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

Abstract

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.

Isolation of Smenopyrone, a Bis-g-Pyrone Polypropionate from the Caribbean Sponge <em>Smenospongia Aurea</em>.

“…The large coupling constant between H-14 and H-15 showed them to be trans-axial and so demonstrated the trans orientation of the groups at C-14 and C-15 (in the following discussion, we will assume the 14S,15S absolute configuration for these carbon atoms, which will be eventually proven to be correct). Configuration at C-9, C-10 and C-16 was based on a comparison of 13 C NMR chemical shifts of smenopyrone (1) with those of the corresponding atoms of synthetic models, i.e. eight diastereomers of maurenone [18] (4-11, Figure 5).…”

“…The chemical shift of C-25, very similar to that of compounds 4-7 but very far from that of compounds, 8-11, clearly demonstrated the S configuration at C-16. Configurations at C-9 and C-10 were based on an overall comparison with 13 C NMR chemical shifts of model compounds, expressed as the sum of the absolute values of chemical shift differences, Σ|Δδ| (Table S1 and Figures 6 and S1). The best fit (Σ|Δδ|=3.1) was shown by model compound 6, and therefore the configuration was assigned as 9S,10S.…”

“…The Caribbean sponges of the genus Smenospongia have been previously shown to contain a wide array of chlorinated metabolites deriving from the PKS-NRPS pathway, such as smenamides, conulothiazoles, and smenothiazoles [ 11 ]. They have been used as guiding structures in our anticancer drug discovery programs [12,13].…”

“…The three possible diastereomers of 2,4-diphenyl-3-pentanol (2), pinnamine (3), and the eight diastereomers of maurenone (4-11, the relative configuration of natural maurenone is as in 6). These compounds were used as model compounds to elucidate the stereochemistry of smenopyrone (1) 13. C NMR chemical shifts shown for 2 are from ref.…”

“…Difference in13 C NMR chemical shift (δ∆) between corresponding atoms of smenopyrone (1) and the four stereoisomers of the model compound maurenone (4-7)…”