Abstract
The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active.
Highlights
The anticancer activity of the platinum-based complex, cisplatin (Figure 1), was discovered in the 1960s and has since been used extensively for the treatment of various cancers including ovarian, testicular, lung and breast cancer [1,2,3]
In attempts to overcome the aforementioned, thousands of analogues have been synthesised, of these, only carboplatin (Figure 1) and oxaliplatin (Figure 1) have been approved for worldwide use. These complexes exhibit different side-effects and overcome some cisplatin resistance, respectively, otherwise they demonstrate no significant improvements in efficacy overall [5,6]. This may be attributed to their similar geometrical configurations as they conform to the original structure-activity relationships that were reported requirements for exhibiting anticancer activity i.e., a neutral platinum(II) complex containing am(m)ine ligands and leaving group(s) that can be replaced during aquation [7,8]
The anticancer activity of cisplatin is generally attributed to its coordinative interaction with DNA
Summary
The anticancer activity of the platinum-based complex, cisplatin (Figure 1), was discovered in the 1960s and has since been used extensively for the treatment of various cancers including ovarian, testicular, lung and breast cancer [1,2,3] This activity, is moderated by dose-limiting side-effects (nephro-, neuro- and ototoxicity) and development of resistance (acquired or intrinsic) [4]. In attempts to overcome the aforementioned, thousands of analogues have been synthesised, of these, only carboplatin (Figure 1) and oxaliplatin (Figure 1) have been approved for worldwide use These complexes exhibit different side-effects and overcome some cisplatin resistance, respectively, otherwise they demonstrate no significant improvements in efficacy overall [5,6]. Due to their intrinsic properties, the impact of transition metals on the binding properties of the intercDaulaetitnogthliegiarnindtcriannsibcepsrtoapgegretriiensg, t[h2e1–im23p];afcotroefxtaramnpsiltei,oannmicekteallscoomn pthleexboinfdpionrgphpyroripnerwtiaessfoofutnhde itnotberincadlattoinDgNliAgabnyd icnatnerbcealsattaigogne, rhinogw[e2v1e–r2t3h];efzoirnecxcaommpplele, xa nofictkheel scaommeplpeoxropfhpyorrinphcyoruilndwoanslyfobuinndd tthorboiungdhtosuDrfNacAe ibnyteirnatcetricoanlsatdioune,thoothweepvreerstehnecezionfcacnoemxptrlaexaxoifalthaequsaamligeapnodrp[2h4y].riTnhcisourelvdieownlycobvienrds trhecroeuntghadsvuarnfacceesiinntearnatcitciaonncsedruinetteorctahleatpinregsecnocmepolfeaxneseoxftraa vaaxriaieltayqoufatlriagnasnidtio[2n4m]. eTthaliss.rIenvipeawrtcicouvlearrs, rweecefnotcuads voannccoems pinleaxnetsictahnatcehraivnetehracdalraetcinengtcdoemvpelloepxemseonftas wvaitrhieitnythofetpraanststihtiroenemyeeatrasl,s.arIne cpoanrftiircmuleadr, wtoeinfotecrucsaolantecowmitphleDxNesAth, aant dhaavlseoheaxdhriebcitenhtigdhevcyeltooptomxceincttsywtoitwhainrdthceanpcaesrtotuhsreceeylles.ars, are confirmed to intercalate with DNA, and exhibit high cytotoxcicty toward cancerous cells
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