This paper describes the first synthesis of
phosmidosine and
phosmidosine B, i.e.,
nucleotide antibiotics composed of
8-oxoadenosine and
L-proline which are connected via a unique N-acyl
phosphoramidate linkage.
Phosmidosine has a yet-undetermined chiral center at the
phosphorus atom of the N-acyl
phosphoramidate linkage.
Phosmidosine B is a demethylated
phosmidosine derivative with no chirality on the
phosphorus.
Phosmidosine B was successfully synthesized by the reaction of an N-acetyl-8-oxoadenosine 5'-O-phosphoramidite derivative with an N-protected
prolinamide in the presence of 5-(3,5-dinitrophenyl)-1H-tetrazole. The successful synthesis of
phosmidosine was achieved by use of a tert-butoxycarbonyl (
Boc) group, which was found to be selectively introduced into the 7-NH function of
8-oxoadenosine and to serve as a pseudo-protecting group due to its steric effect in such manner that the unmasked 6-amino group was not phosphitylated. Final coupling reaction of the
8-oxoadenosine 5'-phosphoramidite derivative with N-tritylprolinamide followed by full deprotection gave a mixture of
phosmidosine and its diastereoisomer. The (13)C NMR spectra of the diastereomers suggest that the slow-eluted diastereomer 1b is the naturally occurring
phosmidosine. The growth inhibitory activity of
phosmidosine 1b, its diastereomer 1a, and
phosmidosine B in various tumor cell lines was evaluated by the MTT assay. As the result,
phosmidosine B showed high anticancer activities and both the diastereomers 1a and 1b of
phosmidosine isolated were found to have similar but approximately 10 times higher anticancer activities than
phosmidosine B. Moreover, it turned out that these
phosmidosine derivatives showed characteristic inhibitory activities against
cancer cells independent of their p53 phenotypes. These results suggest that
phosmidosine and its related compounds would be promising as a new type of
anticancer agents having a wide range of inhibitory activities against
tumor cells.