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为了寻找选择性高、亲和性强的新型明胶酶抑制剂类抗肿瘤药物,以(R)-(-)-扁桃酸与合成中间体5-取代-1,3,4-噻二唑-2-胺为原料,基于三甲基氯硅烷的羟基保护作用,经酰氯化、酰胺化等反应合成出12个扁桃酸-噻二唑酰胺衍生物,并对明胶酶(MMP-2,MMP-9)进行初步体外抑酶活性评价。结果显示,浓度为10μmol/L时,(2R)-N-[2-[5-(4-硝基苯基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-2和MMP-9同时具有最强的抑制活性,抑制率分别为80.17%和70.16%,化合物(2R)-N-[2-[5-(3-硝基苯基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺、(2R)-N-[2-[5-苯甲基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺和(2R)-N-[2-[5-(4-氯苯氧甲基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-2有较强的抑制活性,化合物(2R)-N-[2-[5-苯甲基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺、(2R)-N-[2-[5-苯乙基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺和(2R)-N-[2-[5-(2,4-二氯苯氧甲基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-9有中等强度的抑制活性。
In order to find a new type of gelatinase inhibitor antitumor drug with high selectivity and affinity, this experiment was carried out with (R) - (-) - mandelic acid and synthetic intermediate 5-substituted-1,3,4-thiadiazole- 2-amine was used as starting material to synthesize 12 mandelic acid-thiadiazole derivatives by acid chlorination and amidation based on the hydroxyl protection of trimethylchlorosilane. The gelatinase (MMP-2, MMP- 9) preliminary inhibition of activity in vitro evaluation. The results showed that (2R) -N- [2- [5- (4-nitrophenyl) -1,3,4-thiadiazole]] - 2-hydroxy-phenylacetamide at a concentration of 10 μmol / The most potent inhibitory activity against MMP-2 and MMP-9 were 80.17% and 70.16%, respectively. The inhibitory rates of the compounds (2R) -N- [2- [5- (3-nitrophenyl) Thiadiazole]] - 2-hydroxy-phenylacetamide, (2R) -N- [2- [5-benzyl- 1,3,4- thiadiazole] Phenylacetamide and (2R) -N- [2- [5- (4-chlorophenoxymethyl) -1,3,4-thiadiazole] -2-hydroxy- Strong inhibitory activity of the compound (2R) -N- [2- [5-benzyl-1,3,4-thiadiazole] 2- [5-phenethyl-1,3,4-thiadiazole]] - 2-hydroxy-phenylacetamide and (2R) -N- [2- [5- Methyl) -1,3,4-thiadiazole]] - 2-hydroxy-phenylacetamide has moderate inhibitory activity on MMP-9.