Synthesis And Biological Activity Of Mandelic Acid-thiadiazole Amide Derivatives

The matrix metalloproteinases(MMPs) is a family of zinc-dependent proteolytic enzyme involved in extracellular matrix degradation, playing a key role in tumor invasion and metastasis, in which gelatinase(MMP-2, MMP-9) is associated with the occurrence of tumor most. Therefore, the development of highly selective gelatinase inhibitor has become one of the hot research direction of anticancer drugs, in particular for controlling the primary tumor and delay disease progression.The structure of MMPs contain catalytic Zn2+ which is necessary to MMPs' activity, and hydrophobic S1' binding cavity that binding with the substrate specificially.(R)-(-)-Mandelic and 5-substituted-1,3,4-thiadiazol-2-amine all contain zinc binding groups, hydrophobic groups. They can bind with zinc and form hydrophobic bonds and hydrogen bonds with MMPs. Therefore, the combination of(R)-(-)-mandelic acid and 5-substituted-1,3,4-thiadiazol-2-amine to amides, with a view to a better enzyme binding capacity.20 mandelic acid-thiadiazole amide derivatives(3a~3t) 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. All the target compounds are currently novel without any report, and the structures of target compounds were confirmed by 1H NMR, IR and ESI-MS. The compounds fully considered matching with gelatinase activity center, and the 1,3,4-thiadiazole structure have antitumor activity.Aminopeptidase N(APN) and MMPs are all zinc-dependent metalloproteinases, participating degradation of extracellular matrix. Therefore, the in vitro enzyme inhibition activity were evaluated against MMP-2, MMP-9 and APN. And the results showed that compound 3n(10 ?mol/L) exhibited both MMP-2 and MMP-9 highest inhibitory activity with the inhibition rate of 80.2% and 70.2% respectively. The advantaged compound 3n were docked to the activity center of MMP-2, MMP-9 and found that: the catalytic Zn2+ formed a bidentate chelate with active domain of MMP-2 and MMP-9. The compound 3n can be used as lead compounds, can lay the foundation for the subsequent synthesis of more selective inhibitors of MMPs.