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

Abstract

Platinum anticancer complexes incorporating 2,2′‐bipyridine (bpy), 4,4′‐dimethyl‐2,2′‐bipyridine (44Me2bpy) or 2‐(2′‐pyridyl)quinoxaline (2pq) as polyaromatic ligands and the S,S or R,R isomer of 1,2‐diaminocyclohexane as ancillary ligands in the form [Pt(PL)(AL)]2+ have been synthesised and characterised. X‐ray diffraction was used to elucidate the structure and stacking behaviour of the complexes, revealing interesting properties that may impact their biological activity. Pulsed gradient spin‐echo NMR experiments elucidated the aggregation behaviour of these complexes in solution. The cytotoxicity of each complex was assessed against the L1210 murine leukaemia, HT29 human colon carcinoma and U87 human glioblastoma cell lines and compared to other complexes within this class. The complexes incorporating 44Me2bpy were found to be the most potent at inhibiting cell growth with IC50 values for the S,S isomer (0.13–0.5 μM) less than that for cisplatin (0.36–11 μM), oxaliplatin (0.9–1.8 μM) or carboplatin (>50 μM). Most complexes were found to be very effective against HT29 colon carcinoma cells.

Synthesis and Analysis of the Structure, Diffusion and Cytotoxicity of Heterocyclic Platinum(IV) Complexes

“…Standard error values were produced from duplicate experiments that were conducted on four separate occasions ( n =4). [b] Aside from complex 5 , the data for each complex in these cell lines was previously reported in reference 35; n.d.=not determined.…”

Multifaceted Studies of the DNA Interactions and In Vitro Cytotoxicity of Anticancer Polyaromatic Platinum(II) Complexes

“…These experiments were conducted to gain a greater understanding of the activity of 1 – 6 and 1′ – 6 , to relate, if possible, the DNA affinity of 1 – 6 with their in vitro activity, and to determine particularly sensitive cell lines to target in further studies. For all cell lines studied, the complexes demonstrated potent, often submicromolar activity, with complexes 3 – 6 demonstrating very high cytotoxicity in the Du145 prostate cancer (some values previously published), SJ‐G2 glioblastoma, and the previously published HT29 colon carcinoma lines (Figure ). These cancer types are therefore good targets for further therapeutic studies.…”

“…As a continuation of the cytotoxicity assays performed in previous work with complexes 1 – 6 and 1′ – 6′ in the L1210 murine leukaemia, HT29 human colon carcinoma and U87 human glioblastoma cell lines, the activity of these complexes was assessed in a further ten cell lines: MCF‐7 breast cancer, A2780 ovarian cancer, H460 lung cancer, A431 skin cancer, Du145 prostate cancer, BE2‐C neuroblastoma, SJ‐G2 human glioblastoma, MIA pancreas cancer, SMA murine glioblastoma and MCF10A breast (normal; Table ). These experiments were conducted to gain a greater understanding of the activity of 1 – 6 and 1′ – 6 , to relate, if possible, the DNA affinity of 1 – 6 with their in vitro activity, and to determine particularly sensitive cell lines to target in further studies.…”

“…The use of a variety of P L s allowed for a comparison between the DNA affinity and aromatic surface area of these complexes; it is known that structural variations can result in different DNA binding behaviour for metal complexes . Methylated variants of each P L were included due to the proven cytotoxic and DNA binding influences of methyl substituents in our complexes, and SS ‐dach was chosen as the A L as complexes of this ligand are the most active overall . The interactions of complexes 1 – 6 with calf‐thymus DNA (CT‐DNA) and some oligonucleotides were analysed using several methods.…”

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).…”