N-Methyl-β-carboline alkaloids: structure-dependent photosensitizing properties and localization in subcellular domains. Issue 33 (6th July 2020)

• Record Type: Journal Article
• Authors: Denofrio, M. Paula; Rasse-Suriani, Federico A. O.; Paredes, Jose M.; Fassetta, Federico; Crovetto, Luis; Giron, Maria D.; Salto, Rafael; Epe, Bernd; Cabrerizo, Franco M.
• Is Part Of: Organic & biomolecular chemistry. Volume 18:Issue 33(2020)
• Page Start: 6519
• Page End: 6530
• Publication Date: 2020-07-06
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d0ob01122c
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Methylation at the N(2) nitrogen atom of β-carbolines: the key to fine-tuning their interaction with DNA and the cellular uptake dynamics. Abstract : 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.