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Synthesis and biological evaluation of novel anthraquinones with alkylating capability

Pors, Klaus; (2002) Synthesis and biological evaluation of novel anthraquinones with alkylating capability. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

1-{2-[N,N-bis(2-chloroethyl)amino]ethylamino} -4- {2-[N,N-(dimethyl)amino]ethylamino} - 5.8-dihydroxy-9,10-anthracenedione (ZP281M) is a lead compound of a novel class of intercalating agents with alkylating capacity. Previously, ZP281M has been shown to evade drug efflux pump mediated resistance and DNA repair mediated resistance in vitro and in vivo. A novel series of chloroalkylaminoanthraquinones (CAQs), modelled on the non- symmetrical configuration of ZP281M, has been developed and is reported in this thesis. N- oxide derivatised CAQs have also been prepared as potentially bioreductive prodrugs. The synthetic route to the target compounds involved preparation of heterocyclic (piperidinyl or pyrrolidinyl) alkylamino sidechains, by alkylating the heterocyclic moiety with halide- acetonitrile followed by reduction of the nitrile to the respective primary amine (R-CH2CH2- NH2, R = heterocyclic). The heterocyclic alkylamino sidechains were then substituted onto anthraquinone chromophores to give a series of 1,4-disubstituted aminoanthraquinones (HAQs). Conversion of these HAQs to CAQs involved treatment with Ph3P-CCl4 complex. A novel route for the development of CAQs was also devised in order to obtain target compounds containing secondary chlorides. This route comprised a 5-step procedure which involved (1) Boc-protection of hydroxylated heterocyclic alkylamino sidechains, (2) mesylation of the hydroxyl group, (3) conversion to the chloride with tetra-n-butylammonium chloride, (4) deprotection of the Boc group and (5) substitution onto either 1,4-difluoro-5,8- dihydroxyanthraquinone or 1-{2-[N,N-(dimethyl)amino]ethylamino]-4-fluoro-5,8-dihydroxy- anthraquinone. Di-N-oxides were obtained by the use of the oxidising agent m- chloroperoxybenzoic acid. The novel CAQs were shown to alkylate guanine residues of linearised pBR322 by using a DNA Taq-polymerase based footprinting assay. Two symmetrical CAQs, 1,4-bis-{2-[(2-chloroethyl)-piperidinyl]-ethylamino} -5,8-dihydroxy- anthracene-9,10-dione CAQ190M and l,4-bis-{2-[(2-chloroethyl)-pyrrolidinyl]-ethylamino}- 5.8-dihydroxyanthracene-9,10-dione CAQ177M were found to interstrand crosslink pBR322 DNA at nM concentration by assessment in an in vitro gel based assay. Selected CAQs and their non-covalent binding HAQ analogues were found to unwind supercoiled pBR322 DNA. Further, ZP281M and its non-covalent binding analogue ZP275 were both found to have preference for topo IIa when investigated by the 'Trapped in Agarose Gel Immunostaining Assay' (TARDIS). The CAQs with alkylating capacity were shown to be nM cytotoxic (IC50 values in the range 24-484 nM) in the A2780 ovarian cancer cell line. Significantly, the CAQs remained cytotoxic in the resistant 2780AD and 2780CP cell Hnes. The di-N-oxides of the CAQs were shown to be 40-100 fold less cytotoxic than their respective tertiary amine analogues in the wild type A2780 cell line.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis and biological evaluation of novel anthraquinones with alkylating capability
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Quinones
URI: https://discovery.ucl.ac.uk/id/eprint/10104518
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