A kind of preparation method of p53 allosteric agent and its application as medicine
A p53 and drug technology, applied in the field of pharmacology, can solve the problems of poor stability of drugs, achieve strong affinity, inhibit tumor proliferation, and broad development prospects
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Embodiment 1
[0030] The compound I structure of the novel p53 allosteric agent is as follows:
[0031]
[0032] The synthetic route of compound I is as follows
[0033]
[0034] The synthetic method of compound I comprises the steps:
[0035] By amide reaction: at room temperature, the reactant 3-aminobenzoic acid methyl ester (20g, 0.13mol) and maleic anhydride (12.9g, 0.13mol) were dissolved in 80mL acetic anhydride (acetic anhydride as solvent) and stirred at room temperature for 2h, then Sodium acetate (1.43 g, 0.10 mol) was added. The mixture was heated to reflux at 120°C for 3 hours. After cooling down to room temperature, 300ml of water was poured into the reaction solution, extracted twice with ethyl acetate (150ml x 2), the organic layer was washed with 50ml of brine, dried over sodium sulfate, concentrated by rotary evaporator, and subjected to column chromatography on silica gel. Purified with petroleum ether:ethyl acetate=10:1 (eluent ratio PE:EA=10:1) to obtain white ...
Embodiment 2
[0039] The synthetic method of embodiment 1 has carried out condition experiment:
[0040] (1) Condition optimization: compound I was synthesized with the synthetic method of Example 1, the difference being that the molar ratio of 3-aminobenzoic acid methyl ester, maleic anhydride, and sodium acetate was 1:1:1.5; the conditions of heating and reflux For: stirring at room temperature overnight; the result is no product.
[0041] (2) Condition optimization: Compound I is synthesized with the synthetic method of Example 1, the difference is that: the molar ratio of methyl 3-aminobenzoate, maleic anhydride, and sodium acetate is 1:1:1; the conditions of heating and reflux For: stirring at 80°C overnight, LCMS checks that the purity of compound I is about 49%.
[0042] (3) Condition optimization: compound I is synthesized with the synthetic method of Example 1, the difference is that: the molar ratio of methyl 3-aminobenzoate, maleic anhydride, and sodium acetate is 1:1:1; the con...
Embodiment 3
[0047] Effect of compound Ⅰ on p53 mutant cell line H1299
[0048] Experimental method: Cell viability was determined by using MTT to test the effect of compound Ⅰ on the proliferation of NCI-H1299 human non-small cell lung cancer cells in vitro, and the cell survival rate was calculated = (administration group-blank group) / (solvent group-blank group).
[0049] Experimental principle: MTT method, also known as MTT colorimetric method, is a common method for detecting cell survival and growth. The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan (Formazan) and deposit in the cells, while dead cells do not have this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at a wavelength of 570nm with an enzyme-linked immunosorbent detector, which can indirectly reflect the number of living cells. Within a certai...
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