Cyclometalated and NNN Terpyridine Ruthenium Photocatalysts and Their Cytotoxic Activity

The cyclometalated terpyridine complexes [Ru(η2-OAc)(NC-tpy)(PP)] (PP = dppb 1, (R,R)-Skewphos 4, (S,S)-Skewphos 5) are easily obtained from the acetate derivatives [Ru(η2-OAc)2(PP)] (PP = dppb, (R,R)-Skewphos 2, (S,S)-Skewphos 3) and tpy in methanol by elimination of AcOH. The precursors 2, 3 are prepared from [Ru(η2-OAc)2(PPh3)2] and Skewphos in cyclohexane. Conversely, the NNN complexes [Ru(η1-OAc)(NNN-tpy)(PP)]OAc (PP = (R,R)-Skewphos 6, (S,S)-Skewphos 7) are synthesized in a one pot reaction from [Ru(η2-OAc)2(PPh3)2], PP and tpy in methanol. The neutral NC-tpy 1, 4, 5 and cationic NNN-tpy 6, 7 complexes catalyze the transfer hydrogenation of acetophenone (S/C = 1000) in 2-propanol with NaOiPr under light irradiation at 30 °C. Formation of (S)-1-phenylethanol has been observed with 4, 6 in a MeOH/iPrOH mixture, whereas the R-enantiomer is obtained with 5, 7 (50–52% ee). The tpy complexes show cytotoxic activity against the anaplastic thyroid cancer 8505C and SW1736 cell lines (ED50 = 0.31–8.53 µM), with the cationic 7 displaying an ED50 of 0.31 µM, four times lower compared to the enantiomer 6.

The 31 P{ 1 H} NMR spectrum of 1 in CD2Cl2 displays two doublets at δ 56.7 and 52.0 with a 2 J(P,P) of 37.1 Hz, for the phosphorous trans to O and N atoms, respectively, as inferred from 2D 1 H-31 P HMBC NMR spectrum (Figure S7).The signals of the H6 and H6″ The 31 P{ 1 H} NMR spectrum of 1 in CD 2 Cl 2 displays two doublets at δ 56.7 and 52.0 with a 2 J(P,P) of 37.1 Hz, for the phosphorous trans to O and N atoms, respectively, as inferred from 2D 1 H-31 P HMBC NMR spectrum (Figure S7).The signals of the H6 and H6 ′′ tpy protons are at δ H 8.61 and 8.48, and the latter upfield shifted compared to the free ligand (δ 8.69) [62] (Figure 1).
tpy protons are at δH 8.61 and 8.48, and the latter upfield shifted compared to the free ligand (δ 8.69) [62] (Figure 1).In the 13 C{ 1 H} NMR spectrum, the cyclometalated carbon C3′ appears at δ 182.7 ( 2 J(C,P) = 18.0 and 8.4 Hz), whereas the signal at δ 184.5 is attributed to the carboxylate CO group.The resonances of the C6 and C6″ carbons are at δ 148.6 and 148.5, close to that of free tpy (δ 149.5) [63], whereas the C4′ carbon atom of the cyclometalated pyridine is significantly downfield shifted at δ 154.5 (Δδ = 16.3) and coupled with a phosphorous atom ( 2 J(C,P) = 3.7 Hz).The structure of 1 in the solid state was confirmed by an X-ray diffraction experiment (Figure 2).Complex 1 crystallizes in a pseudo-octahedral geometry, showing a cyclometalated NC-terpyridine, a diphosphine and a chelate acetate ligand.The distortions arise from the small O1-Ru-O2 angle of the acetate (58.52(8)°), with similar Ru-O bond distances of 2.256(3) and 2.231(2) Å, not affected by the different trans P and C ligands.The Ru1-N1 In the 13 C{ 1 H} NMR spectrum, the cyclometalated carbon C3 ′ appears at δ 182.7 ( 2 J(C,P) = 18.0 and 8.4 Hz), whereas the signal at δ 184.5 is attributed to the carboxylate CO group.The resonances of the C6 and C6 ′′ carbons are at δ 148.6 and 148.5, close to that of free tpy (δ 149.5) [63], whereas the C4 ′ carbon atom of the cyclometalated pyridine is significantly downfield shifted at δ 154.5 (∆δ = 16.3) and coupled with a phosphorous atom ( 2 J(C,P) = 3.7 Hz).The structure of 1 in the solid state was confirmed by an X-ray diffraction experiment (Figure 2).
tpy protons are at δH 8.61 and 8.48, and the latter upfield shifted compared to the free ligand (δ 8.69) [62] (Figure 1).In the 13 C{ 1 H} NMR spectrum, the cyclometalated carbon C3′ appears at δ 182.7 ( 2 J(C,P) = 18.0 and 8.4 Hz), whereas the signal at δ 184.5 is attributed to the carboxylate CO group.The resonances of the C6 and C6″ carbons are at δ 148.6 and 148.5, close to that of free tpy (δ 149.5) [63], whereas the C4′ carbon atom of the cyclometalated pyridine is significantly downfield shifted at δ 154.5 (Δδ = 16.3) and coupled with a phosphorous atom ( 2 J(C,P) = 3.7 Hz).The structure of 1 in the solid state was confirmed by an X-ray diffraction experiment (Figure 2).Complex 1 crystallizes in a pseudo-octahedral geometry, showing a cyclometalated NC-terpyridine, a diphosphine and a chelate acetate ligand.The distortions arise from the small O1-Ru-O2 angle of the acetate (58.52(8)°), with similar Ru-O bond distances of 2.256(3) and 2.231(2) Å, not affected by the different trans P and C ligands.The Ru1-N1 Complex 1 crystallizes in a pseudo-octahedral geometry, showing a cyclometalated NC-terpyridine, a diphosphine and a chelate acetate ligand.The distortions arise from the small O1-Ru-O2 angle of the acetate (58.52(8) • ), with similar Ru-O bond distances of 2.256(3) and 2.231(2) Å, not affected by the different trans P and C ligands.The Ru1-N1 (2.114(3) Å) and the Ru1-C7 (2.026(4) Å) lengths are in line with those of tpy [64][65][66][67], and NC-cyclometalated [65,68,69] ruthenium complexes.The X-ray analysis shows the presence of additional intramolecular π-π interactions between a phenyl group of dppb and the Ncoordinated pyridine ring, in agreement with the behavior of 1 in solution with one phenyl displaying an upfield 1 H NMR signal (δ H 5.93).Although the "rollover" cyclometalation of tpy, affording a bidentate NC-ligand with a pendant pyridine, has been sparingly described for Pd, Pt and Zn complexes [16,18,20,21], no examples of this type of tpy coordination at ruthenium have been reported.It is worth noting that this ruthenium C-H activation may allow for the functionalization of tpy at the 3 ′ and 5 ′ positions of the internal pyridine [15].
Following the procedure described for 1, chiral NC-terpyridine complexes have been obtained from diacetate ruthenium precursors containing chiral diphosphines.Thus, treatment of [Ru(η 2 -OAc) 2 (PPh 3 ) 2 ] with the (R,R)-Skewphos (1 equiv) in cyclohexane at reflux (4 h) results in the formation of the intermediate (2.114(3) Å ) and the Ru1-C7 (2.026(4) Å ) lengths are in line with those of tpy [64,65,66,67], and NC-cyclometalated [65,68,69] ruthenium complexes.The X-ray analysis shows the presence of additional intramolecular π-π interactions between a phenyl group of dppb and the N-coordinated pyridine ring, in agreement with the behavior of 1 in solution with one phenyl displaying an upfield 1 H NMR signal (δH 5.93).Although the "rollover" cyclometalation of tpy, affording a bidentate NC-ligand with a pendant pyridine, has been sparingly described for Pd, Pt and Zn complexes [16,18,20,21], no examples of this type of tpy coordination at ruthenium have been reported.It is worth noting that this ruthenium C-H activation may allow for the functionalization of tpy at the 3′ and 5′ positions of the internal pyridine.[15].
Reaction of the precursor 2 with tpy (1 equiv) in methanol at 55 °C for 1 h results in the formation of the neutral NC-terpyridine derivative [Ru(η 2 -OAc)(NC-tpy)((R,R)-Skewphos)] (4), isolated in 65% yield as a single stereoisomer, as revealed by NMR analysis (Scheme 2).The 31 P{ 1 H} NMR spectrum of 4 in CD2Cl2 shows two doublets at δ 70.6 and 54.0 with a 2 J(P,P) value of 45.0 Hz for the phosphorous trans to the acetate O and N atoms, respectively (Figure S22).The resonances of the terminal H6 and H6″ pyridine protons of tpy are at δH 8.63 and 8.30, the latter showing a long-range coupling with the P atom at δP 54.0.Finally, the broad singlet at δC 184.1 is for the acetate CO and the doublet of doublets at δC 182.4 with 2 J(C,P) = 16.1, and 8.8 Hz is for the cyclometalated Ru-C3′ atom.Also, in this case, the resonance of C4′ is significantly downfield shifted compared to that of the free ligand (Δδ = 15.9)[62].According to the procedure described for 4, the reaction of 3 with tpy affords the acetate [Ru(η 2 -OAc)(NC-tpy)((S,S)-Skewphos)] (5) isolated in 70% yield (Scheme 2).The 31 P{ 1 H} NMR spectrum of 2 in CD 3 OD shows a singlet at δ P 65.9, whereas the 1 H signal at δ H 1.67 is for the two acetate methyl groups, in accordance with a complex of C 2 symmetry.Similarly, the enantiomer [Ru(η 2 -OAc) 2 ((S,S)-Skewphos)] (3) has been prepared from [Ru(η 2 -OAc) 2 (PPh 3 ) 2 ] and (S,S)-Skewphos and isolated in 83% yield (Scheme 2).
Reaction of the precursor 2 with tpy (1 equiv) in methanol at 55 • C for 1 h results in the formation of the neutral NC-terpyridine derivative [Ru(η 2 -OAc)(NC-tpy)((R,R)-Skewphos)] (4), isolated in 65% yield as a single stereoisomer, as revealed by NMR analysis (Scheme 2).The 31 P{ 1 H} NMR spectrum of 4 in CD 2 Cl 2 shows two doublets at δ 70.6 and 54.0 with a 2 J(P,P) value of 45.0 Hz for the phosphorous trans to the acetate O and N atoms, respectively (Figure S22).The resonances of the terminal H6 and H6 ′′ pyridine protons of tpy are at δ H 8.63 and 8.30, the latter showing a long-range coupling with the P atom at δ P 54.0.Finally, the broad singlet at δ C 184.1 is for the acetate CO and the doublet of doublets at δ C 182.4 with 2 J(C,P) = 16.1, and 8.8 Hz is for the cyclometalated Ru-C3 ′ atom.Also, in this case, the resonance of C4 ′ is significantly downfield shifted compared to that of the free ligand (∆δ = 15.9)[62].According to the procedure described for 4, the reaction of 3 with tpy affords the acetate [Ru(η 2 -OAc)(NC-tpy)((S,S)-Skewphos)] (5) isolated in 70% yield (Scheme 2).
The formation of the neutral and cationic tpy chiral ruthenium complexes is summarized in Scheme 4.

TH of Acetophenone Photocatalyzed by Tpy Ruthenium Complexes.
Complexes 1 and 4-7 (S/C = 1000) with NaOiPr have been found to be active in the TH of acetophenone at 30 °C under light irradiation using a solar simulator (Scheme 5), whereas 2, 3, which do not contain tpy, show no activity.The reactions were carried out using 2-propanol as the only hydrogen donor, without sacrificial agents (e.g., triethanolamine) and with no addition of photosensitizers.

TH of Acetophenone Photocatalyzed by Tpy Ruthenium Complexes
Complexes 1 and 4-7 (S/C = 1000) with NaOiPr have been found to be active in the TH of acetophenone at 30 • C under light irradiation using a solar simulator (Scheme 5), whereas 2, 3, which do not contain tpy, show no activity.The reactions were carried out using 2propanol as the only hydrogen donor, without sacrificial agents (e.g., triethanolamine) and with no addition of photosensitizers.S33).Conversely, these derivatives can be easily obtained by reaction of [Ru(η 2 -OAc)2(PPh3)2] with PP and tpy in methanol, by displacement of PPh3 and acetate (Scheme 4).Thus, the facile metalation of the species [Ru(η 2 -OAc)2(PP)] with tpy, compared to [Ru(η 1 -OAc)(η 2 -OAc)(PP)(PPh3)], clearly indicates that the C-H cleavage, which requires a free coordination site, is prevented by the presence of a coordinated triphenylphosphine.It is worth noting that the acetate ligand plays a noninnocent role stabilizing coordinatively unsaturated intermediate species and acting as a weak base for the C-H bond activation, with the solvent (cyclohexane vs. methanol) strongly affecting the resulting products.

TH of Acetophenone Photocatalyzed by Tpy Ruthenium Complexes.
Complexes 1 and 4-7 (S/C = 1000) with NaOiPr have been found to be active in the TH of acetophenone at 30 °C under light irradiation using a solar simulator (Scheme 5), whereas 2, 3, which do not contain tpy, show no activity.The reactions were carried out using 2-propanol as the only hydrogen donor, without sacrificial agents (e.g., triethanolamine) and with no addition of photosensitizers.The cyclometalated 1 photocatalyzes the TH of acetophenone (0.1 M) in 2-propanol with NaOiPr (2 mol %) at 30 • C, affording 93% conversion into 1-phenylethanol in 18 h and with TOF of 83 h −1 (entry 1 of Table 1), whereas in the dark, 1 is completely inactive, affording no significant formation of alcohol (<2 %) at reflux temperature.

Scheme 5. Photocatalytic transfer hydrogenation of acetophenone
With the chiral derivative 4, acetophenone is quantitatively reduced in 2-propanol in 16 h to the alcohol racemate (TOF = 81 h −1 , entry 2), whereas in an iPrOH/MeOH mixture (1/1 in volume), (S)-1-phenylethanol (93% conv.) is formed with 52% ee (TOF = 47 h −1 , entry 3).Conversely, the enantiomer 5 gives (R)-1-phenylethanol (91% conv) with 50% ee in the iPrOH/MeOH mixture, whereas a racemic mixture is obtained in 2-propanol (entries 5 and 4).The cationic NNN-ruthenium complexes 6 and 7 afford 97 and 99% conversion of acetophenone in 9 h with TOF = 136 and 140 h −1 , respectively (entries 6 and 8).By employment of the iPrOH/MeOH (1/1) mixture, 6 affords (S)-1-phenylethanol (92% conv) with 51% ee after 28 h of irradiation, while 7 gives the R-alcohol with 52% ee and 94% conv.(entries 7 and 9).An effect of the media on the catalytic asymmetric reduction of ketones with ruthenium catalysts has been described, resulting in some cases in an inversion of enantioselectivity by changing the polarity and bulkiness of the solvent [4,70].It is worth noting that no reductive pinacol coupling of acetophenone has been observed upon irradiation in the presence of these tpy ruthenium complexes in basic 2-propanol [71].Control experiments show that the neutral NC and cationic NNN complexes 5 and 7 are active only upon irradiation showing an "on/off" behavior and that the conversion follows a zero-order kinetic with respect to the substrate (Figure 3).Based on these results, it is likely that with the NNN-tpy complexes, the photocatalytic TH occurs through the substitution of the coordinated acetate induced by light, affording the isopropoxide species a. Subsequently, the hydride b is formed via a light-driven β-H-elimination, which may occur through displacement of a pyridine moiety, with acetone extrusion [72].The insertion of acetophenone into the Ru-H bond affords the alkoxide c that reacts with 2-propanol, leading to 1-phenylethanol and the isopropoxide a (Scheme 6).Conversely, the use of the cyclometalated NC-tpy derivatives requires the conversion to NNN species.The asymmetric TH of acetophenone with the NC and NNN-tpy ruthenium complexes 4-7 indicates that this reduction takes place Based on these results, it is likely that with the NNN-tpy complexes, the photocatalytic TH occurs through the substitution of the coordinated acetate induced by light, affording the isopropoxide species a. Subsequently, the hydride b is formed via a light-driven β-Helimination, which may occur through displacement of a pyridine moiety, with acetone extrusion [72].The insertion of acetophenone into the Ru-H bond affords the alkoxide c that reacts with 2-propanol, leading to 1-phenylethanol and the isopropoxide a (Scheme 6).Conversely, the use of the cyclometalated NC-tpy derivatives requires the conversion to NNN species.The asymmetric TH of acetophenone with the NC and NNN-tpy ruthenium complexes 4-7 indicates that this reduction takes place through a well-defined and robust chiral photocatalyst, without release of the N and P ligands.

Effects of Ruthenium Complexes on Cell Viability in ATC Cell Lines
Anaplastic thyroid cancer (ATC), while rare, remains one of the deadliest cancers known, showing a median overall survival of 3 months [73].The lack of a standardized treatment protocol for the therapy of this type of neoplasm has resulted in a strong pressure to search for new therapeutic approaches in the cure of this cancer.Several therapeutic strategies were thus developed, ranging from more classical methods such as inhibition of cyclin-dependent kinases [74], to more innovative ones including the use of epigenetic drugs [75][76][77].However, so far, all efforts made in the search for new molecules that can counteract the very high mortality of ATC have often been thwarted by the relative ease with which cancer cells are able to gain drug resistance.For these reasons, the development of new molecules that can increase ATC treatment options is crucial in an effort to extend the life expectancy.A preliminary assessment of the effects of the compounds under consideration involved studying their effectiveness in terms of cell viability.In order to evaluate the antitumor efficacy of ruthenium compounds, they were administered to ATC cells (SW1736 and 8505C) and to a non-tumorigenic thyroid cell line (Nthy-ori 3-1) at increasing doses, and an MTT assay was performed.Once the effects in terms of cell viability were observed, the effective dose 50 (ED 50 ) was calculated by interpolation of the scatter plot curve (dose/effect).The two lines of ATC were similarly sensitive to each of the compounds tested, with the ED 50 spanning from 0.3 to 8 µM, calculated at a 72 h time point (Table 2).Overall, all tested compounds proved less effective at reducing the cell viability of nontumorigenic cells.This is evidenced by the fact that ED 50 in Nthy-ori 3-1 cells was consistently higher than that of SW1736 and 8505C, with increases ranging from 1.4-to 16-fold.Interestingly, compound 7 showed the highest difference between effects in ATC lines and nontumorigenic cells (Table 2).The neutral complexes 1, 4 and 5 show moderate cytotoxicity, with the Skewphos derivatives being more efficient with respect to the dppb one, but no effect of chirality has been observed.For the cationic complexes, 7 bearing (S,S)-Skewphos displays a cytotoxicity (ED 50 = 0.31 µM) four times higher with respect to its enantiomer 6 (ED 50 = 1.39 µM).In addition, the related chloride [RuCl(NNN-tpy)((S,S)-Skewphos)]PF 6 shows a higher ED 50 value of 2.63 µM, indicating that the cell viability depends on the chirality of the complex and the nature of the anionic ligand, with the acetate derivative being more cytotoxic with respect to the chloride one.These chiral tpy acetate compounds show ED 50 2 to 20 times lower than cisplatin, confirming that these derivatives are more efficient than the classical chemotherapy agents in reducing cell viability in ATC cells.Viability effects were also observed on a non-tumor line, although they were significantly less relevant than in ATC cells.Analysis of cell viability alone is not sufficient to formulate hypotheses about the mechanism of action of these molecules, but it is presumable that they act at the level of the cell cycle or cell proliferation.For this reason, noncancer cells also experience their effects even if attenuated, since, as an in vitro model, they are immortalized and subject to a high rate of cell proliferation.The present data on ruthenium compounds on cell viability should be considered as the first step, as well as the starting point of further, more specific and more in-depth studies, aimed at evaluating other biological effects (cell aggressiveness, change in gene expression pattern) as well.Despite the preliminary nature of the results, the evidence of greater efficacy of these compounds than cisplatin is a very encouraging indication, especially considering that one of the main problems in the management of ATC is the high growth rate of this tumor, which makes blocking proliferation necessary as a first approach before enacting more targeted therapies.In addition, the lower ED 50 of the compounds here investigated compared with cisplatin could suggest the use at lower doses, thus limiting the known adverse effects.

General Experimental Information
All reactions were carried out under an argon atmosphere using standard Schlenk techniques.The solvents were carefully dried by standard methods and distilled under argon before use.The ruthenium complexes [RuCl 2 (PPh 3 ) 3 ] [78], [RuCl 2 (dppb)(PPh 3 )] [79] and [Ru(η 2 -OAc) 2 (dppb)] [80] were prepared according to the literature procedures, whereas all other chemicals were purchased from Merck and Strem and used without further purification.NMR measurements were recorded on an Avance III HD NMR 400 spectrometer.Chemical shifts (ppm) are relative to TMS for 1 H and 13 C{ 1 H}, whereas H 3 PO 4 was used for 31 P{ 1 H}.The atom-numbering scheme for the NMR assignment of the terpyridine ligand in the ruthenium complexes is presented in Figure 1.Elemental analyses (C, H, N) were carried out with a Carlo Erba 1106 analyzer, whereas GC analyses were performed with a Varian CP-3380 gas chromatograph equipped with a 25 m length MEGADEX-ETTBDMS-β chiral column, with hydrogen (5 psi) as the carrier gas and flame ionization detector (FID).The injector and detector temperature was 250 • C, with initial T = 95 • C ramped to 140 • C at 3 • C/min for a total of 20 min of analysis.The t R of acetophenone was 7.55 min, while the t R of (R)-and (S)-1-phenylethanol was 10.49 min and 10.71 min, respectively.

Typical Procedure for the Photocatalytic TH of Acetophenone
The ruthenium catalyst solution used for the photocatalytic TH was prepared by dissolving the complexes 1, 4-7 (0.02 mmol) in 2-propanol (5 mL).The catalyst solution (250 µL, 1.0 µmol) and a 0.1 M solution of NaOiPr (200 µL, 20 µmol) in 2-propanol were added subsequently to the acetophenone solution (1.0 mmol) in 2-propanol or a 2-propanol/MeOH (1:1 v/v) mixture (final volume 10 mL).The resulting solutions were stirred in a thermostated water bath at 30 • C. Irradiation of the samples was carried out using a 300 W Xenon Arc Lamp (LSB530A, LOT-Oriel, Darmstadt, Germany), emitting in the range 200-2500 nm (solar simulator).Samples were purged with Ar at least 15 min before irradiation.The reaction was sampled by removing an aliquot of the reaction mixture, which was quenched by the addition of diethyl ether (1:1 v/v), filtered over a short silica pad and submitted to GC analysis.The base addition was considered as the start time of the reaction.The S/C molar ratio was 1000/1, whereas the base concentration was 2 mol% with respect to the ketone substrate (0.1 M).

MTT Cell Viability Assay
In order to test cell viability, we applied the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay as previously described [82].SW1736, 8505C and Nthy-ori 3-1cells (3000 cells/well) were plated onto 96-well plates in 200 µL medium/well and were allowed to attach to the plate for 24 h (t 0 ).Plates were then treated either with DMSO or with each of the different compounds at different concentrations for 72 h.Then, 4 mg/mL MTT (Merck, Darmstadt, Germany) was added to the cell medium, and cells were cultivated for another 4 h in the incubator.The supernatant was removed, 100 µL/well of DMSO (Merck, Darmstadt, Germany) was added, and the absorbance at 570 nm was measured.All experiments were run sixfold and cell viability was expressed as a fold change compared to control.ED 50 was calculated by interpolation of the scatter plot obtained by crossing each dose with its own observed effect.

X-ray Crystallography
Single crystals of the complex 1 were obtained by slow cooling of a concentrated solution of the species in CH 2 Cl 2 /heptane.X-ray diffraction data were collected on a Bruker D8 Venture single crystal x-ray diffractometer equipped with a CPAD detector (Bruker Photon II), an IMS microsource with MoK α radiation (λ = 0.71073 Å) and a Helios optic using the APEX3 Version 2019-1.0software package.For additional details about collection and refining of data, see the Supporting Information.CCDC 2302606 contains the supplementary crystallographic data for this paper.These data are provided free of charge by The Cambridge Crystallographic Data Centre.

Conclusions
In summary, we have reported a straightforward preparation of a rare example of NC-cyclometalated terpyridine complexes [Ru(η 2 -OAc)(NC-tpy)(PP)] (PP = dppb, Skewphos) from the acetate compounds [Ru(η 2 -OAc) 2 (PP)] and tpy, the chiral derivatives being isolated as single stereoisomers.Conversely, the cationic NNN-terpyridine derivatives [Ru(η 1 -OAc)(Skewphos)(NNN-tpy)]OAc are prepared from [Ru(η 2 -OAc) 2 (PPh 3 ) 2 ], Skewphos and tpy.The neutral NC-tpy and the cationic NNN-tpy complexes catalyze the transfer hydrogenation of acetophenone under light irradiation at 30 • C and with an enantioselectivity of 50-52% with the chiral phosphine and using an iPrOH/MeOH mixture.The tpy complexes have proven to be cytotoxic against the anaplastic thyroid cancer 8505C and SW1736 cell lines, with ED 50 values ranging from 0.31 to 8.53 µM.The NNN-tpy derivative with (S,S)-Skewphos displays an ED 50 = 0.31 µM, four times higher compared to its enantiomer.Further studies are ongoing to broaden the chemistry of chiral ruthenium complexes based on polypyridine and phosphine ligands for photocatalytic transformations and for their use as metallodrugs.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules29092146/s1:copies of NMR spectra of the isolated complexes 1-7 and mechanistic NMR studies, X-ray diffraction parameters of compound 1, GC-FID chromatograms related to the catalytic reactions promoted by the ruthenium derivatives and diagrams that demonstrate the effect of complex on cell viability in ATC cells.References [83][84][85][86][87][88][89][90] are cited in the supplementary materials.

Scheme 4 .
Scheme 4. Pathways of the formation of the neutral and cationic tpy ruthenium complexes, with the proposed intermediates in the blue boxes.

Scheme 4 .
Scheme 4. Pathways of the formation of the neutral and cationic tpy ruthenium complexes, with the proposed intermediates in the blue boxes.
a Irradiation hours.b The conversions and ee were determined by GC analysis.c Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion.