Methylselenol release as a cytotoxic tool: a study of the mechanism of the activity achieved by two series of methylselenocarbamate derivatives

• Published in: Metallomics 2018-08, Vol.1 (8), p.1128-114
• Main Authors: Font, María, Romano, Beatriz, González-Peñas, Elena, Sanmartín, Carmen, Plano, Daniel, Palop, Juan A
• Format: Article
• Language: English
• Subjects: Alcohols; Aliphatic compounds; Cancer; Carbamates (tradename); Carbon; Cytotoxicity; Derivatives; Molecular modelling; Phenols; Topology; Tumor cell lines
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c8mt00140e

A molecular modeling study has been carried out on two previously reported series of methylselenocarbamate derivatives that show remarkable antiproliferative and cytotoxic in vitro activity, against a panel of human cancer cell lines. These derivatives can be considered as having been constructed by a selenomethyl fragment located over a carbon atom which is decorated with two carbamate moieties, both aliphatic and aromatic, one of them attached by a single bond to the central carbon atom, while the second is connected by a double bond. According to the data obtained, these derivatives can undergo a water-mediated nucleophilic attack on the carbons with marked electrophilic character, which leads to the rupture of C-Se and carbamate C-O bonds. The aliphatic derivatives, series 1, show an early release of methylselenol and a further release of hydroxyl derivatives (alcohols), whereas the aromatic carbamates, series 2, show an early release of phenols followed by the subsequent release of methylselenol. Thus, the activity of the compounds can be related to the progressive release of active fragments. The data that support this connection are related to the overall molecular topology, volume and surface area as well as to quantum parameters such as the relative electrophilic character of the target carbon atoms (measured in terms of positive charge values) or the bond order values, especially concerning the central C-SeCH 3 bond and the carbamate ones. Moreover, the data obtained regarding the chromatographic behavior of some representative compounds confirm this proposal. Cytotoxic activity is related to the progressive release of active fragments, methylselenol and phenols. The structural variations influence the relative reactivity of the target atoms to the nucleophilic agent, as well as the overall stability and the accessibility to the hydrolysis point.