Mysterious Degradative Mechanisms in DMSO: Pyrimidine-2,4-dione


Storage of compounds in DMSO may lead to significant compound degradation resulting in compromised data in biological screens. Pyrimidine-2,4-dione substructures represent a commonly occurring core present in AstraZeneca's compound library. Kinetic studies monitoring compound stability highlighted unexpected purity fluctuations consistently in every reaction condition studied (temperature and humidity) over a 15 week timescale. Purity profiles indicated compound degradation via oxidation which could only have arisen from DMSO storage milieu. Initially a reversible (double) oxidation pathway was proposed in accordance with the presence of new molecular ion peaks by LC-UV-MS analyses, occurring at +16, +32 Da mass shifts from the expected parent ion. However unexpected LC polarity prompted further investigation into the degradation pathway. A range of spectroscopic analytical techniques were then employed to identify the structure as a pyrimidine ring open methyl ester although subsequent isotopic incorporation experiments indicate this is not a result of atmospheric- or DMSO-derived O2 , and that neither methyls originate from DMSO. Additionally several structural analogues containing the same substructure were found to be stable. The origin of the degradation still remains elusive.

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