5,7-Disubstituted analogues of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): DNA binding and patterns of cytotoxicity.
DACA is a DNA-intercalating agent and dual topoisomerase (topo) I/II inhibitor currently in clinical trial as an anticancer drug. Substitutions in the acridine ring of DACA have significant effects on biological activity, with 5-substituted analogues being more potent but relatively less active against cell lines that underexpress topo II, and the converse for 7-substituted analogues. A small series of 5,7-disubstituted analogues was therefore prepared and evaluated. The compounds were prepared by CDI-assisted coupling of the appropriate acridine acids. When these contained no or only one halogen atom, they could be prepared by Al/Hg amalgam reduction of the corresponding acridine acids. However, this method could not be used to prepare dihalogen-substituted acridine acids due to substantial dehalogenation, and these intermediates were synthesized via cyclization of the appropriate aldehydes to give the acridines directly. These compounds showed enhanced DNA binding compared with the parent DACA, indicating that the known favourable influence of 5-substituents on DNA binding is retained. Cell line studies showed that the 5,7-disubstituted compounds retained both the broad-spectrum effectiveness of the 7-monosubstituted analogues and the higher cytotoxic potency of the 5-monosubstituted analogues. The 7-chloro-5-methyl and 5-chloro-7-methyl analogues showed comparable in vivo antitumour activity to DACA in the subcutaneous colon 38 model, but were substantially more potent (optimal doses of 60 mg/kg compared with 200 mg/kg for DACA).
Spicer
J A
JA
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, University of Auckland, New Zealand.
Finlay
G J
GJ
Baguley
B C
BC
Velea
L
L
Graves
D E
DE
Denny
W A
WA
D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy; D004273:DNA, Neoplasm / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009368:Neoplasm Transplantation; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000166:Acridines; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide