Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent
Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent
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DOI：
10.1021/bc0600517
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发表时间：
2006-09-20
影响因子：
4.7
通讯作者：
Nowotnik, David P.
中科院分区：
文献类型：
--
作者：
Sood, Paul;Thurmond, K. Bruce, II;Nowotnik, David P.
报道了新型聚合物结合铂基化疗药物poly(HPMA)-GGG-Amad=Pt= (1R, 2R)-DACH、AP5346及其前体的合成。本文描述用于AP5346临床前开发的方法。此外，还报道了一种改进的合成方法，表明离子交换树脂可以被去除，当反应混合物的ph值为规定值时，铂的用量明显减少，合成可以在更高的浓度下进行。这些综合改进使手术更具成本效益和可扩展性。还讨论了原料药的各种分析方法。具体来说，H-1核磁共振光谱用于鉴别，也可以区分0.1%以下的小分子杂质。Pt-195核磁共振决定了铂的配位环境以及与铂螯合有关的结构的身份和纯度。采用粒径排斥色谱法确定AP5346的分子量，ICP-AES法测定磷酸缓冲盐水中铂的含量和铂的释放率。这项工作的累积结果产生了一种高效合成的聚合物基化疗药物，并具有随后的详细表征方法。
Syntheses of the novel polymer-bound platinum-based chemotherapeutic agent poly( HPMA)-GGG-Amad=Pt= (1R, 2R)-DACH, AP5346, and its precursors are reported. The method utilized in preclinical development of AP5346 is described herein. Additionally, an improved synthesis, which has shown that ion exchange resins can be removed, significantly less platinum can be used when the reaction mixture is pH-stated, and the synthesis can be performed at a higher concentration, is reported. These combined improvements result in a more cost-effective, scaleable procedure. Various methods of analysis of the drug substance are also discussed. Specifically, H-1 NMR spectroscopy is used for identity and can also distinguish small molecule impurities to below 0.1%. Pt-195 NMR determines the coordination environment of the platinum and also identity and purity in relation to platinum chelation of the construct. Size exclusion chromatography is used to establish the molecular weight of AP5346 while ICP-AES determines platinum content and platinum release rates in phosphate-buffered saline. The cumulative results of this work have yielded an efficient syntheses of a polymer-based chemotherapeutic agent with subsequent detailed characterization methods.