Acridine and acridone derivatives, anticancer properties and synthetic methods: where are we now?
Acridine derivatives are interesting chemotherapeutic agents that were first used as antibacterial and antiparasite agents. In this review we wish to concentrate our attention on the anticancer properties of acridines used in clinics since the 1970's. Based on recent results, an outlook on antitumour acridine chemotherapy will be proposed. The biological activity of acridines is mainly attributed to the planarity of these aromatic structures, which can intercalate within the double-stranded DNA structure, thus interfering with the cellular machinery. Recent understanding of the mode of action of acridines leads to continuous and exciting research in this heterocyclic family. Indeed, biological targets such as topoisomerases I and II, telomerase/telomere and protein kinases emerge and allow the design of novel acridine-based patterns. This review further pinpoints the latest progress in the development of anticancer agents based on naturally occurring and synthetic acridines (e.g. acridones, pyridoacridines); for this matter in vitro/in vivo studies and clinical trial results will be discussed. The DNA-affinic property of acridine is also useful to vectorise drugs into cell nuclei and some applications in hypoxia-selective treatment, platinum or N-mustard derived conjugates will be reported. Some other properties including inhibition of multidrug resistance or potential impact on Alzheimer disease will be treated. It is noteworthy that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity observed. So, we wish also to disclose a summary of recent synthetic methodologies developed for acridine synthesis.
Belmont
Philippe
P
Université Claude Bernard - Lyon I, UMR CNRS 5181, Méthodologie de Synthèse et Molécules Bioactives, Laboratoire de Synthèse et Méthodologie Organiques, Bâtiment CPE, Villeurbanne cedex, France. philippe.belmont@cpe.fr
Bosson
Johann
J
Godet
Thomas
T
Tiano
Martin
M
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors; D059004:Topoisomerase I Inhibitors
D000166:Acridines; D000470:Alkaloids; D000970:Antineoplastic Agents; D001688:Biological Products; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D059004:Topoisomerase I Inhibitors; D019098:Telomerase