Poster Session 1 — Medicinal Chemistry

Sequences of DNA rich in guanine can adopt unusual DNA secondary structural forms. In particular, four guanine bases can associate in a planar hydrogen-bonded assembly called a G-tetrad (for review, see Cairns et al 2002a). Successive layers of G-tetrads allow single stranded DNA to adopt a high-order foldback structure in solution termed a G-tetraplex (or quadruplex). Stabilisation of G-tetrad structures by intercalation or end-pasting has been shown to be useful for the inhibition of telomerase, an enzyme responsible for the elongation of telomere structures in DNA, (Cairns et al 2002b; Kim et al 2002). As part of a programme of work in our laboratories, several functionalised amino-anthraquinones (AAQ) have been examined as selective ligands to stabilise four-stranded DNA structures. Such complexes would prevent access of telomerase to its linear DNA substrate and thereby elicit a possible chemotherapeutic response for tumour control. Certain AAQs have previously been examined as intercalators for duplex DNA in the quest for cytotoxic agents (Agbandje et al 1992) but not examined in the context of highorder DNA. Uncyclised and cyclised 1-mono, 1,5-di-and 1,8-di-AAQs of different complexion have been synthesised with differing side-chains (e.g. -NH(CH 2 ) 2 OH, -NH(CH 2 ) 2 NH(CH 2 ) 2 OH and -NH(CH 2 ) 2 N(CH 2 CH 3 ) 2 ). A cleaner, more flexible, route to these compounds has been developed in the course of our work. Binding energies for novel cyclised compounds have been calculated using molecular modelling techniques (SGI Octane R12000 workstation using the Insight-II 2000 graphics interface and Discover 98.0 simulation software (Accelrys, Cambridge, UK)) with two reported (NMR and crystal) DNA tetraplex structures (Wang & Patel 1993; Parkinson et al 2002). Early findings show that energies appear superior for the NMR rather than the crystal structure (~7 700 vs ~7 400 kcal mol 71 ) using one selected quinoxaline-functionalised AAQ ligand, and that the available binding sites differ markedly in affinity for ligand. Biophysical examination of the interaction using thermal DNA denaturation methods (McConnaughie & Jenkins 1995) show stabilisation of calf thymus DNA, ([duplex]/[drug] ratio = 10:4) for uncyclised compounds with negligible effect for the cyclised AAQ series. For example, 1-[2-(2-hydroxyethylamino)ethylamino] anthraquinone, DT m = 108C; 4-(2-hydroxyethyl)-1,2,3,4-tetrahydro-1,4-diazabenzo[a]anthracene-7,12-dione, DT m 4 18C.