title: Novel trisubstituted harmine derivatives with original in vitro anticancer activity.
abstract: To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel β-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel β-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active β-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.
authors: Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (FUNDP), 61, Rue de Bruxelles, 5000 Namur, Belgium. raphael.frederick@fundp.ac.be
authors: Raphaël
authors: R
authors: Frédérick
authors: Céline
authors: C
authors: Bruyère
authors: Christelle
authors: C
authors: Vancraeynest
authors: Jérémy
authors: J
authors: Reniers
authors: Céline
authors: C
authors: Meinguet
authors: Lionel
authors: L
authors: Pochet
authors: Anders
authors: A
authors: Backlund
authors: Bernard
authors: B
authors: Masereel
authors: Robert
authors: R
authors: Kiss
authors: Johan
authors: J
authors: Wouters
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006247:Harmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D000970:Antineoplastic Agents; D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases