1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation.
A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity.
Antonini
I
I
Department of Chemical Sciences, University of Camerino, Italy.
Polucci
P
P
Jenkins
T C
TC
Kelland
L R
LR
Menta
E
E
Pescalli
N
N
Stefanska
B
B
Mazerski
J
J
Martelli
S
S
D000166:Acridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009691:Nucleic Acid Denaturation; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D004247:DNA