A NOVEL2-ALKOXY-3, 5-DIHYDROXYPYRIDINE MEDIATED REGULATION OF GELATINASES

Abstract

Aberrant expression of Matrix Metalloproteinases (MMPs) has been correlated with a wide range of diseases including several forms of cancers. MMPs are implicated in tumor cell invasion and metastasis as well as abnormalities of oncogenicsignalling cascades like the Epidermal Growth Factor (EGF) pathway. We have recently reported the synthesis of 3,5-dihydroxypyridine derivativesvia 2-pyridone produced in an unusual aromatization of a lactam intermediate derived from d-galactose. The present study demonstrates for the first time, that one such pyridone derivative, 3, 5-dihydroxypyridinewith a C2 substituted tetradecyloxy chain (TD-2), showed inhibition of gelatinases, both at the level of activity and RNA expression without affecting the viability of the fibrosarcoma cell line HT1080. Further, TD-2 was also shown to inhibit Akt, one of the major components of the oncogenic EGF cascade. These studies provide evidence for a novel TD-2 mediated regulation of MMPs and the EGF pathway.