Novel polyamide amidine anthraquinone platinum(II) complexes for enhancing DNA binding and tumour penetration

Abstract

A set of aminoalkylamine substituted anthraquinones (AAQs) was successfully synthesised by aminating 1- or 1,5-chloroanthraquinones in a single reaction step. These substituted anthraquinones, 1C3 or 1,5C3, were tethered to minor groove binding polyamides with between 1 - 3 N-methyl pyrrole units (Py) to produce a library of Py-AAQ compounds. It was envisaged that these compounds could improve cytotoxicity through bimodal damage to DNA relative to the individual polyamide or AAQ moieties. A set of py-AAQ platinum complexes was also successfully synthesised by a platinum-mediated alkylamine to nitrile addition. The additional conjugation of a platinum nitrile complex to Py-AAQ conjugates was predicted to generate agents that are more cytotoxic than the Py-AAQ conjugates by damaging DNA via a minor groove binding (MGB)-intercalation-platination mechanism. All newly synthesised Py-AAQs and associated imino coordinated platinum(II) complexes were examined for cytotoxic activity in DLD-1 colon and MDA-MB-231 breast carcinoma cells using MTT assays. Tethering polyamides to AAQs was found to diminish the activity of the anthraquinones, while the platinum(II) conjugates exhibited moderate cytotoxicity in both carcinoma cell lines (IC50 16–30 µM). Subcellular distribution studies showed that the inactive Py-AAQ compounds tended to be localised in the lysosomes or pinocytic vesicles. Three-dimensional spheroid tumour penetration studies showed that Py-AAQ conjugates can be taken up slowly by cells enabling deeper penetration (60-100 µm) into the tumour than either of the individual 1C3 or 1,5C3 moieties (20-30 µm). Subcellular distribution studies indicated that the platinum(II) conjugates were localised in the nucleoli. The 1C3 tethered platinum complexes were found to have a binding specificity of 3’-(A/T)GTA-5’ nucleotide sequence using a polymerase stop assay whereas the 1-3py-1,5C3 tethered platinum complexes were found to have a similar binding specificity as cisplatin.