Synthesis, toxicity and chemo-sensitization of HeLa cells to etoposide, of some 2-methyl amino acid ester-substituted-1,3-benzoxazines

Abstract

A number of new L- or LD-2-amino acid ester-(substituted)-benz[1,3]oxazines 12–17 were synthesized from the reaction of free L- or LD-amino acid ester 9a–d with 2-methylthio-1,3-benzoxazines 11a–g. The structures of the new products 12–17 were confirmed from their 1H, 13CNMR and IR spectra and CHN microanalysis. Some of these compounds weakly inhibited DNA-PK and platelet aggregation. Studies of the toxicity for some of the new compounds showed mostly no inhibitory effects on HeLa cell growth at 1 and 10 µM and some up to 40 µM. The chemo-sensitization to etoposide by some of the compounds revealed that the most effective chemo-sensitizers at 10 µM were 14c (1.83 fold), 12e (1.42 fold), 15a (0.8 fold), 16d (0.76 fold) and 1c (0.74). However, at 1 µM in the presence of etoposide, some compounds were shown to be more effective. No direct link was observed between the type of the L-amino acid methyl ester as well as the 7-, 8-, or 7, 8-substitution on the aromatic ring on the effectiveness of the chemo-sensitizers; however, the 7-hydroxy group did lower the effective chemo-sensitizers values.