Structural differences in diarylheptanoids analogues from Alnus viridis and Alnus glutinosa influence their activity and selectivity towards cancer cells. (5th April 2016)

• Record Type: Journal Article
• Authors: Dinić, Jelena; Novaković, Miroslav; Podolski-Renić, Ana; Vajs, Vlatka; Tešević, Vele; Isaković, Aleksandra; Pešić, Milica
• Is Part Of: Chemico-biological interactions. Volume 249(2016)
• Page Start: 36
• Page End: 45
• Publication Date: 2016-04-05
• Subjects: Diarylheptanoids -- Structure-activity relationship -- Reactive oxygen species -- Mitochondrial transmembrane potential; AV Annexin-V-FITC -- DHE Dihydroethidium -- JC-1 5, 5′, 6, 6′-Tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolocarbocyanine iodide -- PI Propidium iodide -- ROS Reactive oxygen species -- SAR structure-activity relationship -- SRB Sulforhodamine B -- ΔΨm Mitochondrial transmembrane potential; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.02.019
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Diarylheptanoids represent a group of plant secondary metabolites that possess multiple biological properties and are increasingly recognized for their therapeutic potential. A comparative study was performed on structurally analogous diarylheptanoids isolated from the bark of green ( Alnus viridis ) and black alder ( Alnus glutinosa ) to address their biological effects and determine structure-activity relationship. The structures and configurations of all compounds were elucidated by NMR, HR-ESI-MS, UV and IR. Diarylheptanoids actions were studied in human non-small cell lung carcinoma cells (NCI-H460) and normal keratinocytes (HaCaT). A. viridis compounds3v, 5v, 8v and9v that possess a carbonyl group at C-3 were considerably more potent than compounds without this group. A. viridis / A. glutinosa analogue pairs, 5v /5g and9v /9g, which differ in the presence of 3′ and 3″-OH groups, were evaluated for anticancer activity and selectivity.5v and9v that do not possess 3′ and 3″-OH groups showed significantly higher cytotoxicity compared to analogues5g and9g . In addition, these two A. viridis compounds induced a more prominent apoptosis in both cell lines and an increase in subG0 cell cycle phase, compared to their A. glutinosa analogues.5v and9v treatment triggered intracellular superoxide anion accumulation and notably decreased mitochondrial transmembrane potential. In HaCaT cells, 9v and9g with a 4, 5 double bond caused a more prominent loss of mitochondrial transmembrane potential compared to5v and5g which possess a 5-methoxy group instead. Although green alder diarylheptanoids5v and9v displayed higher cytotoxicity, their analogues from black alder5g and9g could be more favorable for therapeutic use since they were more active in cancer cells than in normal keratinocytes. These results indicate that minor differences in the chemical structure can greatly influence the effect of diarylheptanoids on apoptosis and redox status and determine their selectivity towards cancer cells. Graphical abstract: Highlights: Nine diarylheptanoids, including a new compound4v, were isolated from the bark of Alnus viridis. Activity of A. viridis diarylheptanoids was compared to structural analogs from Alnus glutinosa. Presence of 3′ and 3″-OH groups had negative influence on cytotoxic activity. Carbonyl group at C-3 positively affected cytotoxicity of A. viridis diarylheptanoids. Small chemical structure differences had major effect on cell cycle, apoptosis and redox status.