Synthesis and Antiproliferative Activity of Simplified Lactone Analogues of Mycalin A, a Polybrominated Metabolite of Marine Origin

Mycalin A (1, Figure 1) is an antiproliferative metabolite isolated from the marine sponge Mycale rotalis that induces cell death by an apoptotic mechanism. Recent studies conducted in our group have shown that a degraded lactone analogue (2, Figure 1) of mycalin A retains the cytotoxic activity of the original substance while displaying a limited killing effect on human dermal fibroblasts (HDF) healthy cells used as control. Preparation of several synthetic analogues of mycalin A, including 2, has shown that their anti-tumour activity is mostly associated with the presence in the molecule of the THF or a THF-mimicking left-hand portion. Based on these observations, we have synthesised some simplified lactone analogues of 2 (Figure 2), including C-3 epimeric analogues, starting from D-ribonolactone and D-xylonolactone. Preliminary results on their cytotoxic activity have shown that some of them possess good antiproliferative activity on the same human tumour cell lines used for assays on mycalin A and on its lactone derivative 2. The identification of the biological target through the Drug Affinity Responsive Target Stability (DARTS) technique is currently under investigation and will also be discussed.