Cyclometalated Pt Complexes of CNC Pincer Ligands: Luminescence and Cytotoxic Evaluation

Abstract

In the framework of our attempts to develop cyclometalated Pt­(II) complexes toward bifunctional targeting inhibitors or agents for photodynamic therapy, diagnostics, and bioimaging, a series of bis-cyclometalated Pt­(II) complexes [Pt­(CNC)­(L)] (L = DMSO, MeCN) containing various (CNC)2– ligands based on 2,6-diphenylpyridine were synthesized and characterized analytically and spectroscopically, focusing on their electrochemical, luminescence, and antiproliferative properties. Electrochemical experiments and UV–vis absorption spectroscopy suggest ligand-centered LUMOs and metal-centered HOMOs in line with DFT calculations. Extension of the ancillary phenyl to naphthyl cores and a central 4-phenylpyridine group instead of pyridine results in bathochromic shifts of the long-wavelength absorption bands ranging from 420 to 440 nm, with the latter shift being more pronounced. The complexes of the fused CNC heterocyclic systems dba (H2dba = dibenzo­[c,h]­acridine), db­(ph)­a (H2db­(ph)­a = 7-phenyldibenzo­[c,h]­acridine), and bzqph (HbzqphH = 2-phenylbenzo­[h]­quinoline) absorb far more red-shifted in the range 500–530 nm. All complexes show reversible first electrochemical reductions and irreversible oxidations with an electrochemical gap of about 3 V, roughly in line with the absorption energies. While the 2,6-diphenylpyridine complexes [Pt­(CNC)­(DMSO)] show no luminescence at ambient temperature in solution, the fused dba, db­(ph)­a, and bzqph derivatives are efficient triplet emitters at ambient temperature with emission wavelengths in the region 575–600 nm and quantum yields ranging from 7 to 23%. Vibrationally resolved emission spectra calculated in the framework of DFT faithfully reproduce the experimental data. TD-DFT calculations at the excited-state T1 geometry reveal intraligand π–π*/MLCT character of the emission for all three investigated complexes. Antiproliferative tests on selected complexes gave very different toxicities, ranging from lower than 1 μM to virtually nontoxic. The data allowed drawing some structure–activity relationships (SAR), even though variations in solubility could also significantly account for the different toxicities.

A Bis‐Chelating / Ligand for the Synthesis of Heterobimetallic Platinum(II)/Rhenium(I) Complexes: Tools for the Optimization of a New Class of Platinum(II) Anticancer Agents

“…Combining these uptake data with partition coefficients (log P o/w ) and DFT calculations enabled us to draw a structure–activity relationship for this new class of Pt II anticancer drug candidates. These data could be correlated to data obtained for very recently reported [( )PtL] complexes …”

Influence of Ligand and Nuclearity on the Cytotoxicity of Cyclometallated C^N^C Platinum(II) Complexes

“…Importantly, 2 is the only compound in this library which has noticeable toxicity towards MCF‐7 (IC 50 =10±1 μ m ), however, it remains >6‐fold less cytotoxic than CDDP ( p <0.05). A recent report by Klein and co‐workers determined that 2 has a IC 50 value against MDA‐MB‐231 of 12.12±1.84 μ m , which is within experimental error [21] . Furthermore, 2 is more active towards the cisplatin‐resistant ovarian cell line A2780cisR than the parental cisplatin‐sensitive A2780 cells.…”

“…Ar ecent reportb yK lein andc o-workers determined that 2 has aI C 50 value against MDA-MB-231o f1 2.12 AE 1.84 mm, which is within experimental error. [21] Furthermore, 2 is more active towards the cisplatin-resistant ovarian cell line A2780cisR than the parental cisplatin-sensitive A2780 cells. On replacing the monodentate DMSO ligand in 2 for PPh 3 in 3, the activity significantly decreases, and 3 is non-toxic against all cell lines tested (IC 50 > 100 mm)( Ta ble 1a nd Figure 3).…”

“…[19,20] Klein and co-workers showed that as eries of cyclometallated complexesb ased on [(C^N^C)Pt II (L)],w herein C^N^C is at ridentate dianionicc yclometallating motif bearing ar ange of aryl groups;i ncluding phenyl, naphthyl and dibenzoacridine derivativesa nd L = DMSO or acetonitrile (MeCN), displayedg ood to moderate cytotoxicity againsth uman cell lines;c olorectala denocarcinoma (HT-29) and breast adenocarcinoma (MDA-MB-231). [21] Polynuclearp latinum(II) complexesr epresent an important growingc lass of anticancera gentsw ith potentialc linical significance. [22][23][24][25] Developing an understandingo ft he structure-activity relationships (SARs) within classes of biologically active complexesi si ntegralf or optimization of their per-formance.…”

“…However, the cytotoxicity of cyclometallated, C^N^C platinum(II) compounds has not been widely studied [19, 20] . Klein and co‐workers showed that a series of cyclometallated complexes based on [(C^N^C)Pt II ( L )], wherein C^N^C is a tridentate dianionic cyclometallating motif bearing a range of aryl groups; including phenyl, naphthyl and dibenzoacridine derivatives and L =DMSO or acetonitrile (MeCN), displayed good to moderate cytotoxicity against human cell lines; colorectal adenocarcinoma (HT‐29) and breast adenocarcinoma (MDA‐MB‐231) [21] …”