Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

Abstract

Eight platinum(II) complexes with anticancer potential have been synthesised and characterised. These complexes are of the type [, where I L is either dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or 2,3-dimethyl-dpq (23Me 2 dpq) and A L is one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SS-dach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RR-dacp). The CT-DNA binding of these complexes and a series of other complexes were assessed using fluorescent intercalator displacement assays, resulting in unexpected trends in DNA binding affinity. The cytotoxicity of the eight synthesised compounds was determined in the L1210 cell line; the most cytotoxic of these were [Pt(dpq)(SS-dach)]Cl 2 and [Pt(dpq)(RR-dach)]Cl 2 , with IC 50 values of 0.19 and 0.80 μM, respectively. The X-ray crystal structure of the complex [Pt(dpq)(SS-dach)](ClO 4 ) 2 ·1.75H 2 O is also reported.

Metal complex interactions with DNA

“…Complexes such as the aforementioned [Pt(phen)(en)] 2+ (10) intercalate into the minor groove of DNA predominantly between the base pairs C 3 -G 4 and T 2 -A 5, and as a result the helix is lengthened and rigidified (Fig. 112,[115][116][117] For example, methyl substituents in the 5/6 position of phen is known to be particularly effective, with some complexes achieving cytotoxicity at nanomolar concentrations. 63 The positive charge of these complexes allows for improved solubility, selective cellular uptake via active transport and high DNA affinity.…”

“…63 The positive charge of these complexes allows for improved solubility, selective cellular uptake via active transport and high DNA affinity. 112 The A L s of these complexes greatly influence their activity, 101,110 which suggests that their cytotoxicity is not just a consequence of DNA binding, but of additional intracellular interactions also. 112,[115][116][117] For example, methyl substituents in the 5/6 position of phen is known to be particularly effective, with some complexes achieving cytotoxicity at nanomolar concentrations.…”

Cytotoxicity and Structural Analyses of 2,2′‐Bipyridine‐, 4,4′‐Dimethyl‐2,2′‐bipyr­idine‐ and 2‐(2′‐Pyridyl)quinoxalineplatinum(II) Complexes

“…These compounds are of the type [Pt(P L )(A L )] 2+ , in which P L is a substituted 1,10‐phenanthroline (phen) polyaromatic ligand and A L is a chiral amine ancillary ligand such as 1 S ,2 S ‐diaminocyclohexane 5. Recently we have also reported that complexes of dipyrido[3,2‐ f :2′,3′‐ h ]quinoxaline (dpq) and 2,3‐dimethyl‐dpq (23Me 2 dpq) exhibit biological activity comparable to complexes with phen derivatives 6. Here we present an expansion of the range of P L s via a study of complexes of 2,2′‐bipyridine (bpy), 4,4′‐dimethyl‐bpy (44Me 2 bpy) and 2‐(2′‐pyridyl)quinoxaline (2pq), with either 1 S ,2 S ‐diaminocyclohexane ( SS ‐dach) or 1 R ,2 R ‐diaminocyclohexane ( RR ‐dach) as an A L (Figure 1).…”

Transition Metal Intercalators as Anticancer Agents—Recent Advances

“…In contrast intercalators have received less attention; however, there are several recent examples of platinum intercalators that exhibit exceptionally high anticancer activity. A prominent series of complexes are composed of a general scaffold of [Pt(H L )(A L )] 2+ , where H L is a heterocyclic intercalating ligand and A L is a bidentate ancillary ligand [25,26]. These complexes include dipyrido[3,2- f :2’,3’- h ]quinoxaline (dpq), 2,3-dimethyl-dpq (23Me 2 dpq), phen, 5,6-dimethyl-phen (56Me 2 phen), bpy or 4,4’-dimethyl-bpy (44Me 2 bpy) as the H L and either the S , S or R , R isomer of 1,2-diaminocyclohexane ( S , S - or R , R -dach) as the A L (Figure 4).…”

“…However, DNA affinity is not the only factor governing the activity of these complexes as the choice of A L has a large effect. For example, complexes of S , S -dach (i.e., Pt1 and Pt3 ) displayed higher cytotoxicity than those of R , R -dach (i.e., Pt1’ and Pt3’ ), despite exhibiting the same DNA affinity [25]. …”