Synthesis, DNA interactions and activation of novel cytotoxic anthraquinones.
type: CreativeWork
description: Mitoxantrone is a dihydroxyanthracenedione derivative with significant clinical activity against advanced breast cancer, lymphoma and several types of leukaemia. However, as with all conventional anticancer agents, its non-specific nature results in dose-limiting systemic toxicity. The pharmacological (and toxicological) effects of mitoxantrone are thought to be mediated through its interaction with DNA and the DNA processing enzyme, topoisomerase II. Hence, an investigation of the DNA binding properties of mitoxantrone and related bis-substituted alkylaminoanthraquinones was undertaken with a view to developing agents with reduced toxicity to normal cells. DNA intercalation was evaluated using spectrophotometric and DNA thermal denaturation (Tm) techniques with calf thymus DNA. Overall, compounds that were hydroxylated at the 5 and 8 positions of the anthraquinone chromophore had increased DNA binding affinity compared to their non-hydroxylated analogues. The ~ Tms of mitoxantrone and its non-hydroxylated analogue ametantrone, were 26.4 °C and 21.5°C respectively. The affinity constants (K) for the chromophore-hydroxylated compounds were between 3.94 and 4.95 xl06M-1 while K values for their non-hydroxylated analogues were between 1.63 and 3.25 xl06M-l. For the di-N-oxide, AQ4N, intercalation was not detectable. The mono-N-oxide, AQ6N, showed modest DNA binding activity, with a ~Tm of7.0°C and an affinity constant of 3.64 Xl06M-l. Several of the alkylaminoanthraquinones were further investigated for their ability to inhibit decatenation of kDNA by topoisomerase II. Mitoxantrone and its analogues, AQ4 and AQ6, inhibited decatenation at concentrations ofO.75IlM, 1.51lM and 1.0llM respectively. In contrast, total inhibition of decatenation by the N-oxides, AQ4N and AQ6N, required concentrations of 50llM and 1 OIlM respectively. Hence modification of the terminal nitrogen on both alkylamino side chains to form a di-N-oxide resulted in a large decrease in DNA binding af…
abstract: Mitoxantrone is a dihydroxyanthracenedione derivative with significant clinical activity against advanced breast cancer, lymphoma and several types of leukaemia. However, as with all conventional anticancer agents, its non-specific nature results in dose-limiting systemic toxicity. The pharmacological (and toxicological) effects of mitoxantrone are thought to be mediated through its interaction with DNA and the DNA processing enzyme, topoisomerase II. Hence, an investigation of the DNA binding properties of mitoxantrone and related bis-substituted alkylaminoanthraquinones was undertaken with a view to developing agents with reduced toxicity to normal cells. DNA intercalation was evaluated using spectrophotometric and DNA thermal denaturation (Tm) techniques with calf thymus DNA. Overall, compounds that were hydroxylated at the 5 and 8 positions of the anthraquinone chromophore had increased DNA binding affinity compared to their non-hydroxylated analogues. The ~ Tms of mitoxantrone and its non-hydroxylated analogue ametantrone, were 26.4 °C and 21.5°C respectively. The affinity constants (K) for the chromophore-hydroxylated compounds were between 3.94 and 4.95 xl06M-1 while K values for their non-hydroxylated analogues were between 1.63 and 3.25 xl06M-l. For the di-N-oxide, AQ4N, intercalation was not detectable. The mono-N-oxide, AQ6N, showed modest DNA binding activity, with a ~Tm of7.0°C and an affinity constant of 3.64 Xl06M-l. Several of the alkylaminoanthraquinones were further investigated for their ability to inhibit decatenation of kDNA by topoisomerase II. Mitoxantrone and its analogues, AQ4 and AQ6, inhibited decatenation at concentrations ofO.75IlM, 1.51lM and 1.0llM respectively. In contrast, total inhibition of decatenation by the N-oxides, AQ4N and AQ6N, required concentrations of 50llM and 1 OIlM respectively. Hence modification of the terminal nitrogen on both alkylamino side chains to form a di-N-oxide resulted in a large decrease in DNA binding af…
author: Giles, Yvonne
license: https://dora.dmu.ac.uk/bitstreams/52b8755b-e79c-47ba-976f-77f2316f856d/download
date published: 1999
date modified: 2026-07-24T06:18:27Z
provider: De Montfort University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: De Montfort University