Structural Modification of the Macrolide Brefeldin A to Analogues with Enhanced Cytotoxicity against KB Cells

The macrolide brefeldin A (BFA, 1) exhibited high cytotoxicity against KB cells. However, it was also toxic against non-cancerous cells. In order to lower toxicity against normal cells while maintaining the cytotoxic potency to the cancer cells, structural modification of this compound was undertaken. Starting from compound 1, the analogues 2-13 were synthesized and evaluated for cytotoxicity against KB cells. The analogue 2 exhibited the most potent cytotoxicity against KB cells, with an IC50 value of 0.034 nM, 67-fold more active than its parent compound 1. It was 41764 and 8235 fold more active than the standard drugs ellipticine and doxorubicin, respectively. The higher cytotoxicity against KB cells and lower toxicity against Vero cells of analogue 2 than those of the parent compound 1 contributed to its exceptionally high selectivity index of 9117. The results suggested that this analogue might be utilized to develop a new candidate for an anticancer drug. HIGHLIGHTS Oral cancer is a major worldwide public health issue and may affect any oral cavity region, including the lips, tongue, mouth and throat The ester analogues (2-13) were the first report of the cytotoxic against human epidermoid carcinoma (KB) cells 7-O-acetyl BFA (2) exhibited the most potent cytotoxicity against KB cells, with an IC50 value of 034 nM, 67-fold more active than its parent compound 1 The essentially structural features for the macrolide of BFA-type to exhibit high cytotoxicity against KB cells are the presence of a free hydroxyl group at the 4-position, a free hydroxyl group or the corresponding ester at the 7-position, and unsaturated functions at the 2- and 10-positions GRAPHICAL ABSTRACT