Synthetic cathinones: Chiral resolution and enantioselectivity studies

Synthetic cathinones, analogs of cathinone (found in plant Catha edulis), are very interesting bioactive compounds and the most representative constituents of "legal highs" [1]. Their consumption has serious health concerns such as hallucinations, hypertension, tachycardia, and may lead to acute liver and/or kidney failure and rhabdomyolysis [2]. For all these reasons, and the fact that new cathinones continue to be synthesized and consumed, the study of these compounds has an enormous interest. All the synthetic cathinone are chiral and, consequently, their biological and toxicological activities could differ for each of the enantiomers. Despite the growing interest regarding synthetic cathinones, there are only few examples of studies concerning their potential enantioselectivity on bioactivity/toxicity [3]. To perform enantioselectivity studies, it is necessary to obtain both enantiomers with very high enantiomeric purity. Recently, we reported the enantiomeric resolution of several synthetic cathinones by liquid chromatography using two analytical chiral stationary phases based on polysaccharide derivatives [4,5]. The enantioresolution of MDPV, pentedrone and methylone (three of the most commonly used synthetic cathinones worldwide) were scaled up to multi-milligrams for further enantioselectivity studies [4,5]. Both enantiomers of the three cathinones were isolated with high enantiomeric purity. Additionally, the absolute configuration of the enantiomers of pentedrone and methylone was determined by electronic circular dichroism (ECD) spectroscopy, with the aid of theoretical calculations [5]. The toxicity of both enantiomers of MDPV was evaluated using primary cultures of rat hepatocytes, showing similar behavior [4]. Nevertheless, enantioselectivity was observed for pentedrone and methylone enantiomers in dopaminergic SH-SY5Y cells cytotoxicity and reactive species production. Moreover, kinetic studies to evaluate the ability of pentedrone and methylone enantiomers to pass across the intestinal barrier model revealed a differentiated passage of the cathinones enantiomers through intestinal membrane.

Acknowledgements:
Financial supported from Universidade do Porto/FMUP through FSE-Fundo Social Europeu, NORTE 2020-Programa Operaconal Regional do Norte (NORTE-08-5369-FSE-000011). Partially supported by the Strategic Funding UID/Multi/04423/2019 through national funds provided by FCT and ERDF, in the framework of the programme PT2020. Partially supported by FEDER funds through the Operational Programme for Competitiveness and Internationalisation (COMPETE 2020), Portugal, and UID/MULTI/04378/2013 - POCI/01/0145/FEDER/07728.

[1] EMCDDA, New psychoactive substances in Europe. European Monitoring Centre for Drugs and Drug Addiction, 2015.

[2] M.J. Valente, et al., Khat and synthetic cathinones: a review. Arch Toxicol, 2014. 88(1): p. 15-45.

[3] B. Silva, et al., Chiral Resolution and Enantioselectivity of Synthetic Cathinones: A Brief Review, J Anal Toxicol, 2018. 42: p. 17-24.

[4] Silva, B., et al., Chiral enantioresolution of cathinone derivatives present in “legal highs”, and enantioselectivity evaluation on cytotoxicity of 3,4-methylenedioxypyrovalerone (MDPV). Forensic Toxicol, 2016. 34(2): p. 372-385.

[5] Silva, B., et al., Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers. J Chromatogr B Analyt Technol Biomed Life Sci, 2018. 1100-1101: p. 158-164.