The design and biological interactions of terpyridineplatinum(II) bisintercalators as potential anticancer compounds

Abstract

Coordinate covalent DNA binding platinum(II) anticancer drugs, such as cisplatin and carboplatin, have many limitations including limited effectiveness against many cancer cell lines, acquired resistance, cross resistance and toxic side effects. Compounds based around the (2,2':6',2''-terpyridine)platinum(II) motif have been previously shown to possess cytotoxicity towards a range of human carcinoma cell lines. Similar activity against cisplatin resistant cell lines has also been demonstrated, suggesting little or no cross resistance. In the search for more effective anticancer drugs, compounds based on the (2,2':6',2''-terpyridine)platinum(II) motif have been shown to intercalate with DNA. Intercalation of complexes with DNA offers a different mode of action and potentially a way to circumvent the limitations of cisplatin. A series of novel (2,2':6',2''-terpyridine)platinum(II) based bisintercalators were synthesised with varying functional groups joined via thiol or pyridine units. All compounds and intermediates were characterised using a combination of H and 195Pt nuclear magnetic resonance, two-dimensional 1H correlation spectroscopy (NOSY), two-dimensional H / 195Pt heteronuclear multiple bond correlation spectroscopy (HMQC), elemental analysis and electrospray ionisation mass spectroscopy (ESI-MS). The biological activity of the synthesised (2,2':6',2''-terpyridine)platinum(II) based bisintercalators was undertaken with the assessment of glutathione degradation, cellular cytotoxicity and proteomic interactions achieved.

Date of Award	2013
Original language	English