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Article

1,10-Phenanthroline and 4,5-Diazafluorene Ketones and Their Silver(I) and Platinum(II) Complexes: Syntheses and Biological Evaluation as Antiproliferative Agents

by
Leonardo Sandin-Mazzondo
1,
Jesús M. Martínez-Ilarduya
1,
Jesús A. Miguel
1,
Camino Bartolomé
1,* and
Concepción Alonso
2,*
1
IU CINQUIMA/Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, 47071 Valladolid, Spain
2
Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del País Vasco, 01006 Vitoria-Gasteiz, Spain
*
Authors to whom correspondence should be addressed.
Inorganics 2025, 13(1), 6; https://doi.org/10.3390/inorganics13010006
Submission received: 27 November 2024 / Revised: 21 December 2024 / Accepted: 24 December 2024 / Published: 28 December 2024
(This article belongs to the Special Issue Noble Metals in Medicinal Inorganic Chemistry)
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Versions Notes

Abstract

:
Using non-classical polyfluorophenyl ligands in Pt(II) complexes and other transition metals such as silver is a promising approach in the search for more effective and safer antitumoral drugs. In this work, a series of chelating N-donor ligands with 1,10-phenanthroline and 4,5-diazafluorene backbones and ketone groups were synthesized (1,10-phenanthroline-5,6-dione, 1; (R/S)-6-hydroxy-6-(2-oxypropyl)-1,10-phenanthroline-5(6H)-one, 2; 4,5-diazafluoren-9-one, 3; 9-hydroxy-9-(2-oxypropyl)-4,5-diazafluorene, 4). The corresponding [Ag(N,N)2]NO3 (1Ag–4Ag) and [Pt(C6F5)2(N,N)] (1Pt–4Pt) complexes were prepared. The stability of these complexes in DMSO solution was studied, showing no dissociation over 48 h for almost all complexes, except 3Pt. The compounds were characterized by NMR (1H, 13C, and 19F), MS, and X-ray diffraction (2, 4, 1Ag, 3Ag, 1Pt, and 3Pt). A study of the cytotoxicity of the compounds in lung carcinoma (A-549) and fetal lung fibroblast (MRC-5) cell lines was performed. Compounds 1, 2, 1Ag, 2Ag, 3Ag, 1Pt, 3Pt, and 4Pt were more active against A-549 cells than cisplatin. Complexes 3Ag and 1Pt showed an acceptable SI and better selectivity than cisplatin, proving that silver(I) complexes and Pt(polyfluorophenyl) complexes are valuable options in searching for new antitumoral drugs.

1. Introduction

Cancer is a complex disease that is responsible for almost one in six deaths (16.8%). In the year 2022, there were nearly 20 million new cases of cancer, and 9.7 million deaths were caused by this disease [1]. It is predicted that the number of new cases of cancer will reach 35 million by the year 2050 [1]; thus, the search for new antitumoral drugs is of paramount importance.
Coordination complexes have been of great interest in cancer research since the approval of cisplatin (I, Figure 1) as an antitumoral drug [2]. After the discovery of cisplatin, other coordination compounds such as carboplatin (II, Figure 1) and oxaliplatin (III, Figure 1) have been approved for the treatment of several solid cancers; however, these compounds show several side effects, such as nephrotoxicity, myelosuppression, or neurotoxicity [3], and all the existing platinum anticancer drugs encounter drug resistance [4,5].
The classic approach for the development of new active Pt(II) complexes is based on the model [PtA2X2], where A acts as a non-labile nitrogen donor ligand and X− as a labile anionic leaving group, with the possibility of A2 and X2 to be bidentate ligands [6]. Some relevant examples of platinum complexes with these kinds of leaving groups that have shown cytotoxicity, as well as the cell lines in which they have been active, are listed in Table 1 (complexes IV–VII).
Additionally, our research group has focused on complexes bearing polyfluorophenyl groups, especially for catalysis and mechanistic studies [11]. Recently, we described the antitumoral properties of Au(I) complexes bearing a pentafluorophenyl ring and phosphine sulfide ligands [12]. The application of polyfluorophenyl groups in Pt(II) complexes as antiproliferative agents has also been previously described. Table 2 shows the structure of some polyfluorophenylplatinum(II) complexes whose activity has been demonstrated (complexes VIII–XV).
These Pt(II) complexes do not follow the classical structure–activity relationship since at least one of the typical leaving ligands (chloride or carboxylates for example) is replaced with the relatively inert polyfluorophenyl group. As a result, these complexes are bulkier, kinetically inert, and acid-stable; therefore, they would be less reactive toward other biomolecules, causing fewer side effects, and are more lipophilic, which enhances cellular penetration [14].
Besides platinum, other transition metals have received attention due to their antiproliferative activities, such as gold, ruthenium, and silver, among others [17]. Silver has been used in medicinal applications since ancient times due to its antibacterial properties. Nowadays, the antibiotic silver sulfadiazine is employed as a topical drug in treating burn wounds [18]. In addition to antibacterial effects, silver compounds have also exhibited antifungal and antitumoral activities. The mechanism through which silver compounds exert their biological effects is complex and has not been fully elucidated. The antitumoral activity of silver compounds might involve the generation of reactive oxygen species (ROS), DNA binding and cleavage, topoisomerase inhibition, or apoptosis induction [19]. A great variety of silver(I) complexes with N-, O-, P-, S-donor ligands, or N-heterocyclic carbenes have proven toxic to cancerous cells [18,19]. Regarding N-donor ligands, the 2,2′-bipyridine moiety has been widely explored and has given many active coordination compounds, and some of them are listed in Table 3.
Another interesting ligand that contains the 2,2′-bipyridine moiety is 4,5-diazafluorene (compound XXI, Figure 2). This compound and its derivatives have a five-membered central ring that provides different coordination properties in comparison with phenanthrolines or 2,2′-bipyridine itself. The biological applications of such ligands are scarce. Only a few examples of complexes with 4,5-diazafluorene derivatives with antitumoral properties are found in the literature, and some of them are depicted in Figure 2. Compounds XXII and XXIII showed in vivo tumor growth inhibition in mice [23]. Mixed ligand silver(I) complex XXIV (Figure 2) has proven to be active against breast carcinoma cell line (MCF-7), and DNA and Topoisomerase I were proposed to be its biological targets [24].
Due to the promising activities reported for N-donor silver(I) complexes and polyfluorophenylplatinum(II) complexes, in this work, we proposed the synthesis and the biological evaluation of a series of chelating N-donor ligands with 1,10-phenanthroline and 4,5-diazafluorene backbones and their corresponding silver(I) and bis(pentafluorophenyl)platinum(II) complexes as potential antiproliferative drug candidates (Scheme 1). The ligands and, thus, the complexes proposed bear ketone groups, which can lead to further interactions with biomolecules and increase their water solubility.

2. Results and Discussion

2.1. Synthesis and Characterization of Ligands

Ligands 2–4 were synthesized following the synthetic route shown in Scheme 2 from 1,10-phenanthroline-5,6-dione (1). The decarbonylation of 1 under basic conditions affords 4,5-diazafluoren-9-one (3) [25,26]. Both compounds (1, 3) have ketone groups in their structure that can undergo aldol addition reactions. Compounds 1 and 3 react with acetone in the presence of alumina as a catalyst [27]. The conversion of 1 into 2 is nearly quantitative, whereas 3 and 4 reach an equilibrium. The first conversion can be understood in terms of product solubility as compound 2 is poorly soluble in acetone and shifts the reaction to the right. Compound 4 has a greater solubility in acetone and it does not precipitate in reaction media. In addition, in 1, the two adjacent ketone groups can act as an electron-withdrawing group to each other, thus, they might be more electrophilic than the carbonyl group in 3.
Ligand 3 was characterized by 1H-NMR [26]. Ligands 2 and 4 were characterized by NMR (1H and 13C{1H}), ESI-TOF mass spectrometry, and additionally, their structure has been confirmed by single-crystal X-ray diffraction (see Figures S32 and S33, Supplementary Materials). The 1H-NMR of compound 2 confirms that the symmetry of the molecule is lost, and, consequently, all the hydrogens of the two pyridine moieties are inequivalent and the hydrogens of the methylene group are diastereotopic (see Figure S3, Supplementary Materials). The aldol reaction on 1 generates a chiral center, thus, compound 2 is obtained as a racemic mixture. In the case of 4, the hydrogen signals of the bipyridine moiety are equivalent, as well as the hydrogens of the methylene group (see Figure S6, Supplementary Materials).

2.2. Synthesis and Characterization of Ag(I) Complexes

The reaction of the compounds 1–4 with AgNO3 in a 2:1 mol ratio yielded complexes 1Ag–4Ag (Scheme 3). All the complexes have been characterized by ESI-TOF mass spectrometry and NMR spectroscopy (see Section 3 Materials and Methods).
The MS data confirm the proposed [Ag(Ligand)2]+ stoichiometry. The presence of the two isotopes of nearly equal abundance of silver, 107Ag (51.8%) and 109Ag (48.2%), are observed in the MS spectra of the complexes. The characteristic isotopic peak doublet with almost equal intensity in the ESI-TOF mass spectra of the complexes 1Ag–4Ag agrees with the proposed mononuclear species (see Figure S28, Supplementary Materials for ESI-TOF mass spectrum of complex 2Ag).
The 1H-NMR spectra for the silver complexes 1Ag–4Ag are different from those of the free ligands. Figure 3 shows the 1H-NMR spectra of both 4 and the corresponding complex 4Ag registered in DMSO-d6. The chemical shifts of the bipyridine hydrogens of the ligands appear deshielded after coordination to the metal center, especially Hb and Hc. This change in the chemical shift is also observed in the hydrogen of the hydroxyl group of 2Ag and 4Ag. The NMR data for 1Ag and 3Ag agree with those previously reported for [Ag(1,10-phenanthroline-5,6-dione)2]PF6 [22] and [Ag(4,5-diazafluoren-9-one)2]NO3 [28], respectively.
Given that in the synthesis of complex 2Ag, the starting material ligand 2 is a racemate, the product obtained is a mixture of diastereoisomers since each enantiomer of 2 has the same capability of coordinating to silver. The distance between the aromatic hydrogens and the chiral center does not allow for differentiation of the signals corresponding to the different expected diastereoisomers (25% of the complex (R,R), 25% of its enantiomer (S,S), and 50% of the (R,S) meso complex).
The X-ray diffraction structure of 1Ag (Figure 4) confirms the expected coordination of two units of the ligand.
The four Ag-N bond lengths (Å) for 1Ag are listed in Table 4. Although the crystal structure of the analogous [Ag(1,10-phenanthroline-5,6-dione)2]PF6 was already reported [22], in our case, the asymmetric unit of 1Ag also has one molecule of H2O and one of MeOH (Figure 4; for structural details see Figure S43 and Table S3, Supplementary Materials). In both cases, the cationic complexes display a distorted tetrahedral geometry, and similar bond lengths and angles have been found.
Two different polymorphs were obtained for 3Ag. In crystal structure A depicted in Figure 5) the NO3− acts as a ligand and binds to the metal center through one of the oxygens, and the adopted geometry is distorted square pyramidal. In addition, the asymmetrical unit has two slightly different molecules (see Figure S45 and Table S4, Supplementary Materials), although only one is depicted in Figure 5 for clarity purposes.
In crystal structure B (Figure 5, right), the NO3− is coordinated to silver in a distorted trigonal bipyramidal structural environment. A similar structure to the latter has already been reported [29]. Selected bond lengths (Å) and angles (deg) for the two different polymorphs are collected in Table 5.

2.3. Synthesis and Characterization of Pt(II) Complexes

The reaction of the compounds 1–4 with [Pt(C6H5)2(THF)2] in a 1:1 mol ratio yielded complexes 1Pt–4Pt (Scheme 4). All the complexes have been characterized by ESI-TOF mass spectrometry and NMR spectroscopy (see Section 3, Materials and Methods).
The 1H-NMR spectra for the Pt(II) complexes confirm the coordination of the ligands to the metal center. Figure 6 shows the 1H-NMR spectra of 1 (spectrum a) and the corresponding complex 1Pt (spectrum b). The chemical shifts of the hydrogens Hb and Hc of the ligands appear deshielded after coordination, whereas for Ha its chemical shift decreases. The X-ray structures of 1Pt and 3Pt (Figure 7) allow us to justify this fact since the Ha hydrogens point toward the center of the pentafluorophenyl rings, which causes a shielding of the signal. Of particular interest are the 1H-NMR spectra of complexes 1Pt and 2Pt (see Figure 6, spectra b and c), in which the hydrogens closest to the nitrogens Ha (and Ha* for 2Pt) have signals with a broad base, which correspond to the 195Pt satellites, confirming the coordination through the N atoms.
The 19F-NMR spectra give information about the structural symmetry of the N,N-ligand. In complex 1Pt, the two pentafluorophenyl rings are equivalent, and a set of signals is observed that corresponds to the Fo, Fm, and Fp (Figure 7, spectrum a). The four F in the ortho position are the most deshielded ones, their multiplicity is a multiplet and the characteristic 195Pt satellites are observed. The four F in the meta position correspond to the most shielded signal, multiplets with a broad base due to the 195Pt satellites. The two F in the para position give a triplet and no 195Pt satellite is observed. In complex 2Pt, the asymmetry of the N,N-ligand makes the two C6F5 inequivalent, and, consequently, two sets of signals are observed—one for each aryl group (Figure 7, spectrum b). Thus, the Fp gives two different signals, two triplets with close chemical shifts. The signals of Fo are overlapped and the same is observed for the Fm. The complex 4Pt 19F-NMR spectrum shows a different scenario (Figure 7, spectrum c): the two pentafluorophenyl rings are equivalent, which justifies the fact that only one signal is observed in 19F-NMR for the Fp. However, as the coordination plane is not a plane of symmetry, the two Fo and the two Fm of each fluorinated aryl are chemically inequivalent, giving rise to two signals.
Regarding chirality, it is necessary to highlight that complex 2Pt is a racemate.
The X-ray diffraction structures of 1Pt and 3Pt are depicted in Figure 8, left and right, respectively. Selected bond lengths (Å) and angles (deg) are collected in Table 6. In both structures, the fluorinated rings are almost perpendicular to the coordination plane, with angles of 69.84(16)° and 64.26(14)° for 1Pt and 58.05(15)° and 75.28(16)° for 3Pt, forcing the aromatic hydrogen Ha of the ligand to point toward the center of the fluorinated rings.
In both cases, Pt-N and Pt-Cipso distances are similar to those found for [PtPf2(bipy)] [30].
In 1Pt, Pt-N distances are longer than those found for [PtCl2(1,10-phenanthroline-5,6-dione)] as a consequence of the higher trans influence of the C6F5 group than the Cl ligand [31]. Elongation of the distances is also observed in 3Pt compared to those observed for [PtCl2(4,5-diazafluoren-9-one)] [32].

2.4. Stability of the Ag(I) and Pt(II) Complexes in DMSO

The solution behavior of the Ag(I) and Pt(II) complexes was studied by 1H-NMR spectroscopy. The complexes were dissolved in DMSO-d6 in a 5 mM concentration and spectra were recorded immediately, after 24 h, and after 48 h standing in the dark at room temperature. The 1H-NMR spectra of all Ag(I) complexes remained unmodified over 48 h and no free ligand was observed. These complexes are stable in solution and no coordination of DMSO to Ag(I) was observed. Figures S29 and S30 (Supplementary Materials) show the aromatic region of the 1H-NMR spectra of the free ligand 2 vs. 2Ag and 4 vs. 4Ag, respectively, registered at room temperature in DMSO-d6 at different times. The Pt(II) complexes 1Pt, 2Pt, and 4Pt are stable in DMSO solution, no free ligand was observed in the experiment conditions. Figure S31 (Supplementary Materials) shows the 1H-NMR spectra of the free ligand 4 vs. 4Pt at the tested times. The scenario for complex 3Pt was much more complicated since a solvolysis reaction was observed in the experiment.
The 1H-NMR of 3Pt (see Figure S32, Supplementary Materials)—registered immediately after dissolving the compound in DMSO-d6—indicated the presence of two species. After 24 h, a third compound, which corresponded to the free ligand 3, was detected. After 48 h, no new chemical species were observed. The 19F-NMR spectra were crucial to identifying the components of the solvolysis reaction (see Figure S33, Supplementary Materials), especially the F signal in the para position. In the 19F-NMR spectra of complex 3Pt immediately after dissolution in DMSO-d6 (Figure 9, spectrum a), three triplets were observed in the region of Fp signals. Two of these signals have the same integration values, which indicates they might be signals of the same compound and suggests that this compound is asymmetrical. In the 19F-NMR spectra of the complex 24 h after dissolution in DMSO-d6 (Figure 9, spectrum b), a new signal arises that corresponds to [Pt(C6F5)2(DMSO)2]. The complex [Pt(C6F5)2(DMSO)2] can be synthesized in situ in the NMR sample tube by dissolving [Pt(C6F5)2(THF)2] in DMSO-d6 (Figure 9, spectrum c). The detection of this compound is in agreement with the detection of free ligand 3 in the 1H-NMR.
The species proposed to be present in the solvolysis mixture of 3Pt are depicted in Figure 10. The detection of free ligand 3 and [Pt(C6F5)2(DMSO)2] indicates that DMSO can displace the two coordination positions of ligand 3 in complex 3Pt. The asymmetric species detected should be the product in which DMSO has substituted only one coordination position (structure 3Pt-DMSO, Figure 10). Lastly, the other species detected immediately after dissolution might correspond to complex 3Pt. After 48 h of dissolution of complex 3Pt 5 mM in DMSO, the concentrations of the species are 0.65 mM for compound 3Pt-DMSO, 1.55 mM for 3Pt, 2.8 mM for ligand 3, and 2.8 mM for [Pt(C6F5)2(DMSO)2] (calculated by 1H and 19F-NMR signal integration).

2.5. Stability of the Ag(I) and Pt(II) Complexes in DMSO-d6:H2O

To study the stability of the complexes in conditions closer to physiological ones, the complexes were dissolved in DMSO-d6:H2O (3:1) in a 2.5 mM concentration, and spectra were recorded immediately, after 24 h, and after 48 h standing in the dark at 37 °C. Complexes 2Ag, 3Ag, 4Ag, 2Pt, and 4Pt remained unmodified over 48 h, and no free ligand was observed. Figures S34 and S35 (Supplementary Materials) show the aromatic region of the 1H-NMR spectra of the free ligand 4 vs. 4Ag and 2 vs. 2Pt, respectively, under these experimental conditions. Complex 3Pt, as analogously observed in DMSO, experiences solvolysis. Figures S36 and S37 (Supplementary Materials) show the NMR spectra for this experiment. Under this scenario, at least five species are detected by NMR, which include complex 3Pt, ligand 3, [Pt(C6F5)2(solvent)2] (solvent: DMSO, and/or H2O), and the other two species are proposed to be 3Pt-DMSO and 3Pt-H2O (the two possible species in which DMSO or water have substituted only one coordination position).
Complexes 1Ag and 1Pt show a new scenario. Ligand 1 in DMSO:H2O (3:1) shows two species in the 1H-NMR spectrum (see Figure 11), whereas in pure DMSO, only one species is detected. This indicates that the ligand reacts with water. The water solution behavior of ligand 1 has already been studied [27] and it was found that the hydration reaction takes place at a pH near neutrality; thus, we hypothesize that in the DMSO:H2O mixture, ligand 1 is in equilibrium with its hydrated form 1-H2O (see Figure 11).
For complex 1Ag, the 1H-NMR spectra for these experimental conditions (see Figure S38, Supplementary Materials) indicate that both ligand 1 and its hydration form (1-H2O) are coordinated to Ag, and neither of the two free ligands are observed; thus, equilibrium between complex 1Ag and the hydrated form 1Ag-H2O occurs. The NMR data indicate that 1Ag is the predominant species. For complex 1Pt, the NMR data prove that no decoordination has occurred since neither [Pt(C6F5)2(solvent)2] nor free ligands 1 or 1-H2O are detected, and that at least three species coexist. The NMR data are complicated and it is not possible to be certain of the structure of these species; however, based on the hydration reaction that takes place for the ligand 1 and complex 1Ag, it is reasonable to propose an equilibrium of 1Pt, its hydrated form 1Pt-H2O, and the double-hydrated form 1Pt-2H2O (Figure 12). The hydration of a complex with 1,10-phenanthroline-5,6-dione as a ligand has been previously reported for [Ru(phen)2(1,10-phenanthroline-5,6-dione)]2+, in fact, the authors indicate that the hydrated form is the biologically active form of the complex [33].
It is also important to highlight that no hydrolysis (C6F5H) nor reductive elimination product (C12F10) are observed in any of the stability tests in DMSO:H2O of the Pt(II) complexes, indicating that the pentafluorophenyl ligand does not act as a leaving group or it is kinetically inert.

2.6. In Vitro Cytotoxicity

The cytotoxicity of the ligands and the complexes was investigated in vitro by testing the antiproliferative activities against the A-549 cell line (carcinomic human alveolar basal epithelial cells). The cell counting kit (CCK8) assay was employed to assess the growth inhibition, and the cell proliferation inhibitory activities of the compounds are shown in Figure 13 and Table 7 as pIC50 and IC50 values, respectively. NH4NO3 was tested as a negative control for nitrate counterion evaluation. No cytotoxicity was observed (Table 7, entry 14), which proves that nitrate does not contribute to the activity of silver(I) complexes. Cisplatin was tested as a reference compound.
Figure 13 shows that phenanthroline-type ligands displayed cytotoxic activity against A-549 cells with IC50 values in the low micromolar range (Table 7, entries 1 and 2). The aldol addition of acetone to compound 1 does not affect its antiproliferative activity since both compounds 1 and 2 have similar IC50 values. The 4,5-diazafluorene-type ligands, compounds 3 and 4, are not toxic on A-549 cells (Table 7, entries 3 and 4). The coordination with silver led to a slight improvement in the activity of complex 1Ag compared to the ligand. The IC50 values observed for ligand 1 and complex 1Ag are similar to those reported for compound 1 and [Ag(1,10-phenanthroline-5,6-dione)2]ClO4 in other cell lines—human kidney adenocarcinoma (A-498) and human hepatocellular carcinoma (Hep-G2) [34]. Complex 2Ag maintains the same activity as the ligand. Compounds 1Ag and 2Ag are slightly more potent than the structurally similar complex [Ag(phen)2]AcO (IC50 = 5.4 μM in A-549) [35]. In the case of the non-active ligands, their coordination with silver gave life to active compounds, complexes 3Ag and 4Ag, with 3Ag being much more toxic with an IC50 of 6.25 ± 1.15 μM. Complex 3Ag has already been described as a DNA intercalator [29], with a DNA affinity bigger than for the free ligand [28]. With these in hand, we can observe that the coordination with silver(I) led to an improvement or maintenance in activity. Among the silver complexes, complex 1Ag is the most toxic with an IC50 of 0.67 ± 0.30 μM.
Regarding the Pt complexes, the coordination of phenanthroline-type ligands to Pt—complexes 1Pt and 2Pt—led to complexes less active than the ligands but still more potent than [PtCl2(phen)] (with an IC50 in the range of 40–80 μM in A-549 cells) [36]. The coordination with Pt of the 4,5-diazafluorene-type ligands surprisingly led to active complexes, complexes 3Pt and 4Pt, with IC50 values below 3 μM. It is important to highlight that all the Pt complexes are active, which reinforces the use of pentafluorophenyl as a viable alternative to classical leaving groups in Pt(II) bioactive complexes. Complex 3Pt is the most toxic Pt complex, with an IC50 of 0.94 ± 0.71 μM. Still, this IC50 value should be compared with caution to others because the cells were exposed to the solvolysis product of 3Pt with DMSO and H2O; thus, it was a mixture of complexes 3Pt, 3Pt-DMSO, 3Pt-H2O, [Pt(C6F5)2(solvent)2], and ligand 3 (see Section 2.4 and Section 2.5). Among the components of this mixture, ligand 3 does not contribute to the cytotoxic activity since its IC50 is greater than 50 μM (Table 7, entry 3). In addition, it is noteworthy to remember that ligand 1 and complexes 1Ag and 1Pt experience hydration in water media, therefore, cells are exposed to an equilibrium of the compounds in ketone form and their hydrated counterparts. Furthermore, it is necessary to mention the compounds with chirality—compounds 2, 2Ag, and 2Pt. The IC50 reported for 2 and 2Pt correspond to the racemic mixture and the value reported for 2Ag to the diastereomeric mixture, and since these three determinations show cytotoxic activity, enantiomeric and diastereomeric separations might be of interest for future research. Finally, a remarkable observation is that eight of the compounds—1, 2, 1Ag, 2Ag, 3Ag, 1Pt, 3Pt, and 4Pt—are more toxic than the reference cisplatin.
In the second step of the biological evaluation, those compounds that showed antiproliferative activity in the A-549 cells were then tested on the MRC-5 non-malignant lung fibroblasts for studying selective toxicity. New candidates for antitumoral therapy should have low toxicity to non-cancerous cells (high IC50 values) but high cytotoxicity (low IC50 values) to cancerous cells. To study the selectivity of the compounds synthesized, the selectivity index (SI) was calculated following Equation (1).
SI = (IC50 MRC-5)/(IC50 A-549)
Those compounds with an SI greater than three are considered highly selective for that cancer cell line [37]. For compounds that are non-cytotoxic to MRC-5 cells (IC50 > 50 μM), they are assigned an SI greater than the value calculated assuming an IC50 = 50 μM. Regarding the ligands, none of the two active ligands (compounds 1 and 2) are selective, on the contrary, they have proven to be more toxic to MRC-5 cells (Table 7, entries 1 and 2). Among silver complexes, only complex 3Ag has an acceptable SI of 3.2 (Table 7, entry 7). For Pt complexes, only complex 1Pt has proven to be selective, with the greatest SI of all compounds tested (SI > 6.1, Table 7, entry 9). It is worth mentioning that the clinically approved antitumoral drug cisplatin did not exhibit enough selectivity for the lung cancerous cell line (Table 7, entry 13), thus, the selective profile of compounds 3Ag and 1Pt are noteworthy.

3. Materials and Methods

3.1. Chemicals

1,10-phenantroline-5,6-dione was purchased from BLD Pharm. Alumina, acetone, chloroform, dichloromethane, tetrahydrofuran, methanol, and diethyl ether were bought from Fisher Chemical. n-Hexane and n-pentane were purchased from Carlo Erba. Ethyl acetate was bought from Dávila Villalobos. NaOH and dimethylsulfoxide were acquired from Panreac AppliChem. MgSO4 was purchased from Scharlau. AgNO3 and silica were bought from Merck. Deuterated solvents were purchased from Cortecnet.

3.2. Measurements

All NMR spectra were recorded at 25 °C on Bruker Avance III 400 MHz (1H at 399.87 MHz, 13C at 100.56 MHz, and 19F at 376.22 MHz) and Agilent 500 NMR (1H at 499.72 MHz, 13C at 125.67 MHz, and 19F at 470.17 MHz) spectrometers. Chemical shifts are reported in ppm (δ) and scalar couplings are reported in Hertz. The MS data correspond to the monoisotopic neutral mass.
For X-ray crystallography analysis, a crystal was attached to a glass fiber and transferred to an Agilent Supernova diffractometer with an Atlas CCD area detector (LTI, University of Valladolid). Data collection was performed with Mo Kα radiation (λ = 0.71073 Å) or Cu Kα (λ = 1.54184 Å). Data integration, scaling, and empirical absorption correction were carried out using the CrysAlisPro program package [38]. The crystals were kept at 293 K during data collection. Using Olex 2 [39], the structure was solved with the olex2.solve [40] program and refined with the Shelx program [41]. The non-hydrogen atoms were refined anisotropically, and hydrogen atoms were placed at idealized positions and refined using the riding model. The refinement proceeded smoothly to give the residuals shown in the Supplementary Materials. CCDC 2405306-2405312 contains the supporting crystallographic data for this paper.

3.3. Synthesis of Ligands

3.3.1. Synthesis of (R/S)-6-Hydroxy-6-(2-oxypropyl)-1,10-phenanthroline-5(6H)-one (2)

Compound 2 was synthesized following the synthetic route described in the literature with some modifications [27]. In a 250 mL flask, compound 1 (300 mg, 1.43 mmol) and 300 mg of alumina (2.94 mmol) were stirred with 75 mL of acetone for 48 h at room temperature. The product precipitated in reaction media. The mixture was centrifuged at 4000 rpm for 5 min. The supernatant was discarded, 40 mL of chloroform was added, and the suspension was stirred for 10 min and centrifuged. The supernatant was dried with MgSO4 and filtered. The solvent was removed under vacuum and a white solid was obtained (yield: 90%). Single crystals suitable for X-ray diffraction were obtained from the slow diffusion of a chloroform-concentrated solution of the compound into n-hexane. 1H-NMR (499.72 MHz, CDCl3) δ: 9.07 (dd, J = 4.7, 1.8 Hz, 1H), 8.84 (dd, J = 4.7, 1.7 Hz, 1H), 8.31 (dd, J = 7.8, 1.8 Hz, 1H), 8.13 (dd, J = 7.9, 1.7 Hz, 1H), 7.52 (dd, J = 7.7, 4.7 Hz, 1H), 7.45 (dd, J = 7.9, 4.7 Hz, 1H), 4.48 (s, 1H), 3.11 (A part of AB spin system, JHA-HB = 15.3 Hz, 1H), 2.90 (B part of AB spin system, JHA-HB = 15.3 Hz, 1H), 2.12 (s, 3H). 13C{1H}-NMR (100.56 MHz, CDCl3) δ: 204.86, 199.95, 155.75, 153.44, 150.50, 146.95, 136.89, 135.45, 134.04, 126.39, 124.91, 124.81, 77.78, 55.18, 31.91. MS calculated for C15H12O3N2Na1—291.075 ([M+Na]+), found—291.0735.

3.3.2. Synthesis of 4,5-Diazafluoren-9-one (3)

4,5-diazafluoren-9-one (3) was synthesized following the synthetic routes described in the literature [25,26].
1H-NMR (499.72 MHz, CDCl3) δ: 8.79 (dd, J = 5.0, 1.5 Hz, 2H), 7.98 (dd, J = 7.6, 1.5 Hz, 2H), 7.34 (dd, J = 7.6, 5.0 Hz, 2H).

3.3.3. Synthesis of 9-Hydroxy-9-(2-oxypropyl)-4,5-diazafluorene (4)

In a 250 mL flask, compound 3 (300 mg, 1.65 mmol) and 300 mg of alumina (2.94 mmol) were stirred with 60 mL of acetone for 1 week at room temperature. Every two days, a new portion of 0.5 mmol of alumina was added. The mixture was centrifuged at 4000 rpm for 5 min. The supernatant was removed and the solid was stirred with 30 mL of chloroform for 10 min. The mixture was centrifuged again and the supernatant was combined with the first portion. The organic solution was dried with MgSO4 and filtered. The solvent was removed under reduced pressure. The residue, which contained a mixture of 3 and 4, was purified by column chromatography using a mixture of ethyl acetate–tetrahydrofuran (5:2) as the mobile phase and silica as the stationary phase to afford compound 4 as a light yellow solid (yield: 51%). Single crystals suitable for X-ray diffraction were obtained from the slow diffusion of a chloroform-concentrated solution of the compound into n-hexane. 1H-NMR (499.72 MHz, CDCl3) δ: 8.65 (m, 2H), 7.89 (m, 2H), 7.25 (ddd, J = 7.7, 4.9, 1.3 Hz, 2H), 5.11 (s, 1H), 3.08 (s, 2H), 2.22 (s, 3H). 13C{1H}-NMR (125.67 MHz, CDCl3) δ: 210.18, 157.20, 151.33, 142.71, 131.74, 123.66, 76.97, 50.66, 31.55. MS calculated for C14H12O2N2Na1—263.0791 ([M+Na]+), found—263.0797.

3.4. Synthesis of Ag(I) Complexes

3.4.1. Synthesis of [Ag(1,10-phenanthroline-5,6-dione)2]NO3 (1Ag)

Compound 1Ag was synthesized following the synthetic route described in the literature with some modifications [22]. Compound 1 (200 mg, 0.950 mmol) was dissolved in 50 mL of acetone in a flask. In a vial, AgNO3 (80.8 mg, 0.475 mmol) was dissolved in 2 mL of water and, then, 4 mL of acetone was added. The silver solution was mixed and added dropwise under continuous stirring to the ligand solution shielding it from light. A solid was then formed. The suspension was stirred for 1 h protecting it from light. The solid was filtered, washed with n-pentane, and dried (yield: 67%). Single crystals suitable for X-ray diffraction were obtained from the slow evaporation and cooling of a hot methanol-concentrated solution of the compound. 1H-NMR (499.72 MHz, DMSO-d6) δ: 8.98 (dd, J = 4.8, 1.7 Hz, 4H), 8.55 (m, 4H), 7.84 (m, 4H). 13C{1H}-NMR (100.56 MHz, DMSO-d6) δ: 177.20, 154.88, 150.10, 137.29, 130.44, 127.06. MS calculated for [C24H12O4N4Ag]+—526.9904, found—526.9914.

3.4.2. Synthesis of [Ag((R/S)-6-Hydroxy-6-(2-oxypropyl)-1,10-phenanthroline-5(6H)-one)2]NO3 (2Ag)

Compound 2 (47.5 mg, 0.177 mmol) was dissolved in 10 mL of dichloromethane. Then, AgNO3 (14.9 mg, 0.088 mmol) was added. The mixture was stirred overnight at room temperature while shielding it from light. Afterward, the solvent was partially removed under reduced pressure and n-hexane was added until precipitation was observed. The yellow solid was washed with n-hexane and dried (yield: 44%). Two different crystal structures were obtained from the solutions of 2. Crystal structure A: single crystals suitable for X-ray diffraction were obtained from the slow diffusion of a methanol-concentrated solution of the compound into diethyl ether. Crystal structure B: single crystals suitable for X-ray diffraction were obtained from the slow diffusion of a chloroform-concentrated solution of the compound into hexane. 1H-NMR (399.87 MHz, DMSO-d6) δ: 9.02 (dd, J = 4.8, 1.7 Hz, 2H), 8.74 (dd, J = 4.8, 1.5 Hz, 2H), 8.53 (d, J = 7.8 Hz, 2H), 8.35 (d, J = 8.0, 2H), 7.86 (dd, J = 7.8, 4.8 Hz, 2H), 7.75 (dd, J = 8.0, 4.8 Hz, 2H), 6.65 (s, 2H), 3.74 (A part of AB spin system, JHA-HB = 17.6 Hz, 2H), 3.65 (B part of AB spin system, JHA-HB = 17.6 Hz, 2H), 2.01 (s, 6H). 13C{1H}-NMR (100.56 MHz, DMSO-d6) δ: 207.13, 196.29, 155.82, 150.78, 150.33, 144.57, 140.19, 138.00, 137.16, 127.21, 127.13, 127.08, 72.69, 55.15, 30.44. MS calculated for [C30H24O6N4Ag]+—643.0741, found—643.0751.

3.4.3. Synthesis of [Ag(4,5-Diazafluoren-9-one)2]NO3 (3Ag)

Compound 3Ag was synthesized following the synthetic route described in the literature with some modifications [28,42]. Compound 3 (54.7 mg, 0.300 mmol) was dissolved in 20 mL of acetone in a flask. In a vial, AgNO3 (25.5 mg, 0.15 mmol) was dissolved in 1 mL of water and then 2 mL of acetone was added. The silver solution was mixed and added dropwise under continuous stirring to the ligand solution shielding it from light. A solid was then formed. The suspension was stirred for 1 h protecting it from light. The solvent was partially removed under reduced pressure and then filtered. The white–yellowish solid was washed with n-hexane and dried (yield: 79%). 1H-NMR (499.72 MHz, DMSO-d6) δ: 8.83 (dd, J = 5.1, 1.5 Hz, 4H), 8.18 (dd, J = 7.5, 1.5 Hz, 4H), 7.62 (dd, J = 7.5, 5.1 Hz, 4H). 13C{1H}-NMR (125.67 MHz, DMSO-d6) δ: 189.20, 162.13, 155.10, 132.89, 129.80, 126.66. MS calculated for [C22H12N4O2Ag]+—471.0006, found—471.0021.

3.4.4. Synthesis of [Ag(9-Hydroxy-9-(2-oxypropyl)-4,5-diazafluorene)2]NO3 (4Ag)

Compound 4 (42.5 mg, 0.177 mmol) was dissolved in 10 mL of dichloromethane. Then, AgNO3 (14.9 mg, 0.088 mmol) was added. The mixture was stirred overnight at room temperature while protecting it from light. Afterward, the solvent was partially removed under reduced pressure and n-hexane was added until a precipitate was obtained. The yellow solid was washed with n-hexane and dried (yield: 80%). 1H-NMR (499.72 MHz, DMSO-d6) δ: 8.64 (dd, J = 5.0, 1.4 Hz, 4H), 8.08 (dd, J = 7.6, 1.5 Hz, 4H), 7.52 (dd, J = 7.6, 5.0 Hz, 4H), 6.15 (s, 2H), 3.49 (s, 4H), 1.98 (s, 6H). 13C{1H}-NMR (125.67 MHz, DMSO-d6) δ: 205.57, 156.35, 150.41, 145.00, 133.18, 125.40, 75.78, 51.02, 31.58. MS calculated for [C28H24O4N4Ag]+—587.0843, found—587.0856.

3.5. Synthesis of Pt(II) Complexes

3.5.1. Synthesis of [Pt(C6F5)2(THF)2]

The complex was synthesized following a procedure described in the literature [43].

3.5.2. Synthesis of [Pt(C6F5)2(Ligand)]—General Procedure

In a flask, the ligand (0.100 mmol), [Pt(C6F5)2(THF)2] (0.100 mmol), and 10 mL of dichloromethane were added. The mixture was stirred for 1 h at room temperature while protecting it from light. The solvent was partially removed under reduced pressure. Pentane or diethyl ether (10–15 mL) was added to precipitate the solid. After filtration and washing with pentane or diethyl ether, the solid was dried.

3.5.3. Synthesis of [Pt(C6F5)2(1,10-Phenanthroline-5,6-dione)] (1Pt)

The complex was synthesized following the general procedure. An orange solid was obtained (yield: 74%). Single crystals suitable for X-ray diffraction were obtained from the slow evaporation of a chloroform-concentrated solution of the compound. 1H-NMR (499.72 MHz, CD2Cl2) δ: 8.87 (dd, J = 7.9, 1.5, 2H), 8.63 (dd, J = 5.5, 1.5 Hz, 2H), 7.82 (dd, J = 7.9, 5.5, 2H). 19F-NMR (470.17 MHz, CD2Cl2) δ: −119.77 (m, 3J19F-195Pt = 450 Hz, 4F), −161.45 (t, J = 19.6 Hz, 2F), −164.18 (m, 4F). 13C{1H}-NMR (125.67 MHz, CD2Cl2) δ: 174.10, 155.46, 154.85, 138.77, 129.63, 129.28. MS calculated for [C24F10H6O2N2NaPt]+—761.9812 ([M+Na]+), found—761.9818.

3.5.4. Synthesis of [Pt(C6F5)2((R/S)-6-Hydroxy-6-(2-oxypropyl)-1,10-phenanthroline-5(6H)-one)] (2Pt)

The complex was synthesized following the general procedure. A yellow solid was obtained (yield: 79%). 1H-NMR (399.87 MHz, CD2Cl2) δ: 8.71 (dd, J = 7.9, 1.5 Hz, 1H), 8.51 (dd, J = 5.5, 1.5 Hz, 1H), 8.45 (dd, J = 8.1, 1.4 Hz, 1H), 8.32 (dd, J = 5.4, 1.4 Hz, 1H), 7.72 (dd, J = 7.9, 5.5 Hz, 1H), 7.65 (dd, J = 8.1, 5.4 Hz, 1H), 4.18 (s, 1H), 3.39 (A part of AB spin system, JHA-HB = 17.1 Hz, 1H), 3.31 (B part of AB spin system, JHA-HB = 17.1 Hz, 1H), 2.10 (s, 3H). 19F-NMR (376.22 MHz, CD2Cl2) δ: −119.71 (m, 3J19F-195Pt = 455 Hz, 4F), −162.02 (t, J = 19.3 Hz, 1F), −162.10 (t, J = 19.7 Hz, 1F), −164.53 (m, 4F). 13C{1H}-NMR (100.56 MHz, CD2Cl2) δ: 204.80, 195.81, 156.25, 153.81, 149.80, 149.69, 139.61, 137.34, 137.12, 128.78, 128.70, 128.46, 74.72, 55.81, 30.60. MS calculated for [C27H12F10O3N2NaPt]+—820.0231 ([M+Na]+), found—820.0252.

3.5.5. Synthesis of [Pt(C6F5)2(4,5-Diazafluoren-9-one)] (3Pt)

The complex was synthesized following the general procedure. A yellow solid was obtained (yield: 69%). Single crystals suitable for X-ray diffraction were obtained from the slow diffusion of a dichloromethane-concentrated solution of the compound into hexane at 0–5 °C. 1H-NMR (499.72 MHz, CDCl3) δ: 8.31 (dd, J = 7.6, 1.0 Hz, 2H), 8.21 (d, J = 5.4 Hz, 2H), 7.64 (dd, J = 7.6, 5.4 Hz, 2H). 19F-NMR (470.17 MHz, CDCl3) δ: −119.87 (m, 3J19F-195Pt = 475 Hz, 4F), −160.29 (t, J = 19.9 Hz, 2F), −163.38 (m, 4F). 13C{1H}-NMR (125.67 MHz, CDCl3) δ: 184.99, 166.97, 152.29, 134.80, 129.35, 129.21. MS calculated for [C23F10H6N2ONaPt]+—733.9863 ([M+Na]+), found—733.9881.

3.5.6. Synthesis of [Pt(C6F5)2(9-Hydroxy-9-(2-oxypropyl)-4,5-diazafluorene)] (4Pt)

The complex was synthesized following the general procedure. A yellow solid was obtained (yield: 77%). 1H-NMR (499.72 MHz, CD2Cl2) δ: 8.24 (dd, J = 7.7, 1.0 Hz, 2H), 8.03 (d, J = 5.4, 2H), 7.52 (dd, J = 7.7, 5.4 Hz, 2H), 5.06 (s, 1H), 3.26 (s, 2H), 2.30 (s, 3H). 19F-NMR (470.17 MHz, CD2Cl2) δ: −119.90 (m, 3J19F-195Pt = 475 Hz, 2F), −120.20 (m, 3J19F-195Pt = 480 Hz, 2F), −162.42 (t, J = 19.9 Hz, 2F), −165.04 (m, 4F). 13C{1H}-NMR (125.67 MHz, CD2Cl2) δ: 209.62, 161.39, 148.50, 141.62, 135.48, 127.55, 84.17, 49.16, 30.96. MS calculated for [C26H12F10O2N2NaPt]+—792.0282 ([M+Na]+), found—792.0314.

3.6. Stability Study of the Complexes in DMSO

A 5 mM solution of the complex in DMSO-d6 was prepared. The 1H-NMR spectrum was recorded immediately after solution preparation. The solution was kept at room temperature and the 1H-NMR spectrum was recorded again at 24 and 48 h. The spectra were compared to the spectrum of the ligand in DMSO-d6.

3.7. Stability Study of the Complexes in DMSO:H2O (3:1).

A 2.5 mM solution of the complex in DMSO-d6:H2O (3:1) was prepared. The 1H-NMR spectrum was recorded immediately after solution preparation. The solution was kept at 37 °C and the 1H-NMR spectrum was recorded again at 24 and 48 h. The spectra were compared to the spectrum of the ligand in DMSO-d6:H2O (3:1).

3.8. Biology

3.8.1. Materials

Reagents and solvents were used as purchased without further purification. All stock solutions of the investigated compounds were prepared by dissolving the powdered materials in appropriate amounts of DMSO. The final concentration of DMSO never exceeded 5% (v/v) in the reactions. Under these conditions, DMSO was also used in the controls and was not seen to affect the tested compounds’ activity. The solutions were stored at 5 °C until they were used.
A-549 (CCL-185™) and MRC-5 (CCL-171™) human cell lines were purchased from the American Type Culture Collection (ATCC).

3.8.2. Cytotoxicity Assays

Cells A-549 (CCL 185) and MRC-5 (CCL 171) were cultured according to the supplier’s instructions (ATCC technologies, Washington DC, USA). Cells were seeded in 96-well plates at a density of 2–2.5 × 103 cells per well and incubated overnight in 0.1 mL of medium supplied with 10% Fetal Bovine Serum (Lonza) in a 5% CO2 incubator at 37 °C. On day 2, drugs were added and samples were incubated for 48 h. After treatment, 10 µL of cell counting kit 8 was added into each well for an additional 2 h incubation at 37 °C. The absorbance of each well was determined by an Automatic Elisa Reader System at 450 nm wavelength.

4. Conclusions

The two selective compounds found in this study, 3Ag and 1Pt, are great examples of how coordination chemistry is a valuable tool in the search for new antitumoral drugs. Complex 3Ag exemplifies how non-active ligands can give rise to active and selective coordination compounds, and complex 1Pt is an example of how a highly potent but not selective organic compound can give life to selective complexes. Furthermore, the group pentafluorophenyl has proven to be a valuable substitute for classical anionic ligands in Pt(II) coordination compounds for cancer applications, and Ag(I) is highlighted as another transition metal with promising antitumoral applications.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/inorganics13010006/s1, Figure S1: 1H-NMR of 1; Figure S2: 1H-NMR of 2; Figure S3: Aromatic and methylene 1H-NMR of 2; Figure S4: 13C-NMR of 2; Figure S5: 1H-NMR of 3; Figure S6: 1H-NMR of 4; Figure S7: 13C-NMR of 4; Figure S8: 1H-NMR of 1Ag; Figure S9: 13C-NMR of 1Ag; Figure S10: 1H-NMR of 2Ag; Figure S11: 13C-NMR of 2Ag; Figure S12: 1H-NMR of 3Ag; Figure S13: 13C-NMR of 3Ag; Figure S14: 1H-NMR of 4Ag; Figure S15: 13C-NMR of 4Ag; Figure S16: 1H-NMR of 1Pt; Figure S17: 19F-NMR of 1Pt; Figure S18: 13C-NMR of 1Pt; Figure S19: 1H-NMR of 2Pt; Figure S20: 19F-NMR of 2Pt; Figure S21: 13C-NMR of 2Pt; Figure S22: 1H-NMR of 3Pt; Figure S23: 19F-NMR of 3Pt; Figure S24: 13C-NMR of 3Pt; Figure S25: 1H-NMR of 4Pt; Figure S26: 19F-NMR of 4Pt; Figure S27: 13C-NMR of 4Pt; Figure S28: ESI-TOF mass spectrum of 2Ag; Figure S29: Comparison of the aromatic zone of the 1H-NMR spectra of 2Ag 5 mM in DMSO-d6 over time vs. ligand 2; Figure S30: Comparison of the aromatic zone of the 1H-NMR spectra of 4Ag 5 mM in DMSO-d6 over time vs. ligand 4; Figure S31: Comparison of the aromatic zone of the 1H-NMR spectra of 4Pt 5 mM in DMSO-d6 over time vs. ligand 4; Figure S32: Comparison of the aromatic zone of the 1H-NMR spectra of 3Pt 5 mM in DMSO-d6 over time vs. ligand 3; Figure S33: Comparison of the 19F-NMR spectra of 3Pt 5 mM in DMSO-d6 over time vs. [Pt(C6F5)2(DMSO)2]; Figure S34: Comparison of the aromatic zone of the 1H-NMR spectra of 4Ag 2.5 mM in DMSO-d6:H2O (3:1) over time vs. ligand 4; Figure S35: Comparison of the aromatic zone of the 1H-NMR spectra of 2Pt 2.5 mM in DMSO-d6:H2O (3:1) over time vs. ligand 2; Figure S36: Comparison of the aromatic zone of the 1H-NMR spectra of 3Pt 2.5 mM in DMSO-d6:H2O (3:1) over time vs. ligand 3; Figure S37: Comparison of the 19F-NMR spectra of 3Pt 2.5 mM in DMSO-d6:H2O (3:1) over time vs. [Pt(C6F5)2(solvent)2]; Figure S38: Comparison of the aromatic zone of the 1H-NMR spectra of 1Ag 2.5 mM in DMSO-d6:H2O (3:1) over time vs. ligand 1; Figure S39: Comparison of the aromatic zone of the 1H-NMR spectra of 1Pt 2.5 mM in DMSO-d6:H2O (3:1) over time vs. ligand 1; Figure S40: Comparison of the 19F-NMR spectra of 1Pt 2.5 mM in DMSO-d6:H2O (3:1) over time vs. [Pt(C6F5)2(solvent)2]; Figure S41: Single-crystal X-ray structure of 2; Table S1: Crystallographic data of compound 2; Figure S42: Single-crystal X-ray structure of 4; Table S2: Crystallographic data of compound 4; Figure S43: Single-crystal X-ray structure of 1Ag; Table S3: Crystallographic data of compound 1Ag; Figure S44: Single-crystal X-ray structure of 3Ag. (a) polymorph A. (b) polymorph B; Figure S45: Single-crystal X-ray structure of 3Ag (structure A); Table S4: Crystallographic data of compound 3Ag polymorph A; Figure S46: Single-crystal X-ray structure of 3Ag (structure B); Table S5: Crystallographic data of compound 3Ag polymorph B; Figure S47: Single-crystal X-ray structure of 1Pt; Table S6: Crystallographic data of compound 1Pt; Figure S48: Single-crystal X-ray structure of 3Pt; Table S7: Crystallographic data of compound 3Pt.

Author Contributions

Conceptualization, L.S.-M., C.B. and J.M.M.-I.; investigation—chemistry, L.S.-M. and J.A.M.; investigation—biology, L.S.-M.; formal analysis—chemistry, L.S.-M. and J.A.M.; formal analysis—biology, L.S.-M.; writing—original draft preparation, L.S.-M.; writing—review and editing, J.M.M.-I., C.B. and C.A.; supervision, J.M.M.-I., C.B. and C.A.; funding acquisition, J.M.M.-I., C.B. and C.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Basque Government (GV, IT1701-22).

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

Acknowledgments

The researchers would like to thank Jose Miguel Martin-Álvarez, Sandra Rico Martínez, and Ángela Trejo for their help and discussions. L.S.-M. has been funded by the pre-doctoral contracts UVa 2021, co-funded by Santander Bank.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024, 74, 229–263. [Google Scholar] [CrossRef] [PubMed]
  2. Rosenberg, B.; VanCamp, L.; Trosko, J.E.; Mansour, V.H. Platinum compounds: A new class of potent antitumour agents. Nature 1969, 222, 385–386. [Google Scholar] [CrossRef] [PubMed]
  3. Oun, R.; Moussa, Y.E.; Wheate, N.J. The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans. 2018, 47, 6645–6653. [Google Scholar] [CrossRef]
  4. Stewart, D.J. Mechanisms of resistance to cisplatin and carboplatin. Crit. Rev. Oncol./Hematol. 2007, 63, 12–31. [Google Scholar] [CrossRef] [PubMed]
  5. Martinez-Balibrea, E.; Martínez-Cardus, A.; Gines, A.; Ruiz de Porras, V.; Moutinho, C.; Layos, L.; Manzano, J.L.; Buges, C.; Bystrup, S.; Esteller, M.; et al. Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance. Mol. Cancer Ther. 2015, 14, 1767–1776. [Google Scholar] [CrossRef] [PubMed]
  6. Montaña, A.M.; Batalla, C. The Rational Design of Anticancer Platinum Complexes: The Importance of the Structure-Activity Relationship. Curr. Med. Chem. 2009, 16, 2235–2260. [Google Scholar] [CrossRef] [PubMed]
  7. Vo, V.; Tanthmanatham, O.; Han, H.; Bhowmik, P.K.; Spangelo, B.L. Synthesis of [PtCl2(4,4′-dialkoxy-2,2′-bipyridine)] complexes and their in vitro anticancer properties. Metallomics 2013, 5, 973–987. [Google Scholar] [CrossRef] [PubMed]
  8. Bose, R.N.; Moghaddas, S.; Belkacemi, L.; Tripathi, S.; Adams, N.R.; Majmudar, P.; McCall, K.; Dezvareh, H.; Nislow, C. Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers. J. Med. Chem. 2015, 58, 8387–8401. [Google Scholar] [CrossRef] [PubMed]
  9. Masaryk, L.; Zoufalý, P.; Słoczyńska, K.; Zahradniková, E.; Milde, D.; Koczurkiewicz-Adamczyk, P.; Štarha, P. New Pt(II) diiodido complexes containing bidentate 1,3,4-thiadiazole-based ligands: Synthesis, characterization, cytotoxicity. Inorganica Chim. Acta 2022, 536, 120891–120899. [Google Scholar] [CrossRef]
  10. Gómez, N.; Santos, D.; Vázquez, R.; Suescun, L.; Mombrffl, A.; Vermeulen, M.; Finkielsztein, L.; Shayo, C.; Moglioni, A.; Gambino, D.; et al. Synthesis, Structural Characterization, and Pro-apoptotic Activity of 1-Indanone Thiosemicarbazone Platinum(II) and Palladium(II) Complexes: Potential as Antileukemic Agents. ChemMedChem 2011, 6, 1485–1494. [Google Scholar] [CrossRef] [PubMed]
  11. Marcos-Ayuso, G.; Peñas-Defrutos, M.N.; Gallego, A.M.; García-Melchor, M.; Martínez-Ilarduya, J.M.; Espinet, P. Problematic ArF–Alkynyl Coupling with Fluorinated Aryls. From Partial Success with Alkynyl Stannanes to Efficient Solutions via Mechanistic Understanding of the Hidden Complexity. J. Am. Chem. Soc. 2023, 145, 527–536. [Google Scholar] [CrossRef] [PubMed]
  12. Martín-Encinas, E.; Conejo-Rodríguez, V.; Miguel, J.A.; Martínez-Ilarduya, J.M.; Rubiales, G.; Knudsen, B.R.; Palacios, F.; Alonso, C. Novel Phosphine Sulphide Gold(I) Complexes: Topoisomerase I Inhibitors and Antiproliferative Agents. Dalton Trans. 2020, 49, 7852–7861. [Google Scholar] [CrossRef]
  13. Cullinane, C.; Deacon, G.B.; Drago, P.R.; Hambley, T.W.; Nelson, K.T.; Webster, L.K. Preparation and cell growth inhibitory activity of [PtR2L2] (R=polyfluorophenyl, L=diene, cyclohexane-1,2-diamine (chxn) or cis-(dimethyl sulfoxide)) and the X-ray crystal structure of [Pt(C6F5)(cis-chxn)]. J. Inorg. Biochem. 2002, 89, 293–301. [Google Scholar] [CrossRef] [PubMed]
  14. Cullinane, C.; Deacon, G.B.; Drago, P.R.; Erven, A.P.; Junk, P.C.; Luu, J.; Meyer, G.; Schmitz, S.; Ott, I.; Schur, J.; et al. Synthesis and antiproliferative activity of a series of new platinum and palladium diphosphane complexes. Dalton Trans. 2018, 47, 1918–1932. [Google Scholar] [CrossRef]
  15. Webster, L.K.; Deacon, G.B.; Buxton, D.P.; Hillcoat, B.L.; James, A.M.; Roos, I.A.G.; Thomson, R.J.; Wakelin, L.P.G.; Williams, T.L. cis-Bis(pyridine)platinum(II) Organoamides with Unexpected Growth Inhibition Properties and Antitumor Activity. J. Med. Chem. 1992, 35, 3349–3353. [Google Scholar] [CrossRef] [PubMed]
  16. Sgarbossa, P.; Śliwińska-Hill, U.; Guedes da Silva, M.F.C.; Bażanów, B.; Pawlak, A.; Jackulak, N.; Poradowski, D.; Pombeiro, A.J.L.; Smoleński, P. Pentafluorophenyl Platinum(II) Complexes of PTA and Its N-Allyl and N-Benzyl Derivatives: Synthesis, Characterization and Biological Activity. Materials 2019, 12, 3907. [Google Scholar] [CrossRef]
  17. Sighn, A.K.; Kumar, A.; Sighn, H.; Sonawane, P.; Pathak, P.; Grishina, M.; Yadav, J.P.; Verma, A.; Kumar, P. Metal complexes in cancer treatment: Journey so far. Chem. Biodiver. 2023, 20, e202300061. [Google Scholar] [CrossRef]
  18. Medici, S.; Peana, M.; Nurchi, V.M.; Zoroddu, M.A. Medical uses of silver: History, myths, and scientific evidence. J. Med. Chem. 2019, 62, 5923–5943. [Google Scholar] [CrossRef] [PubMed]
  19. Raju, S.K.; Karunakaran, A.; Kumar, S.; Sekar, P.; Murugesan, M.; Karthikeyan, M. Silver Complexes as Anticancer Agents: A Perspective Review. Ger. J. Pharm. Biomater. 2022, 1, 6–28. [Google Scholar] [CrossRef]
  20. Thornton, L.; Dixit, V.; Assad, L.O.N.; Ribeiro, T.P.; Queiroz, D.D.; Kellett, A.; Casey, A.; Colleran, J.; Pereira, M.D.; Rochford, G.; et al. Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity. J. Inorg. Biochem. 2016, 159, 120–132. [Google Scholar] [CrossRef] [PubMed]
  21. Teixeira, R.G.; Stefanelli, A.; Pilon, A.; Warmers, R.; Fontrodona, X.; Romero, I.; Costa, P.J.; Villa de Brito, M.J.; Hudec, X.; Pirker, C.; et al. Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands. J. Med. Chem. 2024, 67, 6081–6098. [Google Scholar] [CrossRef]
  22. Jaros, S.W.; Śliwińska-Hill, U.; Białońska, A.; Nesterov, D.S.; Kuropka, P.; Sokolnicki, J.; Bażanówe, B.; Smoleński, P. Light-stable polypyridine silver(I) complexes of 1,3,5-triaza-7-phosphaadamantane (PTA) and 1,3,5-triaza-7-phosphaadamantane-7-sulfide (PTA=S): Significant antiproliferative activity of representative examples in aqueous media. Dalton Trans. 2019, 48, 11235–11249. [Google Scholar] [CrossRef]
  23. Wang, Q.-W.; Lam, P.-L.; Wong, R.S.-M.; Cheng, G.Y.-M.; Lam, K.-H.; Bian, Z.-X.; Ho, C.-L.; Feng, Y.-H.; Gambari, R.; Lo, Y.-H.; et al. Synthesis of platinum(II) and palladium(II) complexes with 9,9-dihexyl-4,5-diazafluorene and their in vivo antitumour activity against Hep3B xenografted mice. Eur. J. Med. Chem. 2016, 124, 537–543. [Google Scholar] [CrossRef]
  24. Movahedi, E.; Razmazma, H.; Rezvani, A.; Ebrahimi, A. Binding profile of a mixed-ligand silver(I) complex with DNA and Topoisomerase I. Comput. Biol. Chem. 2023, 103, 107831–107842. [Google Scholar] [CrossRef] [PubMed]
  25. Zhao, J.F.; Chen, L.; Sun, P.J.; Hou, X.Y.; Zhao, X.H.; Li, W.J.; Xie, L.H.; Qian, Y.; Shi, N.E.; Lai, W.Y.; et al. One-pot synthesis of 2-bromo-4,5-diazafluoren-9-one via a tandem oxidation-bromination-rearrangement of phenanthroline and its hammer-shaped donor-acceptor organic semiconductors. Tetrahedron 2011, 67, 1977–1982. [Google Scholar] [CrossRef]
  26. Esteban, N.; Ferrer, M.L.; Ania, C.O.; de la Campa, J.G.; Lozano, A.E.; Álvarez, C.; Miguel, J.A. Porous Organic Polymers Containing Active Metal Centers for Suzuki−Miyaura Heterocoupling Reactions. ACS Appl. Mater. Interfaces 2020, 12, 56974–56986. [Google Scholar] [CrossRef] [PubMed]
  27. Eckert, T.S.; Bruice, T.C.; Gainor, J.A.; Weinreb, S.M. Some electrochemical and chemical properties of methoxatin and analogous quinoquinones. Proc. Nat. Acad. Sci. USA 1982, 79, 2533–2536. [Google Scholar] [CrossRef] [PubMed]
  28. Massoud, A.A.; Gohar, Y.M.; Langer, V.; Lincoln, P.; Svensson, F.R.; Jänis, J.; Gårdebjer, S.T.; Haukka, M.; Jonsson, F.; Aneheim, E.; et al. Bis 4,5-diazafluoren-9-one silver(I) nitrate: Synthesis, X-ray structures, solution chemistry, hydrogel loading, DNA coupling and anti-bacterial screening. New J. Chem. 2011, 35, 640–648. [Google Scholar] [CrossRef]
  29. Zhang, R.; Zhao, J.; Xi, X.; Yang, P.; Shi, Q. A Novel Silver(I) Complex with 4,5-Diazafluoren-9-one and the Interaction Study Between the Complex and DNA. J. Chem. Crystallogr. 2011, 41, 209–213. [Google Scholar] [CrossRef]
  30. Casas, J.M.; Diosdado, B.E.; Falvello, L.R.; Forniés, J.; Martín, A.; Rueda, A.J. Hydrogen-bond mediation of supramolecular aggregation in neutral bis-(C6F5)Pt complexes with aromatic H-bond donating ligands. A synthetic and structural study. Dalton Trans. 2004, 17, 2733–2740. [Google Scholar] [CrossRef] [PubMed]
  31. Roy, S.; Hagen, K.D.; Maheswari, P.U.; Lutz, M.; Spek, A.L.; Reedijk, J.; van Wezel, G.P. Phenanthroline Derivatives with Improved Selectivity as DNA-Targeting Anticancer or Antimicrobial Drugs. ChemMedChem 2008, 3, 1427–1434. [Google Scholar] [CrossRef]
  32. Biju, A.R.; Rajasekharan, M.V.; Bhat, S.S.; Khan, A.A.; Kumbhar, A.S. Synthesis, crystal structure and cytotoxicity studies of cis-dichloro(4,5-diazafluoren-9-one)platinum(II). Inorganica Chim. Acta 2014, 423, 93–97. [Google Scholar] [CrossRef]
  33. Poteet, S.A.; Majewski, M.B.; Breitbach, Z.S.; Griffith, C.A.; Singh, S.; Armstrong, D.W.; Wolf, M.O.; MacDonnell, F.M. Cleavage of DNA by proton-coupled electron transfer to a photoexcited, hydrated Ru(II) 1,10-phenanthroline-5,6-dione complex. J. Am. Chem. Soc. 2013, 135, 2419–2422. [Google Scholar] [CrossRef] [PubMed]
  34. Deegan, C.; Coyle, B.; McCanna, M.; Devereux, M.; Egana, D.A. In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines. Chem.-Biol. Interact. 2006, 164, 115–125. [Google Scholar] [CrossRef] [PubMed]
  35. Sidambaram, P.; Colleran, J. Evaluating the anticancer properties and real-time electrochemical extracellular bio-speciation of bis (1,10-phenanthroline) silver (I) acetate monohydrate in the presence of A549 lung cancer cells. Biosens. Bioelectron. 2021, 175, 112876. [Google Scholar] [CrossRef] [PubMed]
  36. Bostancıoğlu, R.B.; Işık, K.; Genç, H.; Benkli, K.; Koparal, A.T. Studies on the cytotoxic, apoptotic and antitumoral effects of Au(III) and Pt(II) complexes of 1, 10-phenanthroline on V79 379A and A549 cell lines. J. Enzym. Inhib. Med. Chem. 2011, 27, 458–466. [Google Scholar] [CrossRef]
  37. Prayong, P.; Barusrux, S.; Weerapreeyakul, N. Cytotoxic activity screening of some indigenous Thai plants. Fitoterapia 2008, 79, 598–601. [Google Scholar] [CrossRef] [PubMed]
  38. CrysAlisPro Software System, version 1.171.40.67a; Oxford Diffraction Ltd.: Oxford, UK, 2009.
  39. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. [Google Scholar] [CrossRef]
  40. Bourhis, L.J.; Dolomanov, O.V.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. The anatomy of a comprehensive constrained, restrained refinement program for the modern computing environment Olex2 dissected. Acta Crystallogr. Sect. A Found. Adv. 2015, 71, 59–75. [Google Scholar] [CrossRef]
  41. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  42. Biju, A.R.; Rajasekharan, M.V. Unusual coordination geometries of silver(I) 4,5-diazafluoren-9-one complexes. Polyhedron 2008, 27, 2065–2068. [Google Scholar] [CrossRef]
  43. Usón, R.; Forniés, J.; Tomás, M.; Menjón, B. Neutral bis(perhalophenyl)dicarbonylpalladium(II) and platinum(II) complexes. Organometallics 1985, 4, 1912–1914. [Google Scholar] [CrossRef]
Inorganics 13 00006 g001
Figure 1. Structure of approved antitumoral platinum drugs.
Figure 1. Structure of approved antitumoral platinum drugs.
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Figure 2. 4,5-diazafluorene XXI, Pd, Pt, and Ag-related active complexes XXII–XXIV.
Figure 2. 4,5-diazafluorene XXI, Pd, Pt, and Ag-related active complexes XXII–XXIV.
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Scheme 1. Workflow of this research.
Scheme 1. Workflow of this research.
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Scheme 2. Synthetic route for the synthesis of ligands, and crystal structures of 2 and 4.
Scheme 2. Synthetic route for the synthesis of ligands, and crystal structures of 2 and 4.
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Scheme 3. Synthetic route for the synthesis of Ag(I) complexes.
Scheme 3. Synthetic route for the synthesis of Ag(I) complexes.
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Figure 3. Comparison of 1H-NMR of ligand 4 and complex 4Ag in DMSO-d6 at 298 K.
Figure 3. Comparison of 1H-NMR of ligand 4 and complex 4Ag in DMSO-d6 at 298 K.
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Figure 4. X-ray structure of 1Ag. NO3− counterion, H2O, and MeOH are omitted for clarity.
Figure 4. X-ray structure of 1Ag. NO3− counterion, H2O, and MeOH are omitted for clarity.
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Figure 5. X-ray structure of 3Ag (left, polymorph A; right, polymorph B).
Figure 5. X-ray structure of 3Ag (left, polymorph A; right, polymorph B).
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Scheme 4. Synthetic route for the synthesis of Pt(II) complexes.
Scheme 4. Synthetic route for the synthesis of Pt(II) complexes.
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Figure 6. Comparison of 1H-NMR (aromatic region) of ligand 1 and complexes 1Pt and 2Pt in CD2Cl2 at 298 K: (a) ligand 1; (b) complex 1Pt; (c) complex 2Pt.
Figure 6. Comparison of 1H-NMR (aromatic region) of ligand 1 and complexes 1Pt and 2Pt in CD2Cl2 at 298 K: (a) ligand 1; (b) complex 1Pt; (c) complex 2Pt.
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Figure 7. Comparison of 19F-NMR of complexes 1Pt (a), 2Pt (b), and 4Pt (c) in CD2Cl2 at 298 K.
Figure 7. Comparison of 19F-NMR of complexes 1Pt (a), 2Pt (b), and 4Pt (c) in CD2Cl2 at 298 K.
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Figure 8. X-ray structures of 1Pt (left) and 3Pt (right).
Figure 8. X-ray structures of 1Pt (left) and 3Pt (right).
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Figure 9. Comparison of the 19F-NMR of complexes 3Pt and [Pt(C6F5)2(DMSO)2] between −159 and −162 ppm in DMSO-d6 at 298 K: (a) 19F-NMR of 3Pt immediately after dissolution; (b) 19F-NMR of 3Pt 24 h after dissolution; (c) 19F-NMR of [Pt(C6F5)2(DMSO)2].
Figure 9. Comparison of the 19F-NMR of complexes 3Pt and [Pt(C6F5)2(DMSO)2] between −159 and −162 ppm in DMSO-d6 at 298 K: (a) 19F-NMR of 3Pt immediately after dissolution; (b) 19F-NMR of 3Pt 24 h after dissolution; (c) 19F-NMR of [Pt(C6F5)2(DMSO)2].
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Figure 10. Proposed species that are present in the solvolysis reaction of 3Pt with DMSO.
Figure 10. Proposed species that are present in the solvolysis reaction of 3Pt with DMSO.
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Figure 11. 1H-NMR of ligand 1 in DMSO-d6:H2O (3:1). The hydration reaction that is proposed to take place is indicated.
Figure 11. 1H-NMR of ligand 1 in DMSO-d6:H2O (3:1). The hydration reaction that is proposed to take place is indicated.
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Figure 12. Proposed species that are present when 1Pt is dissolved in DMSO:H2O.
Figure 12. Proposed species that are present when 1Pt is dissolved in DMSO:H2O.
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Figure 13. pIC50 of the compounds tested on A-549 cell line (calculated with IC50 values expressed in M). The response to the treatment is quantified to reflect the inverse logarithmic concentration of the compound required to inhibit cell viability by 50% (pIC50), providing a comparative measure of the compounds’ cytotoxic potency. The uncertainty associated with the measurement is indicated with gray bars. The columns with the lowest value correspond to a pIC50 < 4.3, which corresponds to IC50 > 50 μM.
Figure 13. pIC50 of the compounds tested on A-549 cell line (calculated with IC50 values expressed in M). The response to the treatment is quantified to reflect the inverse logarithmic concentration of the compound required to inhibit cell viability by 50% (pIC50), providing a comparative measure of the compounds’ cytotoxic potency. The uncertainty associated with the measurement is indicated with gray bars. The columns with the lowest value correspond to a pIC50 < 4.3, which corresponds to IC50 > 50 μM.
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Table 1. Structure of cytotoxic [PtA2X2] complexes.
Table 1. Structure of cytotoxic [PtA2X2] complexes.
ComplexStructureCell Lines *Ref.
IVInorganics 13 00006 i001A-549, DU145, MCF-7, MDA-MB-435[7]
VInorganics 13 00006 i002A2780 **[8]
VIInorganics 13 00006 i003A-549, HepG-2[9]
VIIInorganics 13 00006 i004U937[10]
* Cell line codes: A-549, human lung carcinoma; DU145, prostate carcinoma; MCF-7, breast carcinoma; MDA-MB-435, melanoma; A2780, human ovarian carcinoma; HepG-2, hepatocellular carcinoma; U937 leukemia. ** Complex V is currently undergoing a phase I/II clinical trial (ClinicalTrials.gov Identifier NCT02266745).
Table 2. Structure of cytotoxic fluoroaryl platinum(II) complexes.
Table 2. Structure of cytotoxic fluoroaryl platinum(II) complexes.
ComplexStructureCell Lines *Ref.
VIIIInorganics 13 00006 i005L1210, L1210/DDP[13]
IXInorganics 13 00006 i006L1210, L1210/DDP[13]
XInorganics 13 00006 i007L1210, L1210/DDP[14]
XI–XIVInorganics 13 00006 i008L1210, L1210/DDP, HT-29, BE[15]
XVInorganics 13 00006 i009A-549, HeLa[16]
* Cell line codes: L1210, leukemia; L1210/DDP, cisplatin-resistant leukemia; HT-29, colon carcinoma; BE, colon carcinoma; A-549, lung carcinoma; HeLa, epithelioid cervix carcinoma.
Table 3. Structure of cytotoxic silver complexes.
Table 3. Structure of cytotoxic silver complexes.
ComplexStructureCell Lines *Ref.
XVIInorganics 13 00006 i010MCF-7, SK-OV-3[20]
XVII–XIXInorganics 13 00006 i011SK-OV-3, MES-OV, HCT-116, SK-OV-3/CBP, MES-OV/CBP, HCT116 WT/OXR[21]
XXInorganics 13 00006 i012A-549, MCF-7, HeLa[22]
* Cell line codes: MCF-7, breast carcinoma; SK-OV-3, ovarian carcinoma; MES-OV, ovarian carcinoma; HCT-116, colon carcinoma; HCT116 WT/OXR, oxaliplatin-resistant colon carcinoma; SK-OV-3/CBP, carboplatin-resistant breast carcinoma; MES-OV/CBP, oxaliplatin-resistant ovarian carcinoma; A-549, lung; HeLa, epithelioid cervix carcinoma.
Table 4. Selected bond lengths (Å) for 1Ag.
Table 4. Selected bond lengths (Å) for 1Ag.
Bond Lengths (Å) for 1Ag
Ag1-N1 = 2.330(3)
Ag1-N2 = 2.290(3)
Ag1-N3 = 2.340(4)
Ag1-N4 = 2.354(4)
Table 5. Selected bond lengths (Å) and angles (deg) for 3Ag.
Table 5. Selected bond lengths (Å) and angles (deg) for 3Ag.
3Ag (Polymorph A)3Ag (Polymorph B)
Bond Lengths (Å)Bond Angles (deg)Bond Lengths (Å)Bond Angles (deg)
Ag1-N1 = 2.391(5)N1-Ag1-N2 = 74.06(16)Ag1-N1 = 2.598(3)N1-Ag1-N2 = 74.33(10)
Ag1-N2 = 2.578(6)N3-Ag1-N4 = 75.94(19)Ag1-N2 = 2.345(3)N3-Ag1-N4 = 72.96(10)
Ag1-N3 = 2.442(6)N1-Ag1-N3 = 110.56(18)Ag1-N3 = 2.422(3)N1-Ag1-N3 = 104.16(10)
Ag1-N4 = 2.426(7N2-Ag1-N4 = 96.30(17)Ag1-N4 = 2.616(3)N2-Ag1-N4 = 100.08(10)
Ag1-O3 = 2.492(8)N1-Ag1-N4 = 163.09(16)Ag1-O3 = 2.424(3)N1-Ag1-N4 = 171.29(9)
N2-Ag1-N3 = 166.65(17) N2-Ag1-N3 = 122.63(10)
O3-Ag1-N1 = 104.1(3) O3-Ag1-N1 = 110.95(11)
O3-Ag1-N2= 102.0(2) O3-Ag1-N2 = 124.53(11)
O3-Ag1-N3 = 89.2(2) O3-Ag1-N3 = 109.75(12)
O3-Ag1-N4 = 91.4(3) O3-Ag1-N4 = 77.69(11)
Table 6. Selected bond lengths (Å) and angles (deg) for 1Pt and 3Pt.
Table 6. Selected bond lengths (Å) and angles (deg) for 1Pt and 3Pt.
1Pt3Pt
Bond Lengths (Å)Bond Angles (deg)Bond Lengths (Å)Bond Angles (deg)
Pt1-N1 = 2.078(3)N1-Pt1-N2 = 79.05(13)Pt1-N1 = 2.135(4)N1-Pt1-N2 = 82.12(14)
Pt1-N2 = 2.073(4)C13-Pt1-C19 = 86.31(16)Pt1-N2 = 2.118(3)C12-Pt1-C18 = 91.38(18)
Pt1-C13 = 1.993(5)N1-Pt1-C13 = 96.33(15)Pt1-C12 = 2.001(4)N1-Pt1-C12 = 94.82(16)
Pt1-C19 = 2.007(4)N2-Pt1-C19 = 98.47(15)Pt1-C18 = 1.992(5)N2-Pt1-C18 = 91.67(16)
Pt1-C19 = 2.007(4)N1-Pt1-C19 = 176.73(17) N1-Pt1-C18 = 173.70(15)
N2-Pt1-C13 = 173.53(15) N2-Pt1-C12 = 176.92(18)
Table 7. IC50 of the compounds in A-549 and MRC-5 cell lines and selectivity indexes (SI). Cisplatin is included for comparison.
Table 7. IC50 of the compounds in A-549 and MRC-5 cell lines and selectivity indexes (SI). Cisplatin is included for comparison.
EntryCompoundIC50 A-549 (μM)IC50 MRC-5 (μM)SI
111.27 ± 0.470.58 ± 0.090.5 ± 0.2
221.19 ± 0.110.86 ± 0.050.7 ± 0.1
33>50--
44>50--
51Ag0.67 ± 0.300.53 ± 0.190.8 ± 0.5
62Ag1.16 ± 0.062.23 ± 1.081.9 ± 0.9
73Ag6.25 ± 1.1520.24 ± 2.563.2 ± 0.7
84Ag41.06 ± 2.62>50>1.2
91Pt8.26 ± 0.63>50>6.1
102Pt17.06 ± 1.318.25 ± 2.440.5 ± 0.2
113Pt0.94 ± 0.711.75 ± 1.541.9 *
124Pt2.78 ± 0.821.13 ± 0.140.4 ± 0.1
13Cisplatin16.41 ± 1.6220.06 ± 1.221.2 ± 0.1
14NH4NO3>50>50 -
* Not reported since the error is greater than the measure.
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Sandin-Mazzondo, L.; Martínez-Ilarduya, J.M.; Miguel, J.A.; Bartolomé, C.; Alonso, C. 1,10-Phenanthroline and 4,5-Diazafluorene Ketones and Their Silver(I) and Platinum(II) Complexes: Syntheses and Biological Evaluation as Antiproliferative Agents. Inorganics 2025, 13, 6. https://doi.org/10.3390/inorganics13010006

AMA Style

Sandin-Mazzondo L, Martínez-Ilarduya JM, Miguel JA, Bartolomé C, Alonso C. 1,10-Phenanthroline and 4,5-Diazafluorene Ketones and Their Silver(I) and Platinum(II) Complexes: Syntheses and Biological Evaluation as Antiproliferative Agents. Inorganics. 2025; 13(1):6. https://doi.org/10.3390/inorganics13010006

Chicago/Turabian Style

Sandin-Mazzondo, Leonardo, Jesús M. Martínez-Ilarduya, Jesús A. Miguel, Camino Bartolomé, and Concepción Alonso. 2025. "1,10-Phenanthroline and 4,5-Diazafluorene Ketones and Their Silver(I) and Platinum(II) Complexes: Syntheses and Biological Evaluation as Antiproliferative Agents" Inorganics 13, no. 1: 6. https://doi.org/10.3390/inorganics13010006

APA Style

Sandin-Mazzondo, L., Martínez-Ilarduya, J. M., Miguel, J. A., Bartolomé, C., & Alonso, C. (2025). 1,10-Phenanthroline and 4,5-Diazafluorene Ketones and Their Silver(I) and Platinum(II) Complexes: Syntheses and Biological Evaluation as Antiproliferative Agents. Inorganics, 13(1), 6. https://doi.org/10.3390/inorganics13010006

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