Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1199432 | Journal of Chromatography A | 2015 | 13 Pages |
•This paper discusses the experiments for identification, isolation, thermal stability, toxicity and biotransformation of various species.•The chromatographic resolution based on the substituted functional groups are discussed.•The thermally stability of the atropisomers are also discussed along with isolation at the preparative scale and subsequent cell viability studies.
Atropisomerism can be a complex concept for those who have not encountered it before. This paper discusses the experiments for identification, isolation, thermal stability, toxicity and biotransformation of various species. The identified atropisomers are a series of rotational hindered biaryl, rotational hindered amide, ring flip, and macrocycles atropisomers identified using supercritical fluid chromatography (SFC) and high performance liquid chromatography (HPLC). These technologies offered the advantage of separating various atropoenantiomers, atropdiastereomers and mixed atropisomers with other forms of stereoisomers in both analytical and preparative scales. With ultra-performance convergence chromatography (UPC2), the detection of N-oxide atropisomer metabolites can be obtained at very low level thus enabling the observation of conversion in human plasma possible. As the resolution of atropisomers are related to the energy barriers on the rotational axis, a calculated computational protocol was developed to predict the formation. A threshold of 10 kcal/mol was established for possible detection of the atropisomers’ existence with chromatographic technologies at room temperature or above. The atropisomer with higher energy barrier (>20 kcal/mol) were isolated via preparative chromatography and the isolates studied in vitro and in vivo for evaluation of their stability in human plasma. The detailed analytical method development to analyze the biotransformation of the atropisomers in human plasma are also discussed in this paper.