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Synthesis of Chemically Stabilized Phosmidosine Analogues and the Structure−Activity Relationship of Phosmidosine

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journal contribution
posted on 23.01.2004, 00:00 by Mitsuo Sekine, Kazuhisa Okada, Kohji Seio, Hideaki Kakeya, Hiroyuki Osada, Tohru Obata, Takuma Sasaki
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 1ad 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 7ad with an 8-oxoadenosine derivative 4 protected with acid-labile protecting groups. Consequently, the O-ethyl ester derivative 1b 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 25ad 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.