4-Hydroxymethyl-3-aminoacridine derivatives as a new family of anticancer agents.
3-Amino- and 3-alkylamino-4-hydroxymethylacridines bearing various substituents on the C ring have been prepared by regioselective electrophilic aromatic substitution of the corresponding 3-aminoacridines and ring opening of the dihydrooxazinoacridine key intermediates. Most of the new compounds show potent cytotoxic activities against murine L1210 (leukemia), human A549 (lung), and HT29 (colon) cancer cell lines. The most cytotoxic molecules, 1 and 13, are active at nanomolar concentrations. As predicted for acridine derivatives, the new compounds intercalate in DNA, but interestingly they do not interfere with topoisomerase I and II activities. The mode of action remains uncertain because intracellular distribution indicated very different behaviors for 1 and 13. Compound 13 is uniformly distributed in the cell both in the cytoplasm and in the nucleus, whereas compound 1 is essentially localized in cytoplasmic granules.
Charmantray
Franck
F
LEDSS, UMR CNRS 5616, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
Demeunynck
Martine
M
Carrez
Danièle
D
Croisy
Alain
A
Lansiaux
Amélie
A
Bailly
Christian
C
Colson
Pierre
P
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000609:Aminoacridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured
C472795:4-hydroxymethyl-3-aminoacridine; C472796:6-ethoxycarbonylamino-4-hydroxymethyl-3-aminoacridine; D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D002219:Carbamates; D007364:Intercalating Agents; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II