(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones

摘要

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene >13, with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC50 values (less than 10 μM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were >7a, >17, and >19c for PC-3 cells; >7a, >17, and >20 for HT-29 cells, and >19a for MCF-7 cells.