Half-sandwich iridium N-heterocyclic carbene anticancer complexes

Abstract

Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir complexes of the type [(η-Cp)Ir(C^C)Cl]PF, where Cp is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cp = CMeCH) or biphenyl (Cp = CMeCHCH) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC values ranging from 2.9 to 46.3 μM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cp > Cp > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η-CMeCHCH)Ir(L4)Cl]PF (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD was studied. Complexes [(η-CMeCHCH)Ir(L2)Cl]PF (2C) and [(η-CMeCHCH)Ir(L3)Cl]PF (3C) cause cell apoptosis and arrest the cell cycle at the G phase and G/M phase when HeLa cancer cells are treated with different IC concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.

Mechanistic Insights on the Functionalization of CO2 with Amines and Hydrosilanes Catalyzed by a Zwitterionic Iridium Carboxylate‐Functionalized Bis‐NHC Catalyst

“…To ascertain the role of the uncoordinated carboxylate fragment on the catalytic activity of 1 , the performance of the related cationic carboxylate‐free iridium(III) species, [Cp*IrCl{(MeIm) 2 CH 2 )}][PF 6 ] ( 5 ), as catalyst for the hydrosilylation of CO 2 (3 bar) with HSiMe 2 Ph has also been investigated. This experiment evidenced that 5 also promotes the formation of silylformate 2 b but showed to be a less active catalyst precursor than 1 (Figure ).…”

“…1 H/ 13 C‐HSQC, 1 H/ 13 C‐HMBC and 1 H/ 29 Si‐HMBC sequences were used to assign the 1 H and 13 C{ 1 H} spectra. The iridium(III) complexes [Cp*IrCl{(MeIm) 2 CHCOO}] ( 1 ) and [Cp*IrCl{(MeIm) 2 CH 2 }][PF 6 ] ( 5 ) were prepared following the reported procedure. Amine (pyrrolidine, piperidine, morpholine, Et 2 NH, Me( c ‐hexyl)NH and i Pr 2 NH) and silane reagents (HSiMe 2 Ph, HSiMePh 2 , HSiEt 3 and 1,4‐(HMe 2 Si) 2 (C 6 H 4 )) used in the catalytic experiments were purchased from commercial sources and dried over 4 Å molecular sieves prior to use.…”

Organometallic ruthenium and iridium phosphorus complexes: Synthesis, cellular imaging, organelle targeting and anticancer applications

“…The reagents IrCl 3 ·nH 2 O (≥ 99% purity), hydrated RuCl 3 ·nH 2 O (≥ 99% purity), octan‐1‐ol (≥ 99%) and nitric acid (72%), 2,3,4,5‐tetramethyl‐2‐cyclopentenone (95%), 1,2,3,4,5‐pentamethyl‐cyclopentadiene (95%), butyllithium solution (1.6 m in hexane), 1,2‐bis (diphenylphosphino) propare (98%), trans‐1,2‐bis (diphenylphosphino) ethylene (96%), 1,2‐bis (diphenylphosphino) benzene (98%), 1,2‐bis (diphenylphosphino) ethane (98%), 2‐phenylethanol‐1‐ol (bz‐EA) (98%), α‐terpinene ( p ‐cym) and cisplatin were purchased from Sigma‐Aldrich. Cp xbiph H and [( η 6 ‐bz‐EA)RuCl 2 ] 2 were prepared as described. For the biological experiments, CCCP, z‐VAD‐fmk and cleaved caspase‐3 were purchased from Apoptosis and Epigenetice Company, NH 4 PF 6 (Alfa Aesar), MTDR (Life Technologies), LTDR (Life Technologies), MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5–diphenyltetrazolium bromide] (Sigma‐Aldrich), Annexin V‐FITC Apoptosis Detection Kit (Sigma‐Aldrich), JC‐1 (Sigma‐Aldrich), PBS (Sangon Biotech), PI (Sigma‐Aldrich) were all used as received.…”

Triphenylamine‐Appended Half‐Sandwich Iridium(III) Complexes and Their Biological Applications

“…In addition, the iridium dimers showedinactivity or only moderate anticancera ctivity. [18] Interestingly,t he complexes formedb yt he coordination of iridium and the TPAl igand possessedh igh potency.…”

“…[16,17] Owing to the advantages of high anticancer activity and unique MoA,h alf-sandwich organometallic Ir III complexes have attractede xtensive interest. [18][19][20] In ar ecent study,S adler and co-workersf ound that half-sandwichC p* (pentamethylcyclopentadienyl)I r III complexes with an N,N-bound ligand, such as 2,2'-bipyridine( bipy),1 ,10-phenanthroline (phen), and ethylenediamine (EDA), were all inactivea gainst A2780 human ovari-an cancer cells with IC 50 values (concentrationsa tw hich5 0% of the cell growth is inhibited) over 100 mm. [21,22] The increase in the number of benzene rings on the Cp ring has ag reat effect on the anticancer activity of the complexes.…”