Anti-tumor drug sensitizer based on N-(3-hydroxypyridine-2-carbonyl) glycine and application thereof
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A technology of anti-tumor drugs and sensitizers, applied in the field of medicine, can solve the problems of high risk of side effects, high price, inconvenient preparation and storage, etc.
Active Publication Date: 2021-06-18
ZHEJIANG UNIV
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However, PD-1 / PD-L1 antibodies have problems such as high risk of side effects, inconvenient preparation and storage, and high price
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Embodiment 1
[0110] Example 1: The preparation route of the esterified derivative of N-(3-hydroxypyridine-2-carbonyl)glycine is as follows.
[0111] R 1 for-O-C 1-20 Alkyl or -O-C 6-12 Aryl.
[0112] Take compound (2) as an example.
[0113]
[0114] Compound (1) (200 mg, 1.02 mmol) was dissolved in 20 mL of dry N,N dimethylformamide, and oleyl alcohol (329 mg, 1.22 mmol) and 4-dimethylaminopyridine (6.23 mg, 0.05 mmol) were added. N 2 Protected and added dicyclohexylcarbodiimide (252 mg, 1.22 mmol) dropwise under ice bath, stirred for 1 h, then removed the ice bath and continued to react overnight. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the compound (2) was obtained as a white solid with a yield of 86.9%. Formula: [C 26 h 45 N 3 o 3 ] + , Calc. 448.33, found 448.23.
Embodiment 2
[0115] Example 2: The preparation route of amidated derivatives of N-(3-hydroxypyridine-2-carbonyl)glycine is as follows.
[0116] R 1 for NH 2 or -NH-C 1-20 .
[0117] Take compound (3) as an example.
[0118]
[0119] Compound (1) (200 mg, 1.02 mmol) was dissolved in 20 mL of dry N, N dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (603 mg , 3.06mmol), 1-hydroxybenzotriazole (207mg, 1.53mmol) and oleylamine (328mg, 1.23mmol), N 2 Protect and add N,N-diisopropylethylamine (527 mg, 4.08 mmol) dropwise under ice bath, stir for 1 h, then remove the ice bath and continue the reaction overnight. After the reaction was completed, most of the solvent was removed by rotary evaporation under reduced pressure, and ethyl acetate was redissolved, followed by washing with 1N hydrochloric acid and saturated brine, drying and concentrating, and using n-hexane:ethyl acetate=3:1 as the mobile phase for column purification. After drying, compound (...
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Abstract
The invention discloses an antitumor drug sensitizer based on N-(3-hydroxypyridine-2-carbonyl) glycine and an application of the antitumor drug sensitizer. The compound shown in a formula (I) can down-regulate PD-L1 of tumor cells, promote polarization of macrophages from M2 to M1, inhibit expression of indoleamine 2,3-dioxygenase and improve the curative effect of immunotherapy; and the expression of hypoxia-inducible factor-1 alpha in tumor cells can be reduced, the expression of P glycoprotein can be reduced, the killing effect of chemotherapeutic drugs on the tumor cells can be improved, and cell immunogenicity death can be enhanced. After the compound shown in the formula (I) is combined with chemotherapeutic drugs, the anti-tumor effect is remarkably improved, and the compound has a good application prospect.
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to the application of N-(3-hydroxypyridine-2-carbonyl)glycine and its derivatives in the preparation of antitumor drug sensitizers. Background technique [0002] With the in-depth study of tumor immunology, researchers have found that tumors, especially solid tumors, have developed into a complex composed of cancer cells, fibroblasts, lymph, blood vessels and a variety of extracellular matrix in order to meet the needs of their rapid growth. Complex tissue structure, also known as tumor microenvironment (TME, tumor microenviroment). Compared with normal tissues, there are a series of unique microenvironmental characteristics in tumors, such as relatively low pH value, elevated interstitial pressure, vascular distortion, insufficient oxygen supply, and elevated reactive oxygen species (ROS) (Microenvironmental regulation of tumor progression and metastasis, Nature Medicine , 2013, ...
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