Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3(2H)-one and its interaction with deoxyribonucleic acids and poly(deoxyribonucleotides).
3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003517:Cyclopentanes / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004247:DNA; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D003854:Deoxyribonucleotides; D003864:Depression, Chemical; D004926:Escherichia coli / Q000201:enzymology; D006358:Hot Temperature; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D009691:Nucleic Acid Denaturation; D011119:Polynucleotides; D013056:Spectrophotometry, Ultraviolet; D013698:Templates, Genetic
D003517:Cyclopentanes; D003854:Deoxyribonucleotides; D007546:Isoquinolines; D011119:Polynucleotides; D004247:DNA; D004254:DNA Nucleotidyltransferases