Toxicity screening of N-alkylazacycloheptan-2-one derivatives in cultured human skin cells: structure-toxicity relationships

Abstract

A number of N-alkylazacycloheptan-2-one derivatives, with the hydrocarbon chain lengths systematically varied from C2 to C16, were tested for their possible skin toxic effects. For this purpose, three in vitro cytotoxicity assays were used: (1) inhibition of proliferation of cultured human fibroblasts and keratinocytes; (2) inhibition of collagen contraction by human fibroblasts; and (3) cell morphology changes in confluent cultures of human fibroblasts and keratinocytes. With all assays used, the toxicity of N-alkylazacycloheptan-2-one derivatives increased from C2 to C8, remained constant at a hydrocarbon chain length between C8 and C14, and subsequently decreased with increasing alkyl chain length. A similar trend has been observed for flux enhancement of nitroglycerine in the presence of these N-alkylazacycloheptan-2-one derivatives, suggesting that with these compounds a parallelism exists between skin cell toxicity and penetration enhancing capacity. Since for practical use it is preferable to find a balance between skin toxicity and the penetration enhancement effect of a particular enhancer, it would be advisable to do QSAR studies of this kind with a number of congeners of a particular compound in order to optimize the choice. In this particular case, further modification of the N-alkylazacycloheptan-2-one structure might lead to an even better choice than the often propagated dodecyl derivative.