439097-95-7Relevant academic research and scientific papers
Synthesis of Chemically Stabilized Phosmidosine Analogues and the Structure-Activity Relationship of Phosmidosine
Sekine, Mitsuo,Okada, Kazuhisa,Seio, Kohji,Kakeya, Hideaki,Osada, Hiroyuki,Obata, Tohru,Sasaki, Takuma
, p. 314 - 326 (2007/10/03)
Phosmidosine is known to have potent antitumor activity and the unique property of stopping cell growth at the G1 phase in the cell cycle. However, this natural product having N-prolylphosphoramidate and O-methyl ester linkages on the 5′-phosphoryl residue is unstable under basic conditions and even during the chemical synthesis due to its inherent methyl transfer activity. To find stable derivatives of phosmidosine, a variety of phosmidosine analogues 1a-d replaced by longer alkyl groups in place of the methyl group on the phosphoramidate linkage were synthesized by reaction of alkyl N-(N-tritylprolyl)phosphorodiamidite derivatives 7a-d with an 8-oxoadenosine derivative 4 protected with acid-labile protecting groups. Consequently, the O-ethyl ester derivative lb was found to be sufficiently stable in aqueous solution. When the prolyl group was replaced by other aminoacyl moieties, the reaction of N-tritylaminoacylamide derivatives 25a-d with an appropriately protected 8-oxoadenosine 5′-(ethyl phosphoramidite) derivative 9 gave better results than the above coupling reaction. A phosphoramidothioate derivative 17 and several simple compounds such as 11, 13, and 15 lacking partial structures of phosmidosine were also synthesized. The antitumor activities of these modified analogues were extensively studied to clarify the structure-activity relationship of phosmidosine. As a result, the two diastereoisomers of longer alkyl-containing phosmidosine analogues both proved to have similar antitumor activities. Replacement of L-proline with other L-amino acids or D-proline resulted in considerable decrease of the antitumor activity. The non-nucleotidic materials 13 did not show any antitumor activity, but a simple core compound of 11 exhibited weak cytotoxicity. The phosphoramidothioate derivative 17 maintained essentially a similar antitumor activity, but the efficiency decreased slightly.
First synthesis and anticancer activity of phosmidosine and its related compounds
Moriguchi, Tomohisa,Asai, Norio,Okada, Kazuhisa,Seio, Kohji,Sasaki, Takuma,Sekine, Mitsuo
, p. 3290 - 3300 (2007/10/03)
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 13C 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 la, 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.
