed.
  • the formation of GST ⁇ is considered to be one of the signs of liver cancer.
  • This characteristic of GST ⁇ makes it an important target in the design of anti-tumor drug prodrugs. In view of this, the use of the highly expressed GST ⁇ in tumor tissues to develop and design cancer chemotherapeutic drugs and probes has great application value.
  • the present invention is based on the structural modification of the natural indole alkaloid ⁇ -carboline with anti-tumor activity.
  • the ⁇ -carboline is connected to the cycloketene through a carbamate bond, and electron donors are introduced into the structure of the ⁇ -carboline.
  • the group can not only produce pH-sensitive fluorescence, but also release fluorescence at 492nm after covalently binding to GSH. It also targets GST ⁇ , which significantly enhances the compound’s anti-tumor proliferation and metastasis activity, achieving early cancer diagnosis and precise treatment. Double targeting effect.
  • R 1 or R 2 are the same or different and represent one or more substituents on the corresponding substituted ring, selected from one of H, amino, halogen, hydroxyl, nitro, alkoxy, alkyl, alkylamino or There are several types, when R 1 or R 2 each represents multiple substituents, the substituents are the same or different;
  • R 4 is selected from H, alkyl, methoxyalkyl or
  • Another object of the present invention is to provide a preparation method of the compound of the general formula of the present invention, which comprises the following steps:
  • Example 1 (6-oxocyclohex-1-en-1-yl)methyl(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indino Dol-3-yl) carbamate (I 1 ) or bis(6-oxocyclohex-1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl) Preparation of -9H-pyrido[3,4-b]indol-3-yl)carbamate (II 1)
  • Example 6 (6-oxocyclohex-1-en-1-yl)methyl(1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole -3-yl) carbamate (I 6 ) or bis(6-oxocyclohex-1-en-1-yl)methyl(1-(2,4-dimethoxyphenyl)-9H -Pyrido[3,4-b]indol-3-yl) carbamate (II 6 ) preparation
  • Example 14 Study on the determination of the tumor cell proliferation inhibition rate of the compound of the present invention by the MTT method
  • the compounds of this invention I 1 -I 13 and II 1 -II 13 at 1 ⁇ M concentration, with the increase of GSH equivalents, characterized in UV absorption peak wavelength gradually decreases between 385 ⁇ 430nm, gradually rises at the peak of 435 ⁇ 470nm ; Its fluorescence spectrum shows that the fluorescence at 470 ⁇ 530nm also gradually increases with the increase of GSH equivalent.
  • the specific experimental method is as follows: Dissolve 1 ⁇ M of the series of compounds in an aqueous solution containing a catalytic amount of GST ⁇ , and add 1mM K + , Na + , Ca 2+ , Mg 2+ , Zn 2+ , Al 3+ , Cu to it 2+ , Fe 2+ ; 100 ⁇ M GSH, lysine, histidine, alanine, cysteine, glutamic acid, serine, glycine, arginine, vitamin C, Na 2 S, H 2 O 2. Bio-endogenous substances such as NADH. All emission spectra were recorded after incubation at 37°C for 0.5 hours, excitation at 430-480nm, and recording at 450nm to 650nm.
  • Fig. 5 is the result of in vivo fluorescence imaging distribution of compound I 1 of the present invention, which shows that the compound of the present invention can selectively show strong fluorescence signals in tumor tissues in vivo.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials Engineering (AREA)
  • Optics & Photonics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un dérivé de β-carboline-cyclocétène, qui a la structure représentée par la formule générale (I). Un dérivé de β-carboline-cyclocétène de type nouveau est conçu et synthétisé par introduction d'un groupe donneur d'électrons à une position appropriée de β-carboline, et la liaison de cyclocétène, qui a une activité antitumorale, au moyen du groupe amino en position 3 de β-carboline et à l'aide d'une liaison carbamate. Le composé peut réaliser, non seulement une imagerie par fluorescence pour une réponse double à un pH et à un GSH et un diagnostic dans un microenvironnement tumoral, mais peut cibler de manière sélective GSTπ, qui est fortement exprimé dans les tissus tumoraux, pour inhiber de manière significative la prolifération des cellules tumorales. La fluorescence à double réponse pH/GSH et le traitement et le diagnostic du cancer ciblés fournissent un nouveau choix pour un diagnostic tumoral précis et une thérapie ciblée, et permettent d'élargir l'utilisation de molécules multifonctionnelles dans un médicament de précision.
PCT/CN2020/121436 2019-12-09 2020-10-16 DÉRIVÉ DE β-CARBOLINE CYCLOCÉTÈNE BASÉ SUR UNE RÉPONSE DOUBLE AU PH ET GSH ET UTILISATION ASSOCIÉE Ceased WO2021114864A1 (fr)

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AU2020356793A AU2020356793B2 (en) 2019-12-09 2020-10-16 PH/glutathione-responsive β-carbolines/cycloketene derivatives and their preparation and application

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CN201911256603.7 2019-12-09
CN201911256603.7A CN110981870B (zh) 2019-12-09 2019-12-09 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN113512022A (zh) * 2021-06-29 2021-10-19 西安交通大学 一种基于pH响应的多功能荧光链接体及制备方法和应用
CN118146218A (zh) * 2024-02-02 2024-06-07 南通大学附属医院 新型β-咔啉-氰基异黄酮化合物及其制备方法与应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110981870B (zh) * 2019-12-09 2020-11-24 南通大学 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途
CN111925369B (zh) * 2020-08-18 2021-09-28 南通大学 一类β-咔啉氰基呋喃衍生物及其制备方法与应用
CN111961049B (zh) * 2020-08-26 2022-07-01 南通大学 含1,3-二甲基-5-芳氧基吡唑的β-咔啉衍生物及其制备方法和用途
CN111892594B (zh) * 2020-08-26 2022-05-13 南通大学 含取代吡唑单元的1-(3,4,5-三甲氧基苯基)-β-咔啉酰腙的制备与应用
CN113717169B (zh) * 2021-09-03 2022-05-17 南通大学 N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用
CN114409594B (zh) * 2021-10-24 2023-09-26 济南大学 靶向高尔基体的谷胱甘肽比率荧光探针、制备方法与应用
CN118994153B (zh) * 2024-08-12 2025-11-21 南通大学 β-咔啉萘醌衍生物及其制备方法和医药用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113512022A (zh) * 2021-06-29 2021-10-19 西安交通大学 一种基于pH响应的多功能荧光链接体及制备方法和应用
CN113512022B (zh) * 2021-06-29 2023-05-16 西安交通大学 一种基于pH响应的多功能荧光链接体及制备方法和应用
CN118146218A (zh) * 2024-02-02 2024-06-07 南通大学附属医院 新型β-咔啉-氰基异黄酮化合物及其制备方法与应用

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CN110981870A (zh) 2020-04-10
AU2020356793B2 (en) 2021-08-05
AU2020356793A1 (en) 2021-06-24

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