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

Abstract

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 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, (1)H NMR spectroscopy is used for identity and can also distinguish small molecule impurities to below 0.1%. (195)Pt 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.

The Relevance of Polar Surface Area (PSA) in Rationalizing Biological Properties of Severalcis‐Diamminemalonatoplatinum(II) Derivatives

“…[32] Interestingly, the macromolecular platinum complexes AP5280 and AP5346 (ProLindac), [33,34] consist of a platinum diamine unit linked to a water-soluble copolymer N-(2-hydroxypropyl)methacrylamide (HPMA) through an amidomalonic acid as a (N,O) chelate, which slows the release of platinum species. Both conjugates reached phase I clinical trials (AP5346 started phase II in 2006), in which they demonstrated similar or better efficacy than carboplatin and oxaliplatin, with the added benefit of a higher therapeutic index (TI), due to the stability of the inactive prodrug conjugate in the systemic circulation.…”

Amorphous Coordination Polymer Particles for Biomedicine

“…Platinum-based drugs have been used as frontline treatment for several cancers since the accidental discovery of the anticancer properties of cisplatin in the 1970s [59][60][61]. Since then, a new generation of platinum derivates, such as carboplatin, and new platinum-based agents (oxaliplatin, satraplatin and picoplatin) have contributed to improve their anticancer properties, time of tumor residence, and selectivity.…”

Synthesis, Characterization and Biological Evaluation of Platinum(II) Complexes with a Chiral N-Monosubstituted 1,2-Cyclohexyldiamine Derivative

“…It has been reported that approximately 90% of patients treated with oxaliplatin suffered from acute neurotoxicity, while 10-15% of patients suffered from cumulative sensory. 10,11) Like other clinically available platinum anticancer drugs, oxaliplatin can not offer any substantial clinical advantages over the existing cisplatin, either. [12][13][14] Considering the advantages of oxaliplatin in treating ACRC and its drawbacks, we have been devoting to studying new platinum compounds with chiral ligands in recent years.…”