Antitumour polycyclic acridines. Palladium(0) mediated syntheses of quino[4,3,2-kl]acridines bearing peripheral substituents as potential telomere maintenance inhibitors.
Pd(0) mediated couplings between substituted 2-(pivaloylamino)benzeneboronic acids and 3,6-disubstituted-10-methylacridones 13 bearing a bromo or trifluoromethylsulfonyloxy substituent in the 1-position yield intermediate 1-arylacridones 16 which can be can be cyclised to new 8-methylquino[4,3,2-kl]acridines 17 with phosphorus oxychloride or 6 M HCI in EtOH. Heck reactions between triflate-substituted substrates 17 and acrylic acid derivatives afforded quinoacridines with unsaturated side-chains in the 6-position. Alkylboranes, prepared by interaction of 9-borabicyclo[3,3,1]nonane (9-BBN) and allyl acetate or N-allyltrifluoroacetamide, participated in Suzuki-Miyaura reactions with chloro-substituted 8-methylquinoacridines to form derivatives bearing functionalised propyl groups in the 6- and 10-positions. Representative 8-methylquinoacridines were methylated with methyl iodide to yield telomerase-inhibitory 8,13-dimethylquinoacridinium iodides 24.
Heald
Robert A
RA
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham, UK NG7 2RD.
Stevens
Malcolm F G
MF
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000475:Alkenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004146:Dioxanes / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D000166:Acridines; D000475:Alkenes; D000970:Antineoplastic Agents; D004146:Dioxanes; D010165:Palladium; D019098:Telomerase; C025223:1,4-dioxane