Bisintercalating threading diacridines: relationships between DNA binding, cytotoxicity, and cell cycle arrest.
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 degrees to 46 degrees, 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 IC(50) 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.
Wakelin
Laurence P G
LP
School of Medical Sciences, and the School of Women's and Children's Health, University of New South Wales, Sydney 2052, New South Wales, Australia. l.Wakelin@unsw.edu.au
Bu
Xianyong
X
Eleftheriou
Alexandra
A
Parmar
Alpesh
A
Hayek
Charbel
C
Stewart
Bernard W
BW
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004278:DNA, Superhelical / Q000737:chemistry; D004587:Electrophoresis, Agar Gel; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006147:Guanine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008938:Mitosis / Q000187:drug effects; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D007364:Intercalating Agents; D006147:Guanine; D004247:DNA