Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline.
By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).
D001665:Binding Sites; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004247:DNA; D006367:HeLa Cells; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008223:Lymphoma / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008961:Models, Structural; D009374:Neoplasms, Experimental / Q000378:metabolism; D009690:Nucleic Acid Conformation; D013056:Spectrophotometry, Ultraviolet
D003517:Cyclopentanes; D007546:Isoquinolines; D004247:DNA