Tryptophan Side Chain As P₂’ Matrix Metalloproteinase Inhibitor Studies

Matrix metalloproteinases (MMP) are a class of zinc metal proteolytic enzymes, they can cleave the extracellular matrix. At present, human has discovered dozens of MMP, in their study found:mammalian MMP are classified into a soluble type and a membrane. Soluble MMP can be further categorizd into the following groups: collagenases, gelatinases, stromelysins, matrilysins, and metalloelastases. Membrane-type MMP are classified into type I transmembrane MMP, and a type Ⅱ transmembrane MMP. Expression of MMP activity loss of balance cause many diseases, such as multiple sclerosis, Alzheimer’s, lung cancer, liver cancer, pancreatic cancer and so on. At present nearly 30 kinds of MMP discovered, MMP-1, MMP-2 and MMP-7 are the target enzyme for treating cancer, the development of selective inhibitors of MMP is essential.The study found that of the MMP, the pseudo-peptide matrix metalloproteinase inhibitors of structure generally comprises two parts:zinc binding group (ZBG) and side chains. Side chains are divided into P1’side chains, P2’ side chains and P3’ side chains. P2’ corresponding to the MMP S2’ pocket exposure to solvents, P2’ side chains have both solvating power and hydrophobic effect. Leucine, phenylalanine, tyrosine, tryptophan, tert-butyl glycine contains almost P2’ side chains peptide inhibitors. Inhibitors used in these amino acids with hydrophobic residues whether there is a fused ring system and related to a heteroatom. This means that P2’ side chain selected point in the plane of a condensed polycyclic aromatic group and a hydrogen bond. Tryptophan indole-both to meet the plane condensed polycyclic aromatic group and a hydrogen bond to meet these two points, so this 2-isobutyl-3-nitro-propionic acid tryptophan amide as a basic skeleton, choose Nitro for zinc ion-binding group designed and synthesized a series of derivatives of tryptophan, explore their selectivity for MMP-1, MMP-2 and MMP-7 suppression.We designed and synthesized a series of 2-isobutyl-3-nitro-propionic acid tryptophan amide compound. The target compound (13a-13d) and MMP-1, MMP-2 and MMP-7 kinetic test. Their Ki values were 27.6 μM、30.0μM、53.2μM、34.9μM; 17.0 μM、26.3 μM、24.9 μM、13.5 μM; 26.1 μM、6.4μM、19.8 μM、22.7 μM. Test results show that:When P2’ choice tryptophan side chain, compound (13a-13d) selective MMP-1, MMP-2 and MMP-7 inhibitory effect is poor.This study shows that, P2’tryptophan side chain, can not achieve the selective inhibition of MMP. Combined with laboratory preliminary work, MMP of Si’, S3’ are preferred to achieve selective suppression.