Pyrimidine benzyl hydroxamic acid histone deacetylase inhibitor, and preparation method and application thereof
A technology of pyrimidine benzylhydroxamic hydroxime and sirtuin, which is applied in the field of medicine and can solve problems such as ineffectiveness of solid tumors, heart disease, and limitations in clinical application of drugs
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Embodiment 1
[0083] Example 1. Synthesis of N-hydroxyl-4-(((4-(5-methylfuran-2-yl)pyrimidin-2-yl)amino)methyl)benzamide (7c)
[0084] Synthesis of 3-(Dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-1-one (4a)
[0085] The compound 1-(5-methylfuran-2-yl)acetyl (3a, 2.5mL, 20mmol) was placed in 8.0mL N,N-dimethylformamide dimethyl acetal and stirred at 115°C for 12h. The reaction was completed and cooled to room temperature, filtered, washed with a small amount of ethyl acetate, and dried to obtain an orange solid (3.25 g, 90.7%). Mp: 121-123°C. 1 H NMR(300MHz,DMSO):δ2.33(s,3H,furan-CH 3 ),2.86(s,3H,N(CH 3 ) 2 ),3.11(s,3H,N(CH 3 ) 2 ),5.57(d,1H,J=12.6Hz,C=C-H),6.21(d,1H,J=3.3Hz,furan-H),7.00(d,1H,J=3.3Hz,furan-H), 7.61(d, 1H, J=12.3Hz, C=C-H).
[0086] Compounds 4b-4h were synthesized according to the method of 4a.
[0087] Synthesis of 4-(5-methylfuran-2-yl)-2-(methylthio)pyrimidine (5a)
[0088] Thiourea (2.60g, 34.2mmol) was dissolved in 20mL EtOH, NaOH (1.37g, 34.2mmol) and 4a (...
Embodiment 2
[0099] Example 2. Synthesis of N-hydroxyl-4-(((4-(5-methylfuran-2-yl)pyrimidin-2-yl)thio)methyl)benzamide (9c)
[0100] Synthesis of Methyl-4-(((4-(5-methylfuran-2-yl)pyrimidin-2-yl)thio)methyl)benzoate (8c)
[0101] Thiourea (2.60g, 34.2mmol) was dissolved in 20mL EtOH, NaOH (1.37g, 34.2mmol) and 4a (3.07g, 17.1mmol) were added, and refluxed at 90°C for 24h. After the reaction, cool to room temperature, spin dry the solvent, dissolve the solid with water, and adjust the pH to neutral with 2N HCl. Filter, wash with water three times, and dry to obtain a yellow solid (2.80 g, 85.0%). Take the yellow solid (0.55g, 2.9mmol) and dissolve it in 10mL acetone, add K 2 CO 3 (0.48g, 3.4mmol), methyl-4-(bromomethyl)benzoate (0.66g, 2.9mmol), refluxed for 12h. After the reaction was completed, the solution was spin-dried, and the solid was purified by column chromatography to obtain 8c (0.77 g, 79.05%) as an off-white solid. Mp:122-123℃. 1 H NMR(300MHz,DMSO):δ2.41(s,3H,CH 3 ),3.83...
experiment example 1
[0107] Experimental example 1, target compound to histone deacetylase inhibition test (in vitro)
[0108] Terminology Explanation:
[0109] SAHA: A marketed histone deacetylase inhibitor with the trade name vorinostat.
[0110] DMSO: dimethyl sulfoxide
[0111] Hela: HeLa cells, cervical cancer cell line
[0112] Buffer: buffer
[0113] Tris: Trishydroxymethylaminomethane
[0114] Color de Lys Developer: deacetylation reaction color developer
[0115] Color de Lys TM Substrate: deacetylation reaction substrate
[0116] Trichostatin A: Trichostatin A, deacetylation reaction terminator
[0117] 1. [Materials] stock solution of target compound and positive control SAHA (50mM, dissolved in DMSO); enzyme (HeLa cell extract, main components are HDAC1 and HDAC2); Color de Lys TM Substrate (oligopeptide substrate containing acetylated lysine side chain); Color de Lys Developer (deacetylation reaction detection reagent); HDAC Assay Buffer (50mM Tris-HCl, pH 8.0, 137mM NaCl, 2...
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