89459-43-8Relevant academic research and scientific papers
DNA threading agents: Effect of sidechain bulk on DNA binding and cytotoxicity of 9-anilinoacridine-4-carboxamides
Searcey, Mark,Martin, P. Noel,Howarth, Nicola M.,Madden, Bernie,Wakelin, Laurence P. G.
, p. 1831 - 1836 (1996)
A series of 9-anilinoacridine-4-carboxamides with cycloalkyl sidechains has been synthesised to study the effect of sidechain bulk on the DNA binding properties and biological activity of these potential threading intercalators. With sidechains larger than cyclohexane the pKa of the acridine is exceptionally low, so that DNA binding is restricted to pHs below 5. The compounds are cytotoxic to human colon carcinoma cells in the μM range irrespective of their ability to bind to DNA.
Bisintercalating Threading Diacridines: Relationships between DNA Binding, Cytotoxicity, and Cell Cycle Arrest
Wakelin, Laurence P. G.,Bu, Xianyong,Eleftheriou, Alexandra,Parmar, Alpesh,Hayek, Charbel,Stewart, Bernard W.
, p. 5790 - 5802 (2007/10/03)
We have synthesized a series of bis(9-aminoacridine-4-carboxamides) linked via the 9-position with neutral flexible alkyl chains, charged flexible polyamine chains, and a semirigid charged piperazine-containing chain. The carboxamide side chains comprise N,N-dimethylaminoethyl and ethylmorpholino groups. The compounds are designed to bisintercalate into DNA by a threading mode, in which the side chains are intended to form hydrogen-bonding contacts with the O6/N7 atoms of guanine in the major groove, and the linkers are intended to lie in the minor groove. By this means, we anticipate that they will dissociate slowly from DNA, and be cytotoxic as a consequence of template inhibition of transcription. The dimers remove and reverse the supercoiling of closed circular DNA with helix unwinding angles ranging from 26° to 46°, confirming bifunctional intercalation in all cases, and the DNA complexes of representative members dissociate many orders of magnitude more slowly than simple aminoacridines. Cytotoxicity for human leukemic CCRF-CEM cells was determined, the most active agents having IC50 values of 35-50 nM in a range extending over 20-fold, with neither the dimethylaminoethyl nor the ethylmorpholino series being intrinsically more toxic. In common with established transcription inhibitors, the morpholino series, with one exception, have no effect on cell cycle distribution in randomly dividing CCRF-CEM populations. By contrast, the dimethylaminoethyl series, with two exceptions, cause G2/M arrest in the manner of topoisomerase poisons, consistent with possible involvement of topoisomerases in their mode of action. Thus, the cellular response to these bisintercalating threading agents is complex and appears to be determined by both their side chain and linker structures. There are no simple relationships between structure, cytotoxicity, and cell cycle arrest, and the origins of this complexity are unclear given that the compounds bind to DNA by a common mechanism.
Potential Antitumor Agents. 46. Structure-Activity Relationships for Acridine Monosubstituted Derivatives of the Antitumor Agent N--9-aminoacridine-4-carboxamide
Rewcastle, Gordon W.,Atwell, Graham J.,Chambers, David,Baguley, Bruce C.,Denny, William A.
, p. 472 - 477 (2007/10/02)
A series of monosubstituted derivatives of the new antitumor agent N--9-aminoacridine-4-carboxamide has been prepared, bearing methyl, methoxy, and chloro groups at available acridine positions.The physicochemical properties and an
Potential antitumor agents. 43. Synthesis and biological activity of dibasic 9-aminoacridine-4-carboxamides, a new class of antitumor agent
Atwell,Cain,Baguley,Finlay,Denny
, p. 1481 - 1485 (2007/10/02)
The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkyl-amino)ethyl-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro
