Synthesis and DNA-binding of Metallocyclic Architectures

Abstract

A new family of cationic N-heterocyclic ligand derivatives was prepared and characterised. Among these compounds are halide salts of the dications [Y(spacer)Y]2+, each of which comprise two N heterocyclic donor groups (Y = 4,4′-bipy, pyz, apyz, apym) linked by a conformationally flexible spacer such as (CH2)n, α,α′-xylylene, 2,6-lutidylene or thiabicyclo[3.3.1]nonane-2,6 diyl. The diquaternary halide salts were converted to NO3- and PF6- salts, and interaction of these bridging ligands with labile palladium(II) and platinum(II) precursors afforded several multinuclear complexes. Bis(4,4′-bipyridinium) dications were incorporated into the dinuclear macrocycles [M2(2,2′ bipy)2{4,4′ bipy(CH2)n4,4′-bipy}2]8+ (M = Pd, Pt; n = 4, 6), cis [Pd2Cl4{4,4′ bipy(CH2)34,4′-bipy}2]4+, [Pt2(dppp)2{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]8+ and cis-[Pt2Cl4{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]4+. While bis(pyrazinium) analogues were unreactive towards the palladium(II) and platinum(II) precursors, the doubly deprotonated bis(3 aminopyrazinium) and bis(2 aminopyrimidinium) derivatives served as charge-neutral quadruply-bridging ligands in the complexes [Pt4(2,2′ bipy)4{apyz(CH2)6apyz–2H}2]8+ and [Pt4(2,2′ bipy)4{apym(CH2)5apym–2H}2]8+, both of which feature Pt(II). Pt(II) interactions. Larger species formed when the diamine O,O′-bis(2-aminoethyl)octadeca(ethylene glycol) (PEGda) was treated with cis dinitratopalladium(II) and platinum(II) precursors. The resulting complexes [M(N,N)(PEGda)]2+ (M = Pd, Pt; N,N = 2,2′-bipy, en, tmeda) possessed great size (62 membered chelate rings) and aqueous solubility. DNA-binding studies were conducted with selected complexes in order to investigate the types of interactions these species might participate in. Equimolar mixtures containing either the 16mer duplex DNA D2 or the single strand D2a and palladium(II)/platinum(II) complexes were prepared and analysed by negative-ion ESI MS. Studies of D2/Pd(II) mixtures suggested extensive fragmentation was occuring, and the use of [Pd(tmeda)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+ resulted in D2 adducts of [Pd(tmeda)]2+ and [4,4′-bipy(CH2)44,4′-bipy]2+, respectively. Decomposition also occurred when D2a was used, although 1 : 1 adducts were observed with [Pd(tmeda)(PEGda)]2+, [Pd(2,2′ bipy)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. The low intensities of these adducts indicated that they are unstable towards ESI MS. Analogous ESI-MS experiments using platinum(II) derivatives were performed and, in contrast to those with palladium(II), indicated that the complexes remained largely intact. ESI-MS analysis of D2/Pt(II) mixtures allowed for the detection of 1 : 1 D2 adducts of [Pt(en)(PEGda)]2+, [Pt(tmeda)(PEGda)]2+ and [Pt2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. Intensities of the adduct ions suggested the greater charge and aryl surface area allow the dinuclear species to bind D2 most strongly. Both [Pt(2,2′-bipy)(Mebipy)2]4+ and [Pt(2,2′ bipy)(NH3)2]2+ gave rise to 1 : 2 adducts of D2, although the latter was found to be a weaker binder, perhaps owing to its lower charge. Data obtained using 1 : 5 (D2 : complex) mixtures were consistent with the results above and suggested that D2 can bind more molecules of daunomycin than any of the platinum(II) species. Analyses of D2a/Pt(II) mixtures gave results similar to those obtained with D2, although fragmentation was more pronounced, indicating that the nucleobases in D2a play more significant roles in mediating decomposition than those in D2, in which they are paired in a complementary manner. Investigations into the effects of selected platinum(II) complexes on the thermal denaturation of calf-thymus DNA (CT-DNA) in solution were conducted. Both [Pt2(2,2′ bipy)2{4,4′-bipy(CH2)64,4′-bipy}2]8+ and [Pt(2,2′-bipy)(Mebipy)2]4+ greatly stabilised CT-DNA, most likely by intercalation. In contrast, [Pt(tmeda)(PEGda)]2+ and [Pt(en)(PEGda)]2+ (as well as PEGda) caused negligible changes in melting temperature (∆Tm), suggesting that these interact weakly with CT-DNA. Data for [Pt(2,2′ bipy)(PEGda)]2+ and [Pt(2,2′-bipy)(NH3)2]2+ indicated that these species perhaps intercalate CT-DNA, with similar ∆Tm values for both complexes implying that PEGda does not play a major role in binding. While findings from ESI-MS experiments were similar to those from the thermal denaturation experiments, discrepancies between results from the two methods could be found. In particular, fragmentation of cyclic species during ESI-MS caused the binding strength of the species to be underestimated when this method was employed.