1.Acid-based approach for separation of peptide epimers using IM-MS
J Mass Spectrom. 2019 Jul;54(7):620-628. doi: 10.1002/jms.4362.
Chiral molecules frequently remain undistinguishable using ion mobility mass spectrometry (IM-MS), due to insufficient differences of their collision cross sections at the available mobility resolution of the ion mobility drift tubes. The influence of the complexation with organic acids on the ion mobility separation of peptide epimers is evaluated using traveling-wave ion mobility (TWIMS). The examined epimeric tripeptides containing Arg residue with the sequence: Ac-Phe-Arg-Trp-NH
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formed stable complexes in the gas phase, and under the increased pressure in ion mobility drift tube, noncovalent associates formed with carboxylic or sulfonic monoacids and diacids with chiral variation of certain acids. Overall, the complexation with an acid leads to the improvement in stereodifferentiation among epimeric peptides, in comparison to the analysis of pure epimers. Detailed characterization of peptide epimer-acid associates obtained for dibenzoyl-D-tartaric acid by theoretical calculations and collisional dissociation studies revealed that the presence of multiple hydrogen bonding interactions between carboxylate anions and hydrogens from N-H of both the guanidinium group of arginine and the indole of tryptophan, as well as the amide backbone hydrogens in the peptide, is responsible for stability of acid-peptide complexes and for their differentiation in the ion mobility drift tube. The specificity of complex formation toward Arg was determined in terms of complex stability. Based on the reported results, we present general conclusions regarding the utility of the acid-based complexation in the separation of peptide isomers.
2.Isolation and structural determination of non-racemic tertiary cathinone derivatives
Org Biomol Chem. 2015 Oct 7;13(37):9629-36. doi: 10.1039/c5ob01306b.
The racemic tertiary cathinones N,N-dimethylcathinone (1), N,N-diethylcathinone (2) and 2-(1-pyrrolidinyl)-propiophenone (3) have been prepared in reasonable yield and characterized using NMR and mass spectroscopy. HPLC indicates that these compounds are isolated as the anticipated racemic mixture. These can then be co-crystallized with (+)-O,O′-di-p-toluoyl-D-tartaric, (+)-O,O′-dibenzoyl-D-tartaric and (−)-O,O′-dibenzoyl-L-tartaric acids giving the single enantiomers S and R respectively of 1, 2 and 3, in the presence of sodium hydroxide through a dynamic kinetic resolution. X-ray structural determination confirmed the enantioselectivity. The free amines could be obtained following basification and extraction. In methanol these are reasonably stable for the period of several hours, and their identity was confirmed by HPLC and CD spectroscopy.
3.Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene: an inhibitor of beta-amyloid(1-42) aggregation
Bioorg Med Chem. 2002 Nov;10(11):3565-9. doi: 10.1016/s0968-0896(02)00251-1.
A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.
