Unlock instant, AI-driven research and patent intelligence for your innovation.

Proteolysis targeting chimera compound using oxygen-bridged bicycloheptene compound as estrogen receptor ligand, preparation method and application

A technology of estrogen receptor and bicycloheptene, applied in the field of medicine, can solve the problems of triplet activity influence and difficulty in regulation

Active Publication Date: 2022-02-15
WUHAN UNIV
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Protein degradation does not only depend on the affinity of the binary target protein and the ligand, but on the activity of the triplet, and the conformation and position of the connection of PROTAC, the modification of the length and composition of the connecting chain, and the concentration will all affect the triplet. The activity of the body is affected, so it is more difficult to control

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Proteolysis targeting chimera compound using oxygen-bridged bicycloheptene compound as estrogen receptor ligand, preparation method and application
  • Proteolysis targeting chimera compound using oxygen-bridged bicycloheptene compound as estrogen receptor ligand, preparation method and application
  • Proteolysis targeting chimera compound using oxygen-bridged bicycloheptene compound as estrogen receptor ligand, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] (2S,2R)-1-((2S)-2-(5-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)pentanamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26a)

[0090]

[0091] Under the protection of argon, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25a (103 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as a cosolvent . The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 87 mg of yellow solid product, 63% yield; m.p.172-173°C; 1 H NMR (400MHz, MeOD) δ8.86 (s, 1H), 7.46 (d, J = 8.1Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 7.12 (dd, J = 11.6, 5.2Hz ,6H),6.82–6.74(m,4H...

Embodiment 2

[0093] (2S,2R)-1-((2S)-2-(6-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)caproylamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26b)

[0094]

[0095] Under the protection of argon, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25b (106 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as a cosolvent . The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 94 mg of yellow solid product, 67% yield; m.p.176-177°C; 1 H NMR (400MHz, MeOD) δ8.82 (s, 1H), 7.43 (d, J = 8.1Hz, 2H), 7.35 (d, J = 8.1Hz, 2H), 7.14–7.04 (m, 6H), 6.74 (t,J=9.1Hz,4H),6.68(...

Embodiment 3

[0097] (2S,2R)-1-((2S)-2-(7-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)heptanamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26c)

[0098]

[0099] Under argon protection, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25c (107 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as a cosolvent . The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 91 mg of yellow solid product, 64% yield; m.p.178-179°C; 1H NMR (400MHz, MeOD) δ8.82 (s, 1H), 7.43 (d, J = 8.2Hz, 2H), 7.36 (d, J = 8.1Hz, 2H), 7.14–7.06 (m, 6H), 6.79 –6.71(m,4H),6.68(d,J=8.6Hz,2H...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a proteolysis-targeting chimera compound using an oxygen-bridged bicycloheptene compound as an estrogen receptor ligand, a preparation method and an application. Using two reasonable synthesis methods, VHL ligand or CRBN ligand is used as the ligand part of E3 ligase, and the oxygen-bridged bicycloheptene sulfonate or sulfonamide estrogen receptor ligand is linked through alkyl side chains of different lengths , a series of target product Protac molecules were synthesized. This type of Protac molecule is different from the existing anti-breast cancer drug tamoxifen, and is a type of targeted estrogen downregulator. Such compounds not only retain a certain ability to bind to estrogen receptors, but also have good estrogen receptor α down-regulation activity comparable to fulvestrant, and can achieve event-driven targeted estrogen receptor degradation. Methods to overcome drug resistance brought about by traditional endocrine therapy for ER-positive breast cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a targeted proteolysis chimera with an oxo-bridged bicycloheptene compound as an estrogen receptor ligand, a preparation method thereof, and an application in treating breast cancer by targeting an estrogen receptor . Background technique [0002] Breast cancer is the most common cancer among women worldwide, and its high morbidity and mortality seriously threaten women's health. Among them, estrogen receptor (ER)-positive breast cancer accounts for about 70% of all breast cancers, and endocrine therapy targeting ER signaling pathway is one of the main means of clinical treatment at present. However, endocrine therapy, such as its representative drug tamoxifen, has both agonistic and antagonistic activities on estrogen receptors, and long-term use will cause drug resistance. Drug resistance to endocrine therapy has become an urgent problem in the treatment of ER-positive breast ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K1/06C07K1/16C07D493/08A61K31/4439A61K38/05A61P35/00
CPCC07K5/06017C07D493/08A61P35/00A61K38/00
Inventor 周海兵胡志烨宁文涛黄健董春娥
Owner WUHAN UNIV