First Synthesis and Anticancer Activity of Phosmidosine and Its Related Compounds

• Published in: Journal of organic chemistry 2002-05, Vol.67 (10), p.3290-3300
• Main Authors: Moriguchi, Tomohisa, Asai, Norio, Okada, Kazuhisa, Seio, Kohji, Sasaki, Takuma, Sekine, Mitsuo
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological Factors - chemical synthesis; Biological Factors - pharmacology; Carbohydrates. Nucleosides and nucleotides; Catalysis; Chemistry; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Exact sciences and technology; Humans; KB Cells - drug effects; Laryngeal Neoplasms; Lung Neoplasms; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Purine Nucleotides - chemical synthesis; Purine Nucleotides - pharmacology; Stereoisomerism; Stomach Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo016176g

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 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.