Affordable Access

Electron-deficient DNA-intercalating agents as antitumor drugs: aza analogues of the experimental clinical agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

Authors
  • Chen, Q
  • Deady, L W
  • Baguley, B C
  • Denny, W A
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Mar 04, 1994
Volume
37
Issue
5
Pages
593–597
Identifiers
PMID: 8126699
Source
Medline
License
Unknown

Abstract

A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.

Report this publication

Statistics

Seen <100 times