Robert W. Dugger

A novel synthesis of nor-C-statine.

Abstract A new synthesis of nor-C-statine is described. Benzylation of a malate dianion, differentiation of the two carboxylates and a Hofmann degradation of one of the carboxylates constitute the key steps of the synthesis.

Resolution of contradiction between in silico predictions and Ames test results for four pharmaceutically relevant impurities

ABSTRACT The ICH M7 Guideline requires low level control of mutagenic impurities in pharmaceutical products to minimize cancer risk in patients (ICHM7, 2014). Bacterial mutagenicity (Ames) data is generally used to determine mutagenic and possible carcinogenic potential of compounds. Recently, a publication on experiences of using two in silico systems to identify potentially mutagenic impurities highlighted the importance of performing a critical review of published Ames data utilized as part of a mutagenicity assessment of impurities (Greene et al., 2015). Four compounds (2‐amino‐5‐hydroxybenzoic acid, 2‐amino‐3‐chlorobenzoic acid, methyl 2‐amino‐4‐chlorobenzoate and 4‐morpholinopyridine) reported mutagenic were identified in a two system in silico assessment and expert review of the structuresas non‐mutagenic. Likely reasons for mutagenicity could not be identified and the purity of the compounds tested was proposed. In the current investigation, the purest available sample of the four compounds was tested in an OECD‐compliant Ames test. The compounds were all found to be non‐mutagenic. Possible reasons for the discrepancy between previously reported and current results are discussed. Additionally, important points to consider when conducting an expert review of available Ames data are provided particularly in cases where reported Ames results are discrepant with a two system in silico assessment. Highlights4 compounds previously reported as mutagenic were identified to be non‐mutagenic.Differences in purity of the compounds may account for contradictory results.It questionable result of compound, retest.If quality of the test article is in question, retest.Difficult interpretation of previous unexpected result, retest.