Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent.
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.
Sood
Paul
P
Access Pharmaceuticals, Inc., 2600 Stemmons Freeway, Suite 176, Dallas, Texas 75207, USA. paul.sood@accesspharma.com
Thurmond
K Bruce
KB
Jacob
Jeremy E
JE
Waller
Lynda K
LK
Silva
George O
GO
Stewart
Donald R
DR
Nowotnik
David P
DP
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011108:Polymers; C511763:ProLindac