High cytotoxic and antimetastatic activities against anaplastic thyroid cancer are displayed by cationic complexes [RuX(CO)(dppb)(phen)]Y (X = Y = OAc, OPiv, SAc, and NCS; X = Cl and Y = PF6).
The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC values against DNA gyrase, and submicromolar IC values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.
A series of novel monocarbonyl ruthenium catalysts containing bidentate dinitrogen or/and diphosphine ligands are easily obtained through a general and straightforward approach.
The chiral cationic complex [Ru(η1‐OAc)(CO)((R,R)‐Skewphos)(phen)]OAc (2R), isolated from reaction of [Ru(η1‐OAc)(η2‐OAc)(R,R)‐Skewphos)(CO)] (1R) with phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)‐Skewphos)(phen)]Y (X=Y=OPiv 3R; X=SAc, Y=OAc 4R). The corresponding enantiomers 2S‐4S have been obtained from 1S containing (S,S)‐Skewphos. Reaction of 2R and 2S with (S)‐cysteine and NaPF6 at pH=9 gives the diastereoisomers [Ru((S)‐Cys)(CO)(PP)(phen)]PF6 (PP=(R,R)‐Skewphos 2R‐Cys; (S,S)‐Skewphos 2S‐Cys). The DFT energetic profile for 2R with (S)‐cysteine in H2O indicates that aquo and hydroxo species are involved in formation of 2R‐Cys. The stability of the ruthenium complexes in 0.9 % w/v NaCl solution, PBS and complete DMEM medium, as well as their n‐octanol/water partition coefficient (logP), have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505 C, HCT‐116 and A549 cell lines with EC50 values of 2.8–0.04 μM. The (R,R)‐Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50=0.04 μM) being 14 times more cytotoxic than 4S against the anaplastic thyroid cancer 8505 C cell line.
Robust and easily accessible CNNOMe pincer ruthenium complexes show unprecedented selectivity and productivity in the TH of lignocellulose-derived carbonyl compounds with 2-propanol.
The diacetate complexes trans-[Ru(κ 1 -OAc) 2 (PPh 3 ) 2 (NN)] (NN = ethylenediamine (en) (1), 2-(aminomethyl)pyridine (ampy) (2), 2-(aminomethyl)pyrimidine (ampyrim) (3)) have been isolated in 76−88% yield by reaction of [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ] with the corresponding nitrogen ligands. The ampy-type derivatives 2 and 3 undergo isomerization to the thermodynamically most stable cationic complexes [Ru(κ 1 -OAc)(PPh 3 ) 2 (NN)]OAc (2a and 3a) and cis-[Ru(κ 1 -OAc) 2 (PPh 3 ) 2 (NN)] (2b and 3b) in methanol at RT. The trans-[Ru(κ 1 -OAc) 2 (P 2 ) 2 ] (P 2 = dppm (4), dppe (5)) compounds have been synthesized from [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ] by reaction with the suitable diphosphine in toluene at 95 °C. The complex cis-[Ru(κ 1 -OAc) 2 (dppm)-(ampy)]( 6) has been obtained from [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ] and dppm in toluene at reflux and reaction with ampy. The derivatives trans-[Ru(κ 1 -OAc) 2 P 2 (NN)] (7−16; NN = en, ampy, ampyrim, 8-aminoquinoline; P 2 = dppp, dppb, dppf, (R)-BINAP) can be easily synthesized from [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ] with a diphosphine and treatment with the NN ligands at RT. Alternatively these compounds have been prepared from trans-[Ru(OAc) 2 (PPh 3 ) 2 (NN)] by reaction with the diphosphine in MEK at 50 °C. The use of (R)-BINAP affords trans-[Ru(κ 1 -OAc) 2 ((R)-BINAP)(NN)] (NN = ampy (11), ampyrim (15)) isolated as single stereoisomers. Treatment of the ampy-type complexes 8−15 with methanol at RT leads to isomerization to the cationic derivatives [Ru(κ 2 -OAc)P 2 (NN)]OAc (8a−15a; NN = ampy, ampyrim; P 2 = dppp, dppb, dppf, (R)-BINAP). Similarly to 2, the dipivalate trans-[Ru(κ 1 -OPiv) 2 (PPh 3 ) 2 (ampy)] ( 18) is prepared from [Ru(κ 2 -OPiv) 2 (PPh 3 ) 2 ] (17) and ampy in CHCl 3 . The pincer acetate [Ru(κ 1 -OAc)(CNN OMe )(PPh 3 ) 2 ] (19) has been synthesized from [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ] and HCNN OMe ligand in 2-propanol with NEt 3 at reflux. In addition, the dppb pincer complexes [Ru(κ 1 -OAc)(CNN)(dppb)] (CNN = AMTP (20), AMBQ Ph (21)) have been obtained from [Ru(κ 2 -OAc) 2 (PPh 3 ) 2 ], dppb, and HAMTP or HAMBQ Ph with NEt 3 , respectively. The acetate NN and pincer complexes are active in transfer hydrogenation with 2-propanol and hydrogenation with H 2 of carbonyl compounds at S/C values of up to 10000 and with TOF values of up to 160000 h −1 .
The cationic achiral and chiral terpyridine diphosphine ruthenium complexes [RuCl(PP)(tpy)]Cl (PP = dppp (1), (R,R)-Skewphos (2) and (S,S)-Skewphos (3)) are easily obtained in 85-88 % yield through a one-pot synthesis from [RuCl 2 (PPh 3 ) 3 ], the diphosphine and 2,2':6',2''-terpyridine (tpy) in 1-butanol. Treatment of 1-3 with NaPF 6 in methanol at RT affords quantitatively the corresponding derivatives [RuCl(PP)(tpy)]PF 6 (PP = dppp (1 a), (R,R)-Skewphos (2 a) and (S,S)-Skewphos (3 a)). Reaction of [RuCl 2 (PPh 3 ) 3 ] with (S,R)-Josiphos or (R)-BINAP in toluene, followed by treatment with tpy in 1-butanol and finally with NaPF 6 in MeOH gives [RuCl(PP)(tpy)]PF 6 (PP = (S,R)-Josiphos (4 a), (R)-BINAP (5 a))isolated in 78 % and 86 % yield, respectively. The chiral derivatives have been isolated as single stereoisomers and 3 a, 4 a have been characterized by single crystal X-ray diffraction studies. The tpy complexes with NaOiPr display high photocatalytic activity in the transfer hydrogenation (TH) of carbonyl compounds using 2-propanol as the only hydrogen donor and visible light at 30 °C, at remarkably high S/C (up to 5000) and TOF values up to 264 h À 1 . The chiral enantiomers 2, 2 a and 3, 3 a induce the asymmetric photocatalytic TH of acetophenone, affording (S)-and (R)-1-phenylethanol with 51 and 52 % ee, respectively, in a MeOH/2propanol mixture.
With the aim to design new water-soluble organometallic Ru(II) complexes acting as anticancer agents catalysing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1-4) featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N^N) ligands, of general formula [Ru(OAc)CO(dppb)(N^N)]n (n = +1, 0; OAc = acetate). The compounds have been characterised by different methods, including 1H and 31P NMR spectroscopy, electrochemistry as well as single crystals X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in aqueous environment, and for the catalytic regioselective reduction of NAD+ to 1,4-NADH in aqueous solution with sodium formate as hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV-Visible spectrophotometry and NMR spectroscopy. Overall, initial structure-activity relationships could be inferred which point towards the influence of the extension of the aromatic N^N ligand in the cationic complexes 1-3 on the TH in both reduction/oxidation processes. The neutral complex 4, featuring a picolinamidate N^N ligand, stands out as the most active catalyst for the reduction of NAD+, while being completely inactive towards NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1-3. Together, insight from the kinetic and electrochemical characterization suggests that, in the case of Ru(II) complexes 1-3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate limiting step, whereas for NAD+ hydrogenation with formate as the H-donor, the rate limiting step is the transfer of the ruthenium hydride to the NAD+ substrate. The latter is further modulated by the presence of di-cationic aquo- or mono-cationic hydroxo-species of complexes 1-3. Instead, compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous and non-tumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1H NMR spectroscopy. Overall, this study paves the way to the application of non-arene based organometallic complexes as TH catalysts in biological environment.
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