Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of pyrimidine derivatives
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A technology of pyrimidine derivatives and structural units, applied in the field of medicinal chemistry
Active Publication Date: 2014-10-29
ZHENGZHOU UNIV
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However, there are few reports on the combination of pyrimidine compounds and the anti-tumor effect based on the LSD1 target, so this study has very important value
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Embodiment 1
[0076] Example 1 general formula( II ), R 2 = Derivatives of Phenyl( II-1 ) preparation
[0077] Add ethyl cyanoacetate (2.3g, 20mmol) and sodium hydroxide (1.2g, 30mmol) into the ethanol solution, under reflux conditions, react for a period of time, then add thiourea (2.3g, 30mmol) and benzaldehyde (3.2 g, 30mmol) was added into the reaction system, stirred and reacted, followed by TLC detection. After the reaction, filter with suction and recrystallize to obtain the pure product. Yield 92%, yellow solid.
Embodiment
[0078] Example 2 general formula( III ), R 1 = Cl, R 2 = Derivatives of Phenyl( III-1 ) preparation
[0079] Add propyne bromide (3.6g, 30mmol) dropwise into the solution of II-1 (2.7g, 10mmol) in 1,4-dioxane, and heat and stir at 60°C for reaction. Monitor the reaction process with TLC until the reaction is complete; without separation, directly dropwise phosphorus oxychloride (4.6g, 30mmol) in the reaction system, after the reaction is completed, it is poured into ice water, stirred, and solids are separated out, pumped Filtration to obtain a solid, the pure compound III-1 solid was obtained by column chromatography. Yield 64%, pale yellow solid. Melting point: 131-132 o c. 1 H NMR (400 MHz, CDCl 3 , δ, ppm) δ 8.20 – 8.07 (m, 2H, Ar-H), 7.70 – 7.52 (m, 3H, Ar-H), 4.01 (d, J = 2.6 Hz, 2H, -CH 2 -), 2.28 (t, J = 2.6 Hz, 1H, ≡C-H). 13 C NMR (100 MHz, CDCl 3 C 14 h 9 ClN 3 S, [M+H] + m / z: 286.0206, found: 286.0202.
[0080] Example 3 general formula( ...
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Abstract
The invention belongs to the field of medicinal chemistry, and discloses pyrimidine compounds containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of the pyrimidine compounds in preparation of antitumor drugs by taking lysine specific demethylase 1 (hereafter referred to as LSD1) as a target. A pyrimidine active fragment is built by adopting a three-component one-pot method, and then the target compounds are prepared by substitution, chlorination and ammonification reaction. The general formulas of the compounds are as shown in the formula I in the specification. An in vitro anti-tumor activity experiment and an LSD1 inhibition activity experiment prove that the compounds have obvious inhibiting and killing action on a plurality of tumor cells by inhibiting the activity of the LSD1, can be used as lead compounds for further development, and are applied to preparation of the antitumor drugs.
Description
technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyrimidine compounds containing semicarbazide and terminal alkyne structural units, their preparation methods and their preparation using histone lysine specific demethylase (hereinafter referred to as LSD1) as Application of targeted anticancer drugs. Background technique [0002] Tumor is a disease that seriously endangers human health and is difficult to overcome. There are many anti-tumor drugs that have been marketed, but there are still some problems in these drugs, such as high toxicity, weak targeting, and easy drug resistance. Therefore, the research and development of new anticancer drugs is particularly important. [0003] Histone covalent modification is an important epigenetic mode, including histone acetylation, methylation, phosphorylation, and ubiquitination, among which acetylation and methylation are more frequently studied for the mecha...
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