Stereoselective Synthesis and Antiproliferative Activity of Nemamide Analogs

The nemamides are hybrid polyketide–nonribosomal
peptides
that are produced in two neurons of the nematode Caenorhabditis
elegans and promote recovery from starvation-induced early
larval stage arrest. Because the worm produces the nemamides in minute
quantities and no total synthesis of these molecules has been reported,
it has been difficult to study their mechanism of action. Here, by
using a miniaturized assay, we demonstrate that nemamides purified
from the worm exhibit antiproliferative activity against mammalian
cancer cells. Moreover, we present the stereoselective synthesis of
two nemamide analogs and evaluate their biological activity in the
proliferation
assay. Comparison of the NMR data of the synthetic analogs with those
of the nemamides provides further confirmation of the absolute configuration
of the nemamides, which was proposed previously based on NMR analysis,
Marfey’s method, model cyclic peptide synthesis, and CD spectroscopy.
While the nemamides exhibit significant biological activity, the analogs
have reduced potency, indicating that the lipid tail, polyene group,
and methoxy group all play crucial roles in the antiproliferative
properties of the nemamides. These findings offer valuable insights
into the structure–activity relationships of the nemamides
and lay the groundwork for future synthetic and mechanistic investigations
of this unique class of natural products.