Gaspar Helena, Bronze Soraia, Oliveira Catarina, Victor Bruno L, Machuqueiro Miguel, Pacheco Rita, Caldeira Maria João, Santos Susana
University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, C8, 1749-016 Lisboa, Portugal; MARE, Marine and Environmental Sciences Centre, ESTM, Polytechnic Institute of Leiria, 2520-641 Peniche, Portugal.
Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
Forensic Sci Int. 2018 Sep;290:146-156. doi: 10.1016/j.forsciint.2018.07.001. Epub 2018 Jul 11.
The emergence of potentially dangerous new psychoactive substances (NPS) imposes enormous challenges on forensic laboratories regarding their rapid and unambiguous identification. Access to comprehensive databases is essential for a quick characterization of these substances, allowing them to be categorized according to national and international legislations. In this work, it is reported the synthesis and structural characterization by NMR and MS of a library encompassing 21 cathinones, 4 of which are not yet reported in the literature, but with structural characteristics that make them a target for clandestine laboratories. This in-house library will be an important tool accessible to forensic laboratories, for the quick identification of seized NPS. The in vitro cytotoxicity of all cathinones was assessed in HepG2 cells, to have a preliminary but effective indication of their human hepatotoxicity potential. The two new cathinones DMB (8) and DMP (9) were the more cytotoxic, followed by the already seized mephedrone (2), 3,4-DMMC (3), 4-MDMC (7), NEB (12) with EC50 values ranging from 0.81mM for (3) to 1.28mM for (2). Results suggest an increase of cytotoxicity with the increase of the chain length of the acyl moiety and with the substitution (with one or two methyl groups) in the aromatic ring. The nature of the amine moiety seems to play only a minor role in the cytotoxic effect. Molecular dynamics simulations were performed to evaluate the molecular details related with the observed cytotoxicities. Although these studies indicated that cathinones are able to cross lipid bilayers with relative ease, when in their neutral forms, it was observed only a partial correlation between lipophilicity and cytotoxicity, indicating that membrane trafficking may not be the only key factor influencing the bioactivity of these compounds. This work is a valuable contribution to the forensic science field since a quick identification of novel cathinones is urgent to match their rapid increase in the market.
潜在危险的新型精神活性物质（NPS）的出现给法医实验室在快速明确鉴定它们方面带来了巨大挑战。获取全面的数据库对于快速鉴定这些物质至关重要，以便能根据国家和国际法规对它们进行分类。在这项工作中，报道了一个包含21种卡西酮的库的合成以及通过核磁共振（NMR）和质谱（MS）进行的结构表征，其中有4种在文献中尚未报道，但因其结构特征使其成为秘密实验室的目标。这个内部库将成为法医实验室可获取的重要工具，用于快速鉴定查获的NPS。对所有卡西酮在肝癌细胞系（HepG2）中进行了体外细胞毒性评估，以初步有效指示它们对人类肝脏的潜在毒性。两种新的卡西酮DMB（8）和DMP（9）细胞毒性更强，其次是已查获的甲麻黄碱（2）、3,4 - 二甲基甲卡西酮（3）、4 - 甲基二甲基卡西酮（7）、N - 乙基苄基胺（12），其半数有效浓度（EC50）值范围从（3）的0.81mM到（2）的1.28mM。结果表明，随着酰基部分链长的增加以及芳香环上（一个或两个甲基）取代基的增加，细胞毒性增强。胺基部分的性质似乎在细胞毒性作用中仅起次要作用。进行了分子动力学模拟以评估与观察到的细胞毒性相关的分子细节。尽管这些研究表明卡西酮在呈中性形式时能够相对容易地穿过脂质双层，但观察到亲脂性与细胞毒性之间仅存在部分相关性，这表明膜转运可能不是影响这些化合物生物活性的唯一关键因素。这项工作对法医学领域有重要贡献，因为快速鉴定新型卡西酮对于应对它们在市场上的迅速增加至关重要。
