Synthesis of platinum(II) based G-quadruplex stabilisers

Abstract

G-quadruplex DNA (QDNA) structures have been identified to provide a role in cell regulation, growth and repair mechanisms and as such, have been recognised as a promising target for anticancer drug design. QDNA has been reported to be stabilised by small molecules including platinum complexes, which is the focus of this project. Here the aim is to contribute to the design of QDNA selective stabilisers through the synthesis of symmetrical 1-10-phenanthroline and 2,2'-bipyridine platinum complexes. Previous designs incorporating platinum phenanthroline based agents have shown both strong QDNA binding affinity and/or improved cytotoxicity compared to current conventional chemotherapeutics. In this project, 5 symmetrical bis-1,10-phenathroline and 4 symmetrical bis-2,2'-bipyridine complexes were synthesised. Of the 9 complexes, 5 were novel, with 5 exhibiting notable binding affinity towards QDNA: (T2G5T)4. Each complex was characterised using a complimentary of techniques, including: NMR, HPLC, HR-MS and UV-Vis. Crystal structures were obtained for [Pt(3,4,7,8-tetramethyl-1,10-phenanthroline)](NO3)2 and [Pt(4,4'-dimethyl-2,2'-bipyridine)2)](NO3)2. The binding affinity of each complex with QDNA was investigated using a series of molecular docking (MD) simulations and electrospray ionisation (ESI) experiments. MD simulations utilised 4 substrate models, including two dsDNA and two QDNA. The results from the experiments highlighted that with greater aromatic surface area, a complex would demonstrate greater affinity towards QDNA. ESI experiments also produced a similar trend, however [Pt(4,4'-ditertbutyl-2,2'-bipyridine)2](PF6)2 exhibited no binding affinity towards QDNA: (T2G5T)4. To identify whether that QDNA binding affinity correlated with cytotoxicity in vitro, a cytotoxicity assessment against several human cancer cell lines was undertaken. Complexes: [Pt(5,6-dimethyl-1,10-phenanthroline)](NO3)2 (BP3), [Pt(3,4,7,8-tetramethyl-1,10-phenanthroline)](NO3)2 (BP4), [Pt(4,7,-diphenyl-1,10-phenanthroline)](PF6)2 (BP5) and [Pt(4,4'-ditertbutyl-2,2'-bipyridine)2](PF6)2 (BB4) exhibited high cytotoxicity, with BP4, BP5, BB4 exhibiting cytotoxicity greater than 2 fold in colon (HT29), breast (MCF-1) and pancreas (MIA) cell lines, compared with cisplatin. Overall this study showed that 5 complexes demonstrated correlations between apparent QDNA binding affinity and cytotoxicity. BB4 produced no correlations, suggesting a different target or mechanism of action for its exhibited cytotoxicity.

Date of Award	2017
Original language	English