Abstract
A variety of derivatives incorporating substituted heterocycle-phosphor motifs is described. Substituted N,P-heterocycles and derived phosphonates were produced efficiently in a tandem operation without intermediate isolation. The synthesis methodology is based on the reaction of dialkyl phosphites with Schiff base Kabachnik-Fields intermediates, which are generated in situ from 2-amino-4,6-di-tert-butylphenol and substituted benzaldehydes in dry THF/FeCl3 (10 %) solution, to yield fused oxazole-2-phosphonates in moderate yield (a parts per thousand 55 %). The latter products could be also obtained in excellent yield (a parts per thousand yen76 %) by directly applying the same P(III) reagents to the parent Schiff bases. On the other hand, oxazaphosphinine-2-amines were isolated in high yields (a parts per thousand 77 %) when the Schiff bases were allowed to react with hexaalkyltriamidophosphites at rt. More P-heterocycles and the derived phosphonates were also obtained when the same reagents were applied to another imino derivative derived from the aminophenol, 2-hydroxybenzaldehyde oxime. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer activities. On the basis of bioassay data, the produced N,P-heterocycles exhibit remarkable antitumor activity against 17 tested human tumor cell lines, representing breast and prostate cancer and melanoma. Several phosphonates were found to possess specific anti-breast cancer activity (especially MDA-MB-435 cell lines) while others possess specific effects against melanoma (MI4 and SK-MEL-2 cancer cell lines). These findings form a foundation for further investigation in our continuing efforts to develop selective anticancer agents.
.