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HPLC and 31P NMR characterization of the reaction between antitumor platinum agents and the phosphorothioate chemoprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721)

jgsun 添加于 2010-10-21 22:08 | 2133 次阅读 | 0 个评论

作者
Thompson D
摘要
In prior studies, we examined the effects of the radioprotective and chemoprotective agent WR-2721 on the in vivo biotransformation of the cisplatin analog ormaplatin . Those data suggested that a direct interaction between WR-2721 and ormaplatin and/or the corresponding Pt(II) drug, Pt(dach)Cl 2 , may be occurring in vivo . This would be in contrast to the generally accepted hypothesis that WR-2721 is a prodrug that must first be converted by alkaline phosphatase to a free thiol compound, WR-1065, before any appreciable reactivity would be evident. However, the major biotransformation product observed in the peritoneal fluid, plasma, and all tissues was Pt(dach)(WR-1065). We report here on further investigations into the in vitro reactivity of Pt(dach) compounds with WR-2721 and WR-1065. Separation of reaction products resulting from incubation of Pt(dach)(malonato) with either WR-2721 or WR-1065 under physiological conditions gave profiles that were indistinguishable by reverse phase HPLC and cation exchange HPLC at two different pHs. 31 P NMR characterization of the dephosphorylation of WR-2721 revealed essentially no loss of inorganic phosphate for up to 24 hr when incubated in unbuffered water at 30 °. In contrast, when incubated with a 1:1 molar ratio of cisplatin under the same conditions, the WR-2721 signal was decreased markedly in the first 5 min, and had disappeared almost completely by 1 hr. The signal corresponding to inorganic phosphate increased in parallel to the decrease in the WR-2721 signal. No intermediate formation of a complex containing both platinum and phosphate could be detected at any time. These data suggest that the reaction between WR-2721 and platinum complexes results in rapid dephosphorylation of WR-2721, and, consequently, that the reaction products formed with either WR-2721 or WR-1065 and Pt(II) complexes are identical.
详细资料
- 文献种类:期刊
- 期刊名称: Biochemical Pharmacology
- 期刊缩写: Biochemical Pharmacology
- 期卷页: 1995年第50卷第9期 1413-1419页
- ISBN: 0006-2952
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