N-methyl-β-carboline alkaloids: structure-dependent photosensitizing properties and localization in subcellular domains

N-methyl-Beta-carboline (bC) alkaloids, including normelinonine F and melinonine F, 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-bC alkaloids were investigated herein. Data reveal that methylation of the bC main ring enhances its photosensitizing properties either by increasing its binding affinity with DNA as biomolecular target and/or by increasing its oxidation potential, in a structure dependent manner. As a general rule, N(9)-substituted bCs showed the highest photosensitizing efficiency. With the exception of 2-methyl-harminium, all the N-methyl-bCs investigated herein induce a similar DNA photodamage profile, dominated largely by oxidized purines. This fact represents a distinctive behavior when comparing with N-unsubstituted-bCs. 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 bCs, an active transport appears to mediate the (reatively slow) uptake of the quaternary cationic bCs. 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.Fil: Denofrio, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Rasse Suriani, Federico Ariel Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Paredes, Jose M.. Universidad de Granada. Facultad de Farmacia. Departamento de Fisicoquimica.; EspañaFil: Fassetta, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Crovetto, Luis. Universidad de Granada. Facultad de Farmacia. Departamento de Fisicoquimica.; EspañaFil: Giron, Maria D.. Universidad de Granada. Facultad de Farmacia.; EspañaFil: Salto, Rafael. Universidad de Granada. Facultad de Farmacia.; EspañaFil: Epe, Bernd. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Cabrerizo, Franco Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentin