扁桃酸-噻二唑酰胺衍生物的合成及明胶酶抑制活性

Synthesis and Gelatinase Inhibitory Activity of Mandelic Acid-thiadiazole Amide Derivatives

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。

To discover novel antitumor drugs which showed high selectivity and affinity toward gelatinase（MMP-2,MMP-9）,twelve mandelic acid-thiadiazole amide derivatives were synthesized from（R）-（-）-mandelic acid by acyl chloridation,amidation reaction with 5-substituted-1,3,4-thiadiazol-2-amine based on the hydroxyl protection of thimethyl chlorosilane.The in vitro enzyme inhibition activity were evaluated against MMP-2 and MMP-9.And the results showed that（2R）-N-[2-[5-（4-nitrophenyl）-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide（10 μmol/L） exhibited both MMP-2 and MMP-9 highest inhibitory activity with the inhibition rate of 80.17% and 70.16%,respectively.（2R）-N-[2-[5-（3-nitrophenyl）-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide,（2R）-N-[2-[5-benzyl-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide and（2R）-N-[2-[5-（4-chlorophenylmethoxy）-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide showed higher MMP-2 inhibition activity,and（2R）-N-[2-[5-benzyl-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide,（2R）-N-[2-[5-phenethyl-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide and（2R）-N-[2-[5-（2,4-dichlorophenylmethoxy）-1,3,4-thiadiazole]]-2-hydroxy-phenylacetamide showed MMP-9 inhibition activity of moderate intensity.