Fluorinated-NHC Transition Metal Complexes: Leading Characters as Potential Anticancer Metallodrugs.

In the last 20 years, N-Heterocyclic Carbene (NHC) ligands have been ubiquitous in biological and medicinal chemistry. Part of their success lies in the tremendous number of topologies that can be synthesized and thus finely tuned that have been described so far. This is particularly true in the case of those derivatives, including fluorine or fluorinated fragments on their NHC moieties, gaining much attention due to their enhanced biological properties and turning them into excellent candidates for the development of novel metallodrugs. Thus, this review summarizes the development that fluorinated-NHC transition metal complexes have had and their impact on cancer treatment.

Synthesis, biological evaluation and model membrane studies on metal complexes containing aromatic N,O-chelate ligands.

Novel lanthanide (Ln) compounds [Ln(L)2]Cl.xH2O (Ln = La3+, Ce3+, Sm3+) containing aromatic N,O-chelate ligands [HL1 = 4-amino-2-(1H-benzimidazol-2-yl)phenol; HL2 = 5-amino-2-(1H-benzimidazol-2-yl)phenol] have been synthesized and structurally characterized by elemental analysis, NMR and IR spectroscopy, molar conductance measurements, and mass spectrometry (MS). The spectroscopic data suggested that the benzimidazolyl-phenol ligands act as N,O-chelate ligands through the iminic nitrogen and phenolic oxygen atoms. Elemental analysis indicated that lanthanide compounds were formed in a 1:2 stoichiometry (metal:ligand). In vitro biological evaluation was carried out using these complexes, exhibiting moderate cytotoxicity against six different human tumor cell lines (U251, human glioblastoma; HCT-15, colorectal carcinoma; MCF-7, breast epithelial adenocarcinoma; PC-3, prostate cancer; K562, myelogenous leukemia; SKLU-1, lung carcinoma) and lower toxicity against a non-cancerous cell line (COS-7, primate kidney). In addition, the antibacterial activity of the compounds was assessed against two gram-positive strains (Staphylococcus aureus ATCC 25923, Listeria monocytogenes ATCC 19115) and two gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27583) using the microdilution method. The results obtained show that the metal complexes exhibit higher biological activity than the free ligands, confirming a synergistic effect. Further benzimidazolyl-phenol derivatives were explored for the detection of bacteria using fluorescence imaging studies. Interestingly, the fluorescent properties of these compounds make them potential candidates to monitor the morphology of bacteria at different compound concentrations. Hence, the interaction of the ligand and complexes with model membranes mimicking those of bacteria was studied by using differential scanning calorimetry (DSC) and molecular dynamics (MD), showing that both compounds decreased the enthalpy of transition in two model membranes as the concentration of the compounds increased. In addition, the main transition temperature was slightly reduced as a result of these interactions.

Bi- and tridentate stannylphosphines and their coordination to low-valent platinum.

Semirigid bifunctional tin-substituted o-tolylphosphines of general formulae [Ph2P(o-C6H4CH2)SnR3] (R = Ph, 1; R = Me, 2) and [{Ph2P(o-C6H4CH2)}2SnPh2] (3) were synthesized and isolated in good yields. The new compounds were fully characterized by single-crystal X-ray diffraction and multinuclear solution NMR spectroscopic techniques. The observed J(119Sn,31P) values in solution NMR spectroscopy as well as the PSn distances in the solid state and DFT calculations (B3LYP) on compounds 1 and 3 do not support the existence of intramolecular P → Sn bond interactions in either of the three compounds. 1 and 2 reacted with stoichiometric amounts of tristriphenylphosphine platinum(0) [Pt(PPh3)3] under toluene refluxing conditions leading to formation of Pt(ii) distorted square-planar complexes [Ph2P(o-C6H4CH2)Pt(SnR3)(PPh3)], (R = Ph, 4; R = Me, 5), each bearing a five-membered carbometallated ring resulting from Pt coordination to P and the benzylic C sp3 atom of the ligand architecture rather than from activation of the terminal Sn-C carbon bonds of the phenyl or methyl substituents which would have rendered six-membered rings. Additionally, the fragment SnR3 also binds to the metal centre disposing cis to the cyclometalated carbon atom and to the single remaining PPh3. This carbometallation takes place affecting the integrity of the ligand skeleton. NBO calculations show the Sn fragment coordinates to the metal as X-type stannyl, SnR3. The analogous reaction of [Pt(PPh3)3] towards the stannyldiphosphine 3 leads to the quantitative formation of complex [(Ph2P-o-C6H4CH2)Pt(Ph2P-o-C6H4CH2SnPh3)], 6, which exhibits five- and six-membered metallacycles at the expense of the ligand frame. All compounds were characterized exhaustively by solution spectroscopic measurements and by single crystal X-ray diffraction analysis. DFT computations corroborate the higher stability of the observed products over those resulting from preservation of the ligand backbone.

A family of rhodium and iridium complexes with semirigid benzylsilyl phosphines: from bidentate to tetradentate coordination modes.

The synthesis of a new trisbenzylsilanephosphine P{(o-C6H4CH2)SiMe2H}3 (1) is shown to proceed with high yields from P(o-tolyl)3. Compound 1 coordinates to the Rh and Ir dimers [MCl(COD)]2 (M = Rh, Ir) in a tetradentate or tridentate fashion, depending on the strict exclusion of water. The dimeric compounds [ClM(SiMe2CH2-o-C6H4)2P(o-C6H4-CH2SiMe2H)]2, 2Rh and 2Ir, feature a tetradentate coordination of the starting ligand with P and two Si atoms as well as a non-classical agostic Si-H group. The presence of adventitious water in the solvents leads to the formation of two new complexes [(µ2-Cl)2M2(SiMe2CH2-o-C6H4)2P(o-C6H4-CH2SiMe2OSiMe2CH2-o-C6H4-)P(SiMe2CH2-o-C6H4)2], 3Rh and 3Ir, which feature a siloxane bridge through Si-H bond breaking in 2. Reaction of [RhCl(COD)]2 with the bisbenzylsilanephosphine PhP{(o-C6H4CH2)SiMe2H}2 leads to the formation of compound 4Rh which features also a dimeric structure with the SiPSi ligand coordinated through the two silicon atoms, one of which occupies the apical position of a square-pyramidal geometry in the solid state, while the second is disposed equatorially trans to π-donor Cl. Finally, bidentate coordination of a PSi ligand is achieved by reaction of [RhCl(COD)]2 with Ph2P{(o-C6H4CH2)SiMe2H} which leads to the monometallic species [RhCl(SiMe2CH2-o-C6H4-PPh2)2], 5Rh, incorporating two chelating PSi ligands and maintaining a Cl ligand.

Lithium Complexes Derived of Benzylphosphines: Synthesis, Characterization and Evaluation in the ROP of rac-Lactide and ε-Caprolactone.

A series of lithium complexes ([Ph2P(o-C6H4-CH2Li·TMEDA)] (1-Li), [PhP(o-C6H4-CH3)(o-C6H4-CH2Li·TMEDA)] (2-Li), [PhP(o-C6H4-CH2Li·TMEDA)2] (2-Li2) and [P(o-C6H4-CH2Li·TMEDA)3] (3-Li3)) was prepared from mono-, di- and tri-benzylphosphines and varying amounts of nBuLi and was characterized extensively by IR and ¹H, 7Li, 13C and 31P NMR spectroscopy. The molecular structures of complexes 1-Li and 2-Li were determined by single-crystal X-ray diffraction studies. The two complexes have monomeric structures in the solid state comprising seesaw lithium atoms. In each case, the ligand exhibits an asymmetric C-C η²-coordination mode and an intramolecular P-Li bond interaction. Theoretical calculations at Density functional theory (DFT) level M06/6111+G(2d,p) show that indeed a P-Li bond is established which can be explained as the P lone pair (sp1.26) being partially delocalized on an available sp² orbital on Li (sp2.04) and additional bonding contribution of the phosphorous atom to Li stems from further delocalization of a σ P-C orbital into the sp² orbital on Li. The observed short contact distances between an aromatic ipso carbon and Li in the crystal structures of 1-Li and 2-Li are explained as due to the interaction of a σ C-Li orbital into the π* orbital of a C-C aromatic bond. Preliminary tests show compounds 1-Li, 2-Li, 2-Li2 and 3-Li3 are active catalysts in the solvent free ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) and rac-lactide (rac-LA). High conversions to polycaprolactones were obtained in short periods of time: 1-6 min at 25 °C. Additionally, all four lithium complexes behave as moderately good initiators for the ROP of rac-LA showing high conversions to polylactides at 140 °C in one hour.

Do planar tetracoordinate tin complexes really exist?

New experimental and theoretical data show that the previously reported planar tetracoordinate Sn complexes [Sn(Ph2P(Se)N(Se)PPh2)2] (1-sq) and [Sn(iPr2P(Se)N(Se)PiPr2)2] (2-sq) were not isolated and rather confused with the selenium complexes [Se(Ph2P(Se)N(Se)PPh2)2] (3-sq) and [Se(iPr2P(Se)N(Se)PiPr2)2] (4-sq), respectively.

Calix[4]arenes of aluminum and gallium with benzimidazolyl ligands: steric control of the conformation via substitution on the ligand.

Complexes [bzimAlR(2)](4) [bzim = benzimidazolate; R = Et (2), (i)Bu (3)], [mbzimAlR(2)](4) [mbzim = 2-methylbenzimidazolate; R = Et (6), (i)Bu (7)], [dmbzimAlR(2)](4) [dmbzim = 5,6-dimethylbenzimidazolate; R = Me (9), Et (10), (i)Bu (11)], and [tmbzimAlR(2)](4) [tmbzim = 2,5,6-trimethylbenzimidazolate; R = Me (12), Et (13), (i)Bu (14)] have been prepared via alkane elimination and coordinative self-assembly upon the reaction of benzimidazole ligands with aluminum alkyls in benzene, toluene, or xylene. Characterization of the complexes was achieved by spectroscopic methods, microanalysis, and X-ray crystallography of 2, 7, 10, 11, 13, and 14. The complexes reported herein and the aluminum and gallium analogues 1, 4, 5, and 8 reported in a previous paper (1) are predominantly tetranuclear aggregates related to calix[4]arenes in which the benzimidazolyl ligands bind two metal atoms in a η(1):η(1) fashion. X-ray crystallography demonstrates that modulation of the conformation adopted by these metallacalix[4]arenes is achieved by proper substitution on the C atom at the 2 position of the benzimidazolyl ligand. An H substituent for 1, 2, 4, 10, and 11 favors a chair conformation with a small cavity and approximate C(2h) symmetry, while a CH(3) substituent for 5, 7, 8, 13, and 14 introduces enough repulsion to switch the conformation to a 1,3-alternate or double cone with a concomitant larger cavity and approximate C(2v) symmetry.

Steric control of conformation in self-assembly metallacalix[4]arenes derived from AlMe3 or GaMe3 with benzimidazolyl ligands.

Metallacalix[4]arenes [bzimAlMe(2)](4) (1), [bzimGaMe(2)](4) (2), [mbzimAlMe(2)](4) (3) and [mbzimGaMe(2)](4) (4) were obtained by self-assembly. The larger cavity of 3 and 4 allows them to function as hosts of benzene molecules.