Sekine Mitsuo, Okada Kazuhisa, Seio Kohji, Kakeya Hideaki, Osada Hiroyuki, Obata Tohru, Sasaki Takuma
Department of Life Science, Tokyo Institute of Technology, Nagatsuda, Midoriku, Yokohama 226-8501, Japan.
J Org Chem. 2004 Jan 23;69(2):314-26. doi: 10.1021/jo0351466.
Phosmidosine is known to have potent antitumor activity and the unique property of stopping cell growth at the G(1) 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 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 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.
磷咪多辛具有强大的抗肿瘤活性，且具有在细胞周期的G(1)期阻止细胞生长的独特特性。然而，这种在5'-磷酰基残基上具有N-脯氨酰磷酰胺酸酯和O-甲基酯键的天然产物，由于其固有的甲基转移活性，在碱性条件下甚至在化学合成过程中都不稳定。为了找到磷咪多辛的稳定衍生物，通过烷基N-(N-三苯甲基脯氨酰)磷二酰胺衍生物7a-d与用酸不稳定保护基保护的8-氧代腺苷衍生物4反应，合成了多种在磷酰胺酸酯键上用较长烷基取代甲基的磷咪多辛类似物1a-d。因此，发现O-乙酯衍生物1b在水溶液中足够稳定。当脯氨酰基被其他氨酰基部分取代时，N-三苯甲基氨酰酰胺衍生物25a-d与适当保护的8-氧代腺苷5'-(乙基磷酰胺)衍生物9的反应比上述偶联反应效果更好。还合成了一种磷酰胺硫代酸酯衍生物17以及几种缺乏磷咪多辛部分结构的简单化合物，如11、13和15。对这些修饰类似物的抗肿瘤活性进行了广泛研究，以阐明磷咪多辛的构效关系。结果，含较长烷基的磷咪多辛类似物的两种非对映异构体均被证明具有相似的抗肿瘤活性。用其他L-氨基酸或D-脯氨酸取代L-脯氨酸导致抗肿瘤活性显著降低。非核苷酸物质13没有显示出任何抗肿瘤活性，但简单的核心化合物11表现出较弱的细胞毒性。磷酰胺硫代酸酯衍生物17基本上保持了相似的抗肿瘤活性，但效率略有下降。
