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A study of the anti-invasive properties of N-alpha-phthalimidomethyl-ketomethylene tripeptide-based metalloprotease inhibitors

Martin, S. L., McDowell, A., Lynas, J. F., Nelson, J. and Walker, B. (2001) A study of the anti-invasive properties of N-alpha-phthalimidomethyl-ketomethylene tripeptide-based metalloprotease inhibitors. Journal of Pharmacy and Pharmacology, 53 (3). pp. 333-343. [Journal article]

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We have developed matrix metalloprotease (MMP) inhibitors based on synthetic peptides incorporating a non-cleavable peptide-bond isostere at the site of the putative scissile bond. These inhibitors, N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tyr-Ala-NH2 (Pht-G-CH2-LYA-NH2) and N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tic-Ala-NH2 (Pht-G-CH2-LTcA-NH2) were kinetically evaluated against the type IV collagenases, gelatinase A (MMP-2) and B (MMP-9), and compared with an exactly analogous chelating-based inhibitor, N-alpha-mercaptoacetyl-Leu-Tyr-Ala-NH2 (HSCH2CO-LYA-NH2). The peptide inhibitors were also tested for their anti-invasive effects on breast carcinoma cell lines using a modification of the Boyden chamber assay. Gelatin zymography was utilized to identify gelatinolytic activities present in media removed from cultured breast cancer cells. Of the two N-alpha-phthalimidomethyl-ketomethylene peptide-based inhibitors, Pht-G-CH2-LYA-NH2 proved the more effective inhibitor of MMP-2 and MMP-9 (Ki 34.27 and 45.75 microM, respectively). However, when tested against two breast cancer cell lines, T47D and MDA-MB-231, both inhibitors were able to effectively reduce tumour cell invasion through a type IV collagen matrix by up to 91.2%. Of particular interest was the observation that Pht-G-CH2-LYA-NH2 was the most potent inhibitor of invasion by the highly aggressive MDA-MB-231 cells, despite the cells' relative lack of active secreted metalloprotease activity. The results obtained from this kinetic and anti-invasive analysis of the new inhibitors suggest that compounds incorporating the N-alpha-phthalimidomethyl-ketomethylene peptide-bond isostere may have potential for development as new agents with anti-metastatic properties.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Stratified Medicine
ID Code:28429
Deposited By: Dr Andrew McDowell
Deposited On:24 Jan 2014 09:50
Last Modified:24 Jan 2014 09:50

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