Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2

• Published in: European journal of medicinal chemistry Vol. 92; pp. 766 - 775
• Main Authors: Christodoulou, Michael S., Calogero, Francesco, Baumann, Marcus, García-Argáez, Aída Nelly, Pieraccini, Stefano, Sironi, Maurizio, Dapiaggi, Federico, Bucci, Raffaella, Broggini, Gianluigi, Gazzola, Silvia, Liekens, Sandra, Silvani, Alessandra, Lahtela-Kakkonen, Maija, Martinet, Nadine, Nonell-Canals, Alfons, Santamaría-Navarro, Eduardo, Baxendale, Ian R., Dalla Via, Lisa, Passarella, Daniele
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 06.03.2015; Elsevier
• Subjects: Boehmeriasin A; Cell Line; Cell Proliferation - drug effects; Chemistry, Medicinal; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Phenanthrenes - chemical synthesis; Phenanthrenes - chemistry; Phenanthrenes - pharmacology; Quinolizidines - chemical synthesis; Quinolizidines - chemistry; Quinolizidines - pharmacology; Science & Technology; Sirtuin 2 - antagonists & inhibitors; Sirtuin 2 - metabolism; Sirtuins inhibition; Structure-Activity Relationship; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Topoisomerases inhibition; Total synthesis; Sirtuins inhibition; Topoisomerases inhibition; Boehmeriasin A; Total synthesis; CRYPTOPLEURINE; BIOLOGICAL EVALUATION; (-)-ANTOFINE; TRI; SHORT ENANTIOSELECTIVE SYNTHESIS; ALKALOIDS; PIPERIDINE-2-ETHANOL
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.01.038

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies. [Display omitted] •We describe two synthetic approaches to the alkaloid boehmeriasin A.•Anti-proliferative activity in 5 cell lines indicates activity at the nanomolar range.•Topoisomerases and SIRT2 are identified as biological targets.•Experimental data are supported by docking studies.