N-Methyl-β-carboline alkaloids: structuredependent photosensitizing properties and localization in subcellular domains Denofrio, M. Paula Rasse-Suriani, Federico A. O. Paredes Martínez, José Manuel Fassetta, Federico Crovetto González, Luis Girón González, María Dolores Salto González, Rafael Epe, Bernd Cabrerizo, Franco M. N-Methyl-β-carboline (βC) alkaloids, including normelinonine F (1b) and melinonine F (2b), have been found in a vast range of living species playing different biological, biomedical and/or pharmacological roles. Despite this, molecular bases of the mechanisms through which these alkaloids would exert their effect still remain unknown. Fundamental aspects including the photosensitizing properties and intracellular internalization of a selected group of N-methyl-βC alkaloids were investigated herein. Data reveal that methylation of the βC main ring enhances its photosensitizing properties either by increasing its binding affinity with DNA as a biomolecular target and/or by increasing its oxidation potential, in a structure- dependent manner. As a general rule, N(9)-substituted βCs showed the highest photosensitizing efficiency. With the exception of 2-methyl-harminium, all the N-methyl-βCs investigated herein induce a similar DNA photodamage profile, dominated largely by oxidized purines. This fact represents a distinctive behavior when comparing with N-unsubstituted-βCs. On the other hand, although all the investigated compounds might accumulate mainly into the mitochondria of HeLa cells, methylation provides a distinctive dynamic pattern for mitochondrial uptake. While rapid (passive) diffusion is most probably reponsible for the prompt uptake/release of neutral βCs, an active transport appears to mediate the (reatively slow) uptake of the quaternary cationic βCs. This might be a consequence of a distinctive subcellular localization (mitochondrial membrane and/or matrix) or interaction with intracellular components. Biomedical and biotechnological implications are also discussed herein. 2020-09-25T06:56:20Z 2020-09-25T06:56:20Z 2020-07-01 info:eu-repo/semantics/article Luis Crovetto, Franco M. Cabrerizo et al.. N-Methyl-β-carboline alkaloids: structuredependent photosensitizing properties and localization in subcellular domains. Org. Biomol. Chem., 2020, 18, 6519 [DOI: 10.1039/d0ob01122c] http://hdl.handle.net/10481/63549 10.1039/d0ob01122c eng http://creativecommons.org/licenses/by-nc/3.0/es/ info:eu-repo/semantics/openAccess Atribución-NoComercial 3.0 España Royal Society of Chemistry