STUDIES ON THE TERATOGEN PHARMACOPHORE OF VALPROIC ACID ANALOGS - EVIDENCE OF INTERACTIONS AT A HYDROPHOBIC CENTER

Propyl-4-yn-valproic acid (2-propyl-4-pentynoic acid), an analogue of valproic acid with a triple bond in one alkyl side chain, potently ind uces exencephaly in mice. Given that propyl-4-yn-valproic acid is a br anched chain carboxylic acid, we synthesized a series of analogues wit h n-alkyl side chains of increasing length and correlated their potent ial to induce neural tube defects and to inhibit proliferation and ind uce differentiation in cells of neural origin, the latter being crucia l to the orderly structuring of the embryo. All analogues significantl y increased the incidence of neural tube defects in the embryos of dam s exposed to a single dose of 1.25 mmol/kg on day 8 of gestation. This effect occurred in a dose-dependent manner and the rate of exencephal y increased with the progressive increase in n-alkyl side chain length . Moreover, increasing chain length resulted in a dose-dependent inhib ition of C6 glioma proliferation rate over a concentration range of 0- 3 mM and this was independent of the cell type employed and mode of es timating proliferative rate. The antiproliferative action of these ana logues was associated with profound shape change in neuro-2A neuroblas toma involving extensive neuritogenesis and an associated increase in neural cell adhesion molecule (NCAM) prevalence at points of cell-cell contact, the latter exhibiting a dose-dependent increase when the n-a lkyl chain was extended to five carbon units. These results suggest an interaction with a specific site in which the n-alkyl side is propose d to serve as an 'anchor' within a hydrophobic pocket to facilitate th e ionic and/or H-bonding of the carboxylic acid and high electron dens ity of the carbon-carbon triple bond. (C) 1998 Elsevier Science B.V. A ll rights reserved.