Synthesis and Characterization of AP5346, a Novel Polymer-Linked Diaminocyclohexyl Platinum Chemotherapeutic Agent

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• 作者：Paul Sood ; K. Bruce Thurmond ; II ; Jeremy E. Jacob ; Lynda K. Waller ; George O. Silva ; Donald R. Stewart ; David P. Nowotnik
• 刊名：Bioconjugate Chemistry
• 出版年：2006
• 出版时间：September 2006
• 年：2006
• 卷：17
• 期：5
• 页码：1270 - 1279
• 全文大小：163K
• 年卷期：v.17,no.5(September 2006)
• ISSN：1520-4812

文摘

Syntheses of the novel polymer-bound platinum-based chemotherapeutic agent poly(HPMA)-GGG-Ama=Pt=(1R,2R)-DACH, AP5346, and its precursors are reported. The method utilized in preclinical development of AP5346is 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 performedat a higher concentration, is reported. These combined improvements result in a more cost-effective, scaleableprocedure. Various methods of analysis of the drug substance are also discussed. Specifically, ¹H NMR spectroscopyis used for identity and can also distinguish small molecule impurities to below 0.1%. ¹⁹⁵Pt NMR determines thecoordination environment of the platinum and also identity and purity in relation to platinum chelation of theconstruct. Size exclusion chromatography is used to establish the molecular weight of AP5346 while ICP-AESdetermines platinum content and platinum release rates in phosphate-buffered saline. The cumulative results ofthis work have yielded an efficient syntheses of a polymer-based chemotherapeutic agent with subsequent detailedcharacterization methods.