Smenamide A Analogues. Synthesis and Biological Activity on Multiple Myeloma Cells.

Smenamides are an intriguing class of peptide/polyketide molecules of marine origin showing antiproliferative activity against lung cancer Calu-1 cells at nanomolar concentrations through a clear pro-apoptotic mechanism. To probe the role of the activity-determining structural features, the 16- epi -analogue of smenamide A and eight simplified analogues in the 16- epi series were prepared using a flexible synthetic route. The synthetic analogues were tested on multiple myeloma (MM) cell lines showing that the configuration at C-16 slightly affects the activity, since the 16- epi -derivative is still active at nanomolar concentrations. Interestingly, it was found that the truncated compound 8 , mainly composed of the pyrrolinone terminus, was not active, while compound 13 , essentially lacking the pyrrolinone moiety, was 1000-fold less active than the intact substance and was the most active among all the synthesized compounds.