Preliminary Study of the Cytotoxic Activity of Pd(II) and Pt(II) Complexes Bearing P-N ligands Derived from Aminoalcohols

Abstract

Iminophosphine ligands find extensive applications in homogeneous catalysis; however, their potential antitumor activity is currently being explored. Including biologically active moieties, such as aminoalcohols, could enhance this activity further. Therefore, we have synthesised a novel series of Pd(II) and Pt(II) iminophosphine complexes incorporating aminoalcohols as biologically active moieties to explore the potential of enhancing this activity. The series of Pd(II) complexes includes complexes 2a, 2f, and 2h, which were previously reported by our research group as catalysts in Suzuki–Miyaura cross-coupling reaction in aqueous media. Besides their complete characterisation, some structures have been unequivocally corroborated by single-crystal X-ray diffraction (SC-XRD). To evaluate the cytotoxic potential of the complexes, a preliminary in vitro study was conducted on different cancerous cell lines, including using COS-7 cells as a healthy cell line. Notably, complexes 2e, 2f, and 3b exhibited selectivity towards human chronic myelogenous leukaemia (K562), demonstrating IC₅₀ values of 7.73 ± 1.4 µM, 8.53 ± 1.9 µM, and 8.83 ± 1.5 µM, respectively. Remarkably, the selectivity of these complexes surpassed that of cisplatin. Furthermore, in silico analysis indicated a higher binding energy of these complexes to DNA when compared to cisplatin.

1. Introduction

Cancer encompasses a wide range of diseases characterised by the uncontrolled and continuous division of abnormal cells that proliferate in the bloodstream, leading to the development of tumours [1]. Based on the specific tissue it impacts, cancer can be categorised into four primary groups—leukaemia, lymphoma, sarcoma, and carcinoma [2].

According to the WHO, there were a total of 18.1 million cancer cases worldwide in 2020. Breast carcinoma represented 2.26 million cases, followed by lung carcinoma with 2.20 million, and colorectal carcinoma accounted for 1.93 million [3]. Notably, cancer-related mortality has globally declined by 16% between 2000 and 2019. This decline can be attributed to the advancements in treatments, such as chemotherapy [4], which extensively employ platinum-based complexes as primary anticancer agents [5,6]. These compounds work as cross-link agents, inhibiting DNA replication, leading to apoptosis [7,8,9]; however, side effects like hepatotoxicity, nephrotoxicity, neurotoxicity, and ototoxicity have been identified due to the lack of selectivity against the cancerous cells [10]. Moreover, resistance may arise due to enhanced DNA repair mechanisms, reduced intracellular drug bioavailability, epigenetic modifications, and other factors [11,12,13]. Therefore, in recent decades, efforts have been made to synthesise new platinum-based metallodrugs with better selectivity and the ability to overcome resistance. In addition, other strategies have focused on non-platinum metal complexes like palladium, which possess structural similarity with Pt complexes and high cytotoxicity against cancerous cells [14,15,16]. In this respect, modification and design of ligands could also be employed to enhance cytotoxic activity and selectivity. Following this approach, investigation has led to ligand bearing nitrogen donor atoms, mainly imines, which have shown cytotoxicity against cancerous cell lines [17,18,19,20,21,22,23].

Iminophosphines are remarkable ligands used in homogeneous catalysis due to their electronic and steric properties, which can be easily tuned to yield specific products [24,25,26]. Their biological activity has recently been explored with metals like gold, iridium, palladium and platinum, affording promising results [27,28,29,30,31,32,33]. For example, Chiririwa and co-workers evaluated the cytotoxicity of a series of Pt(II) iminophosphine complexes against human oesophageal cancer cell lines WHCO1 and KYSE450, with IC₅₀ values between 5.29 and 9.47 µM [31]. Likewise, Motswainyana group obtained Pd(II) complexes with IC₅₀ values of 28.5 ± 0.21 and 29 ± 0.15 µM towards human breast (MCF-7) and colon (HT-29) cancer cell lines [33].

Conversely, cytotoxicity may be enhanced by functionalised ligands with biologically active fragments like amino alcohols. This moiety is found in serine and sphingosine compounds, playing a critical role in metabolomics and signalling pathways [34,35,36]. Inspired by the previous studies related to the use of iminophosphines and considering the biological activity of aminoalcohols, we decided to evaluate the preliminary cytotoxic activity of a novel series of Pd(II) and Pt(II) iminophosphine complexes bearing aminoalcohols against several cancerous cells.

2. Results and Discussion

2.1. Synthesis of Pd(II) and Pt(II) Complexes with PN Ligands

The iminophosphine (PN) ligands (1a–h) were synthesised in exceptional yields (91 to 99%) by the reaction of 2-(diphenylphosphanyl)benzaldehyde with the corresponding aminoalcohol. After purification, these ligands were subjected to reaction with dichloro(1,5-cyclooctadiene)palladium(II) [Pd(COD)₂Cl₂] or dichlorobis(dimethyl sulfide)platinum(II) [Pt(SMe₂)₂Cl₂], resulting in the formation of the Pd(II) complexes (2a–h) and the Pt(II) complexes (3a–h), according to Scheme 1. These compounds were characterised by ¹H, ¹³C{¹H} and ³¹P{¹H} NMR; FAB⁺ MS, ATR-IR, and elemental analysis. It is worth noting that the catalytic activity of the Pd(II) complexes (2a, 2f, 2h) has been previously reported in studies conducted by our research group [36]. The ν(C=N) stretching was identified using IR spectroscopy ranging from 1614 to 1639 cm⁻¹, with small shifts between Pd and Pt complexes. NMR signals exhibited successful correlations with the proposed structures of the ligands and their complexes, Figures S1–S16. Specifically, imine signals were observed in the 8.60 to 9.18 ppm range in ¹H NMR and 154.9 to 166.2 ppm in ¹³C{¹H} NMR, with a slight upfield shift upon metal coordination. In ³¹P{¹H} NMR, a more pronounced shift was observed, as the signals of the free ligands (from −14.79 to −11.95 ppm) shifted from 32.58 to 39.77 ppm for the Pd(II) complexes and from 2.90 to 5.77 ppm for the Pt(II) complexes.

The structures of ligands 1d and 1e and complexes 2d, 3d, and 3e were unequivocally determined by single-crystal X-ray diffraction (SC-XRD); crystal data and other details are shown in

Table 1. Crystal data and details of structure determination of compounds 1d, 1e, 2d, 3d and 3e.

Compound	1d	1e	2d	3d	3e
Empirical formula	C22H22NOP	C23H24NOP	C22H22Cl2NOPPd(DMSO)	C22H22Cl2NOPPt(DMSO)	C23H24Cl2NOPPt
Formula weight	347.58	361.40	602.80	705.07	627.39
Temperature (K)	298(2)	298(2)	298(2)	298(2)	278(2)
Wavelength (Å)	0.71073	0.71073	0.71073	0.71073	0.71073
Crystal system	Orthorhombic	Orthorhombic	Triclinic	Triclinic	Orthorhombic
Space group	Pbca	Pbca	P-1	P-1	Pna21
Unit cell dimensions	a = 9.4896(8) Å b = 18.4909(16) Å c = 21.8278(18) Å α = 90° β = 90° γ = 90°	a = 9.9814(10) Å b = 18.6026(17) Å c = 21.742(2) Å α = 90° β = 90° γ = 90°	a = 9.1743(9) Å b = 10.0623(9) Å c = 14.0908(14) Å α = 92.699(3)° β = 99.021(3)° γ = 96.608(3)°	a = 9.1506(4) Å b = 10.0932(4) Å c = 14.1360(5) Å α = 92.7657(9)° β = 99.0621(8)° γ = 95.9741(8)°	a = 19.2035(11) Å b = 13.0441(8) Å c = 9.6781(6) Å α = 90° β = 90° γ = 90°
Volume (Å3)	3830.2(6)	4037.1(7)	1273.3(2)	1279.51(9)	2424.3(3)
Z	8	8	2	2	4
Density (calc.) (Mg/m3)	1.205	1.189	1.572	1.831	1.719
Absorption coefficient	0.152 mm−1	0.147 mm−1	1.105 mm−1	5.861 mm−1	6.088 mm−1
F (0 0 0)	1472.0	1536.0	612.0	690.0	1216.0
Crystal size (mm3)	0.333 × 0.254 × 0.222	0.6 × 0.19 × 0.1	0.274 × 0.101 × 0.088	0.419 × 0.329 × 0.201	0.31 × 0.077 × 0.041
Theta range for data collection (°)	4.406 to 50.706°	3.746 to 50.816°	4.53 to 50.874°	4.536 to 50.62°	5.242 to 50.508°
Index ranges	−11 ≤ h ≤ 11, −16 ≤ k ≤ 22, −17 ≤ l ≤ 26	−12 ≤ h ≤ 12, −17 ≤ k ≤ 22, −26 ≤ l ≤ 26	−11 ≤ h ≤ 11, −11 ≤ k ≤ 12, −16 ≤ l ≤ 16	−10 ≤ h ≤ 10, −12 ≤ k ≤ 12, −16 ≤ l ≤ 16	−22 ≤ h ≤ 22, −14 ≤ k ≤ 15, −4 ≤ l ≤ 11
Reflections collected	11,885	21,288	27,896	22,812	6987
Independent reflections	3502 [R(int) = 0.0841, R(sigma) =0.0708]	3698 [R(int) = 0.1135, R(sigma) = 0.0943]	4464 [R(int) = 0.0697, R(sigma) = 0.0456]	4634 [R(int) = 0.0266, R(sigma) = 0.0185]	2766 [R(int) = 0.0277, R(sigma) = 0.0374]
Data/restraints/parameters	3502/1/230	3698/1/239	4464/180/356	4634/214/365	2766/331/361
Goodness-of-fit on F2	0.946	1.030	1.120	0.991	1.074
Final R indices [I > 2sigma(I)]	R1 = 0.0521, wR2 = 0.1057	R1 = 0.0793, wR2 = 0.1776	R1 = 0.0695, wR2 = 0.1843	R1 = 0.0214, wR2 = 0.0618	R1 = 0.0238, wR2 = 0.0520
R indices (all data)	R1 = 0.0835, wR2 = 0.1226	R1 = 0.1663, wR2 = 0.2340	R1 = 0.0779, wR2 = 0.1955	R1 = 0.0223, wR2 = 0.0623	R1 = 0.0301, wR2 = 0.0556
Largest diff. peak and hole (e.Å−3)	0.47 and −0.37	0.53 and −0.28	1.24 and −1.83	1.01 and −0.80	0.70 and −0.41

. Ligands 1d and 1e crystallised in an orthorhombic system (Pbca) with one molecule per asymmetric unit, displaying an E-configuration about the imine group in both cases, Figure 1. The supramolecular arrangements were mainly stabilised by a polymeric hydrogen bond along the a-axis with an N(1)-O(1) distance of 2.883 Å [−1/2 + x, y, 1/2 − z] and 2.909(5) Å [−1/2 + x, y, 1/2 − z], respectively, having in both cases a graph set descriptor C(5), Figure S17.

Complexes 2d and 3d were crystallised in dimethyl sulfoxide and are isostructural. Both complexes crystallised in a triclinic system (P-1), including a free solvent molecule in the asymmetric unit, exhibiting a distorted square-planar geometry around the metal atom bearing the bidentate PN ligand, Figure 2. The average M-N(1) and M-P(1) bond lengths were 2.041(7) and 2.202(3) Å, respectively, which is in agreement with similar complexes previously reported [26,31,33]. Moreover, a trans-influence could also be identified since the M-Cl bond distance trans to the phosphine is ca. 0.1 Å longer than that M-Cl bond distance trans to the imine [25]. Both crystalline arrangements are supported by the interaction of one or two molecules of solvent between two molecules of 3d and 2d, which gives rise to the propagation in a chain and 2D array, respectively, as shown in Figures S18 and S19.

On the other hand, complex 3e crystallised in an orthorhombic system (Pna2₁), where a tridentate PNO ligand coordinated the Pt(II) atom, Figure 3. The hapticity change in 3e compared to 3d would be related to a chloride ligand displacement by the –OH group. The angles and distances of 3e are similar to those of the 3d complex. However, a trans-influence was observed because the Pt(1)-P(2) bond distance is smaller in 3e (2.178(2) Å) than that in 3d (2.205(1) Å). This influence could be associated with a better back bonding in the M-P bond due to the oxygen donor ligand. The crystal packing in 3e was mainly established by a hydrogen bond interaction between the –OH group and the outer Cl, with an O(1)-H(1)∙∙∙Cl(2) distance of 1.882 Å [1 − x, −y, −1/2 + z]. Principal interaction parameters found for the three complexes are summarised in

Table 2. Intermolecular interaction parameters of complexes 2d, 3d and 3e.

Compound	Interaction	Length (Å) D–X···A	Length (Å) D···A	Angle (°) D–X···A	Symmetry Operation
2d	C5H5···Cl1 C23H23A···Cl1 C23H23B···S1	2.902 2.936 2.727	3.723 3.886 3.405	147.97 172.39 127.96	x, −1 + y, z −x, 1 − y, 2 − z −x, 2 − y, 2 − z
3d	C5H5···Cl1 C14H14···O2 C23H23A···Cl1 O1H1···O2	2.895 2.399 2.860 1.885	3.727 3.311 3.608 2.673	149.53 166.37 135.66 152.33	x, −1 + y, z x, y, 1 + z 1 − x, 1 − y, −z x, y, z
3e	C9H9B···Cl1 C8H8···O1 C6H6···Cl2 C7H7···Cl2 O1H1···Cl2 C16H16···Cl2 C20H20···Cl1	2.942 2.512 2.835 2.800 1.882 2.842 2.912	3.638 3.456 3.706 3.690 2.849 3.760 3.563	129.58 102.23 156.66 160.54 171.19 169.55 127.99	1 − x, −y, 1/2 + z 1 − x, −y, 1/2 + z x, y, 1 + z x, y, 1 + z 1 − x, −y, 1/2 + z 1/2 + x, 1/2 − y, z 1/2−x, −1/2 + y, 1.5 + z

.

2.2. Supramolecular Analysis

Supramolecular interactions analyses are very important to describe noncovalent interactions in a quantitative and/or qualitative manner. These analyses provide valuable insight into intermolecular forces, that could be determining to biological activity. These interactions are derived from solid-state packing, where the crystallisation solvent may play a role; therefore, direct extrapolation of such interactions from solid state to solution should be made with caution [37,38,39].

To analyse these supramolecular interactions related to close contact in molecular packing, Hirshfeld surfaces were mapped using Crystal Explorer software [40,41], which helps to distinguish between strong and weak interactions. The Hirshfeld surfaces mapped on d_norm for complexes 2d and 3d indicated strong interactions by the red dots on the hydroxyl moiety, which has close contact with the dimethyl sulfoxide solvent. In contrast, for complex 3e, the red dots are due to contacts of the hydroxyl group with the chloride anion, Figure 4 and Figure S20.

The 2D fingerprint plots of the Hirshfeld surfaces of complexes 2d, 3d, and 3e are shown in

Table 3. Representative fingerprints of non-covalent interactions of 2d, 3d, and 3e.

Compound	O∙∙∙H/H∙∙∙O (%)	Cl∙∙∙H/H∙∙∙Cl (%)	C∙∙∙H/H∙∙∙C (%)	H∙∙∙H (%)
2d	3.4	19.0	21.3	54.1
3d	7.4	19.2	21.6	48.0
3e	1.3	21.8	15.8	58.9

, while those of ligands 1d and 1e are shown in Table S1. Peaks originated by Cl∙∙∙H/H∙∙∙Cl contacts were evident, as demonstrated by the two symmetric peaks of the decomposed fingerprint of complexes 2d, 3d, and 3e. Similarly, the C∙∙∙H/H∙∙∙C contacts were close to 20% in complexes 2d and 3d. The O∙∙∙H/H∙∙∙O contacts in complex 3e were found as two classical symmetric peaks. Most peaks were found for H∙∙∙H contacts at more than 50% in all three complexes, as seen in Chart 1.

2.3. Cytotoxic Evaluation

The complexes 2a–d and 3a–d were tested on different cancer cell lines using the sulforhodamine B (SRB) protocol during a 48 h incubation period at a concentration of 25 µM and using DMSO as the solvent. Six cancer cell lines were used: U251 (human glioblastoma), PC-3 (human prostate adenocarcinoma), K562 (human chronic myelogenous leukaemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma). The National Cancer Institute, USA, provided the first five cell lines, while the National Cancer Institute, Mexico, donated the last one. A healthy monkey kidney cell line (COS-7) was included for comparative purposes. The Pd(II) complexes 2a, 2b, and 2d–f showed the highest inhibition percentages against the K562 (34.5–94.2 µM) and MCF-7 (29.1–85.3 µM) cell lines,

Table 4. Growth inhibition percentages of cancerous and non-cancerous cell lines caused by Pd(II) complexes (25 µM, 48 h).

Compound	% Inhibition
	U251	PC-3	K562	HCT-15	MCF-7	SKLU-1	COS-7
2a	11.8	25.3	34.5	9.2	44.3	18.7	26.2
2b	0	13.0	59.1	0	29.1	12.9	18.6
2c	10.7	10.9	19.3	17.1	21.3	11.3	18.2
2d	4.0	20.7	64.7	2.8	43.5	14.0	20.0
2e	21.1	31.6	89.7	33.5	85.3	15.6	30.7
2f	4.6	29.5	94.2	13.4	63.3	26.1	24.4
2g	10.06	12.5	34.6	6.0	15.3	17.1	16.2
2h	23.0	5.9	100	0	25.8	0	62.5
cisplatin	97.9	96.7	81.8	54.2	66.5	100	100

. Pd(II) complexes with a single hydroxyl group in the PN ligand exhibit greater cytotoxicity towards cancer cell lines than complexes with two hydroxyl groups in the PN ligand.

Conversely, the Pt(II) complexes (3a–h) exhibited higher cytotoxicity against the studied cancer cell lines, closely resembling the activity of the widely used metallodrug (cisplatin),

Table 5. Growth inhibition percentages of cancerous and non-cancerous cell lines caused by Pt(II) complexes (25 µM, 48 h).

Compound	% Inhibition
	U251	PC-3	K562	HCT-15	MCF-7	SKLU-1	COS-7
3a	0	0	9.9	2.4	5.4	3.0	7.4
3b	77.6	30.0	98.7	18.5	42.26	87.7	25.6
3c	0	0	12.6	0	3.6	26.2	0
3d	95.9	93.4	100	74.6	85.5	100	100
3e	100	100	100	100	100	100	100
3f	100	100	100	100	100	100	100
3g	100	1.8	100	92.3	100	97.9	100
3h	73.2	53.9	97.2	88.5	89.2	96.6	100
cisplatin	97.9	96.7	81.8	54.2	66.5	100	100

. However, 3b was the only one that showed selectivity against the K562 and SKLU-1 cell lines (98.7% and 87.7%) and low inhibition on COS-7 cells (25.6%).

The previous preliminary studies determined that the complexes 2a, 2b, 2d–f, and 3b were the best candidates for IC₅₀ studies on the K562 and COS-7 cell lines,

Table 6. IC₅₀ values (µM) of Pd(II) and Pt(II) complexes ^a.

Compound	IC50 (µM)
	K562	COS-7	SI b
2a	30.00 ± 3.0	----	----
2b	20.17 ± 0.6	56.1 ± 9.3	2.8
2d	14.96 ± 1.2	----	----
2e	7.73 ± 1.4	11.2 ± 2.5	1.4
2f	8.53 ± 1.9	26.4 ± 1.7	3.1
3b	8.83 ± 1.5	77.9 ± 7.5	8.8
cisplatin	5.30 ± 1.3	5.8 ± 0.7	1.1

^a Cell viability determined by SRB assay after treatment for 48 h; ^b SI (Selectivity Index) = IC₅₀ (COS-7)/IC₅₀ (K562).

. Compounds 2b, 2f, and 3b demonstrated a higher SI than cisplatin (SI = 1.1), with compound 3b being the most active in this study. This analysis emphasises that compound 3b proved to be the most selective, encouraging future studies to understand the mechanism of action of this compound. The stability of these compounds was explored using the most active compounds 2e and 3b by ¹H NMR spectroscopy for 24 h in DMSO-d₆ (Figures S21 and S22). No significant changes were observed over time, suggesting that the complexes were stable under the assay conditions.

2.4. Computational Results

2.4.1. Electronic Structure Optimisation

The geometrical comparison between the crystal and optimised structure for the complex 2d is reported in Table S2. As can be seen, the calculated Pd-X bonds (X = heteroatom) are similar to those obtained by the SC-XRD experiments. In addition, the angles reported for P-Pd-Cl(1) and P-Pd-N are close, with a variation of four degrees. This is expected due to the relaxation of the geometry when the implicit solvent is considered, in contrast to the solid state in the SC-XRD experiments. In the same way, the comparison between the reported crystal structure and optimised geometry for complex 3d is presented in Table S3. As in complex 2d, the electronic structure method used to describe the Pt(II) complex showed that the structural parameters remain unchanged even when implicit solvent effects are considered.

2.4.2. Molecular Docking Results

The binding energies obtained from the docking simulations are presented in

Table 7. Molecular docking between the 1AIO model and Pt(II) (2a–h) and Pd(II) (3a–h) complexes. Binding energies in Kcal/mol.

Compound	Binding Energy	Compound	Binding Energy
2a	−5.58	3a	−5.61
2b	−5.56	3b	−6.49
2c	−5.07	3c	−6.26
2d	−5.57	3d	−5.51
2e	−6.60	3e	−5.78
2f	−6.55	3f	−5.76
2g	−6.08	3g	−5.64
2h	−6.25	3h	−5.55
cisplatin	−6.25

. Complexes 2e, 2f, and 3b exhibited the highest binding energies in the DNA model with values down to −6.60 Kcal/mol. These interaction energies surpassed that of cisplatin (−6.25 Kcal/mol), used as a reference. Interestingly, the same complexes (2e, 2f, and 3b) were as well the most cytotoxic complexes with IC₅₀ ranging from 7.73 to 8.83 µM and selectivity indexes equal or higher than that of cisplatin (vide supra). Therefore, a correlation can be stablished between calculated DNA binding energy and the observed cytotoxic activity.

Figure 5 illustrates the interactions between molecules 2e, 2f, and 3b, which exhibited selectivity against the K562 cell line. Notably, substituent variations in the amino group lead to changes in hydrophilic interactions due to significant modifications in the coupling position, as depicted in complexes 2e and 2f. In the case of molecule 2e, the formation of hydrogen bonds with guanine 16B and thiamine 8A results in an inter-catenary crosslink. Conversely, molecule 2f forms an intra-catenary crosslink with adenine 15, exhibiting a distinct bonding mode and mechanism of action. On the other hand, molecule 3b demonstrated a 180° shift in the binding mode compared to the previous cases; this was attributed to a change in the metal moiety. This shift leads to hydrophobic interactions with the DNA strand’s skeleton and hydrophobic interactions with the phosphate group of thymine 15A.

3. Materials and Methods

All reagents were commercially obtained from Sigma-Aldrich (USA)and used without further purification (PdCl₂ > 99.9%, PtCl₂ > 99.9%). The ¹H, ¹³C{¹H}, ³¹P{¹H} NMR spectra were obtained on a Bruker Ascend 300 MHz NMR spectrometer and a Varian Unity Inova 500 MHz NMR spectrometer.

Chemical shifts were reported in ppm relative to TMS employing the residual signals in the solvent (DMSO-d₆) as an internal standard. ATR-IR measurements were performed on a Thermo Fisher Scientific Nicolet iS50 FTIR Spectrometer (USA). Elemental analyses were made on a Thermo Scientific Flash 2000 elemental analyser (USA), using a Mettler Toledo XP6 Automated-S Microbalance (USA) and sulfanilamide as standard (Thermo Scientific BN 217826, attained values N = 16.40%, C = 41.91%, H = 4.65%, and S = 18.63%; certified values N = 16.26%, C = 41.81%, H = 4.71%, and S = 18.62%). MS-FAB⁺ determinations were recorded in a Jeol JMS-SX102A Mass spectrometer.

3.1. General Procedure for the Synthesis of Ligands (1a–h)

A mixture containing 2-(diphenylphosphine)benzaldehyde (58 mg, 0.2 mmol) and the corresponding aminoalcohol in methanol (30 mL) was stirred for 4 h. In most cases, the yield was quantitative; therefore, further purification was unnecessary. Subsequently, the solution was evaporated under vacuum, yielding the product as a colourless oil.

For 1a: Yield: 66.1 mg (>99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (m, 1H, -CH=N), 7.96 (dd, 1H, CHAr, ³J_H-H = 7.74 Hz, ⁴J_H-H = 3.98 Hz), 7.47–7.16 (m, 8H, CHAr), 7.21 (m, 4H, CHAr), 6.83 (dd, 1H, CHAr, ³J_H-H = 7.61 Hz, ³J_H-P = 4.56 Hz), 3.40–3.54 (m, 4H, -CH₂). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 159.5 (d, -CH=N, ³J_C-P = 20.1 Hz), 139.0 (d, C-H, ²J_C-P = 17.0 Hz), 136.8 (d, C-P, ¹J_C-P = 20.7 Hz), 136.4 (d, C-P, ¹J_C-P = 10.1 Hz), 133.4 (d, C-H, ²J_C-P = 19.8 Hz), 133.3 (s, C-H), 130.0 (s, C-H), 129.0–128.6 (m, C-H), 127.8 (d, C-H, ³J_C-P = 4.32 Hz), 63.3 (s, -CH₂), 60.6 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -14.72. Elem. Anal. Calcd. for C₂₁H₂₀NOP: C, 75.66; H, 6.05; N, 4.20. Found: C, 74.62; H, 5.99; N, 4.12.

For 1b: Yield: 68.2 mg (>98%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.76 (m, 1H, -CH=N), 7.96 (dd, 1H, CHAr, ³J_H-H = 7.72 Hz, ⁴J_H-H = 3.93 Hz), 7.47–7.27 (m, 8H, CHAr), 7.19 (m, 4H, CHAr), 6.81 (dd, 1H, CHAr, ³J_H-H = 7.64 Hz, ³J_H-P = 4.53 Hz), 3.70 (m, 1H, -CH), 3.43 (m, 1H, -CHH), 3.31 (m, 1H, -CHH), 0.89 (d, 3H, -CH₃, ³J_H-H = 6.10 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 159.5 (s, -CH=N, ³J_C-P = 20.1 Hz), 139.0 (d, C-H, ²J_C-P = 17.0 Hz), 136.8 (d, C-P, ¹J_C-P = 20.9 Hz), 136.5 (d, C-P, ¹J_C-P = 10.2 Hz), 136.4 (d, C-P, ¹J_C-P = 9.8 Hz), 133.54 (d, C-H, ²J_C-P = 20.08 Hz), 133.5 (d, C-H, ²J_C-P = 19.96 Hz), 130.3 (s, C-H), 133.0 (s, C-H), 129.1–128.6 (m, C-H), 128.2 (d, C-H, ³J_C-P = 4.1 Hz), 68.87 (s, -CH₂), 65.97 (s,-CH), 21.27 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -14.18. Elem. Anal. Calcd. for C₂₂H₂₂NOP: C, 76.06; H, 6.38; N, 4.03. Found: C, 74.68; H, 6.33; N, 3.96.

For 1c: Yield: 72.0 mg (>99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (m, 1H, -CH=N), 7.96 (dd, 1H, CHAr, ³J_H-H = 7.75 Hz, ⁴J_H-H = 3.97 Hz), 7.50–7.30 (m, 8H, CHAr), 7.20 (m, 4H, CHAr), 6.84 (dd, 1H, CHAr, ³J_H-H = 7.72 Hz, ³J_H-P = 4.55 Hz), 3.62 (m, 1H, -CH), 3.61 (m, 1H, -CHH), 3.40–3.28 (m, 2H, -CH₂), 3.34 (m, 1H, -CHH). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 159.7 (s, -CH=N, ³J_C-P = 19.79 Hz), 139.1 (d, C-H, ²J_C-P = 17.3 Hz), 136.5 (d, C-P, ¹J_C-P = 10.1 Hz), 136.4 (d, C-P, ¹J_C-P = 10.1 Hz), 133.51 (d, C-H, ²J_C-P = 19.9 Hz), 133.5 (d, C-H, ²J_C-P = 20.6 Hz), 133.1 (s, C-H), 130.3 (s, C-H), 129.1–128.7 (m, C-H), 128.2 (d, C-H, ³J_C-P = 4.2 Hz), 71.18 (s,-CH), 64.17 (s, -CH₂), 64.01 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -14.79. Elem. Anal. Calcd. for C₂₂H₂₂NO₂P: C, 72.71; H, 6.10; N, 3.85. Found: C, 73.40; H, 6.00; N, 3.83.

For 1d: Yield: 68.9 mg (>99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.77 (m, 1H, -CH=N), 7.93 (dd, 1H, CHAr, ³J_H-H = 7.68 Hz, ⁴J_H-H = 3.92 Hz), 7.46–7.27 (m, 8H, CHAr), 7.20 (m, 4H, CHAr), 6.81 (dd, 1H, CHAr, ³J_H-H = 7.71 Hz, ³J_H-P = 4.58 Hz), 3.32–3.17 (m, 1H, -CH), 3.32–3.17 (m, 2H, -CH₂), 0.89 (d, 3H, -CH₃, ³J_H-H = 5.59 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 159.6 (s, -CH=N, ³J_C-P = 18.13 Hz), 139.0 (d, C-H, ²J_C-P = 16.5 Hz), 136.8 (d, C-P, ¹J_C-P = 21.4 Hz), 136.7 (d, C-P, ¹J_C-P = 9.70 Hz), 136.5 (d, C-P, ¹J_C-P = 9.8 Hz), 133.56 (d, C-H, ²J_C-P = 19.9 Hz), 133.5 (d, C-H, ²J_C-P = 19.9 Hz), 132.9 (s, C-H), 130.1 (s, C-H), 129.0–128.5 (m, C-H), 128.2 (d, C-H, ³J_C-P = 4.0 Hz), 67.5 (s, -CH), 65.9 (s, -CH₂), 18.5 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -13.57. Elem. Anal. Calcd. for C₂₂H₂₂NOP: C, 76.06; H, 6.38; N, 4.03. Found: C, 75.27; H, 6.45; N, 4.05.

For 1e: Yield: 71.6 mg (>99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.71 (m, 1H, -CH=N), 7.94 (ddd, 1H, CHAr, ³J_H-H = 7.75 Hz, ⁴J_H-H = 3.94 Hz, ⁵J_H-H = 1.40 Hz), 7.50–7.28 (m, 8H, CHAr), 7.20 (m, 4H, CHAr), 6.79 (dd, 1H, CHAr, ³J_H-H = 7.63 Hz, ³J_H-P = 4.47 Hz), 3.42 (m, 1H, -CHH), 3.15 (m, 1H, -CHH), 2.92 (m, 1H, -CH), 1.47 (m, 1H, -CHH), 1.21 (m, 1H, -CHH), 0.46 (t, 3H, -CH₃, ³J_H-H = 7.64 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 158.1 (s, -CH=N, ³J_C-P = 17.7 Hz), 139.0 (d, C-H, ²J_C-P = 16.5 Hz), 136.8 (d, C-P, ¹J_C-P = 20.9 Hz), 136.7 (d, C-P, ¹J_C-P = 10.0 Hz), 136.5 (d, C-P, ¹J_C-P = 9.8 Hz), 133.52 (d, C-H, ²J_C-P = 20.03 Hz), 132.8 (s, C-H), 130.1 (s, C-H), 129.0–128.5 (m, C-H), 128.3 (d, C-H, ³J_C-P = 4.0 Hz), 74.58 (s, -CH), 64.76 (s, -CH₂), 24.61 (s, -CH₂), 10.25 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -13.39. Elem. Anal. Calcd. for C₂₃H₂₄NOP: C, 76.43; H, 6.69; N, 3.88. Found: C, 77.11; H, 6.74; N, 3.92.

For 1f: Yield: 65.8 mg (91%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (m, 1H, -CH=N), 7.91 (dd, 1H, CHAr, ³J_H-H = 7.74 Hz, ⁴J_H-H = 4.70 Hz), 7.46–7.36 (m, 8H, CHAr), 7.21 (m, 4H, CHAr), 6.76 (dd, 1H, CHAr, ³J_H-H = 7.96 Hz, ³J_H-P = 4.70 Hz), 3.15 (s, 2H, -CH₂), 0.90 (s, 6H, -CH₃). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 154.9 (s, -CH=N, ³J_C-P = 16.1 Hz), 139.1 (d, C-H, ²J_C-P = 15.1 Hz), 136.9 (d, C-P, ¹J_C-P = 19.7 Hz), 136.8 (d, C-P, ¹J_C-P = 10.0 Hz), 133.65 (d, C-H, ²J_C-P = 20.0 Hz), 132.7 (s, C-H), 129.93 (s, C-H), 129.0 -128.5 (m, C-H), 128.2 (d, C-H, ³J_C-P = 3.7 Hz), 69.47 (s,-CH₂), 61.73 (s, -CC₃), 23.75 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -12.03. Elem. Anal. Calcd. for C₂₃H₂₄NOP: C, 76.43; H, 6.69; N, 3.88. Found: C, 75.23; H, 6.68; N, 3.86.

For 1g: Yield: 72.0 mg (99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.80 (m, 1H, -CH=N), 7.96 (ddd, 1H, CHAr, ³J_H-H = 7.82 Hz, ⁴J_H-H = 4.03 Hz, ⁵J_H-H = 1.39 Hz), 7.48–7.30 (m, 8H, CHAr), 7.19 (m, 4H, CHAr), 6.82 (dd, 1H, CHAr, ³J_H-H = 7.70 Hz, ³J_H-P = 4.50 Hz), 3.49 (m, 2H, -CHH), 3.22 (m, 2H, -CHH), 3.19 (m, 1H, -CH). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 159.0 (s, -CH=N, ³J_C-P = 18.5 Hz), 139.2 (d, C-H, ²J_C-P = 16.9 Hz), 136.9–136.6 (m, C-P), 136.7 (d, C-P, ¹J_C-P = 9.8 Hz), 133.50 (d, C-H, ²J_C-P = 19.9 Hz), 133.1 (s, C-H), 130.3 (s, C-H), 129.0–128.6 (m, C-H), 128.4 (d, C-H, ³J_C-P = 4.3 Hz), 74.75 (s, -CH), 62.28 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -14.18. Elem. Anal. Calcd. for C₂₂H₂₂NO₂P: C, 72.71; H, 6.10; N, 3.85. Found: C, 71.80; H, 6.19; N, 3.78.

For 1h: Yield: 74.7 mg (99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (m, 1H, -CH=N), 7.96 (dd, 1H, CHAr, ³J_H-H = 7.64 Hz, ⁴J_H-H = 3.91 Hz), 7.48–7.28 (m, 8H, CHAr), 7.20 (m, 4H, CHAr), 6.77 (dd, 1H, CHAr, ³J_H-H = 7.65 Hz, ³J_H-P = 4.61 Hz), 3.32 (d, 2H, -CHH, ³J_H-H = 10.44 Hz), 3.16 (d, 2H, -CHH, ³J_H-H = 10.47 Hz), 0.88 (s, 3H, -CH₃). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 156.5 (s, -CH=N, ³J_C-P = 20.1 Hz), 139.3 (d, C-H, ²J_C-P = 15.3 Hz), 137.0–136.6 (m, C-P), 136.9 (d, C-P, ¹J_C-P = 9.6 Hz), 133.58 (d, C-H, ²J_C-P = 20.1 Hz), 132.8 (s, C-H), 129.8 (s, C-H), 128.9–128.4 (m, C-H), 128.8–128.4 (m, C-H), 65.58 (s, -CC₃), 65.31 (s, -CH₂), 17.97 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ -11.95. Elem. Anal. Calcd. for C₂₃H₂₄NO₂P: C, 73.19; H, 6.41; N, 3.71. Found: C, 72.94; H, 6.39; N, 3.70.

3.2. General Procedure for Synthesis of Pd(II)-Complexes (2a–h)

The corresponding iminophosphine ligand (1a–h, 0.2 mmol) and [Pd(COD)Cl₂] (0.2 mmol) were dissolved in 25 mL of THF. The mixture was refluxed for 12 h, and the product was obtained as a yellow precipitate. After that, the product (2a–h) was collected by filtration and washed with THF and cold ethyl ether.

For 2a: Yield: 101.2 mg (>99%). M. p. 220 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H, -CH=N), 8.04 (dd, 1H, CHAr, ³J_H-H = 7.86 Hz, 4.16 Hz), 7.91 (t, 1H, CHAr, ³J_H-H = 7.53 Hz), 7.77 (t, 1H, CHAr, ³J_H-H = 7.63 Hz), 7.65 (m, 2H, CHAr), 7.55 (dd, 4H, CHAr, ³J_H-H = 7.76 Hz, 3.02 Hz), 7.44 (dd, 4H, CHAr, ³J_H-H = 12.96 Hz, 7.58 Hz), 7.07 (dd, 1H, CHAr, ³J_H-H = 9.08 Hz, 9.08 Hz), 4.32 (t, 2H, -CH₂, ³J_H-H = 5.73 Hz), 3.56 (t, 2H, -CH₂, ³J_H-H = 5.33 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 166.2 (d, -CH=N, ³J_C-P = 8.5 Hz), 136.8 (d, C-H, ³J_C-P = 8.8 Hz), 136.5 (d, C-H, ¹J_C-P = 50.7 Hz), 134.4 (d, C-H, ³J_C-P = 7.8 Hz), 133.66 (d, C-H, ²J_C-P = 2.2 Hz), 133.6 (d, C-H, ²J_C-P = 16.2 Hz), 133.6 (d, C-H, ²J_C-P = 11.1 Hz), 133.4 (d, C-H, ⁴J_C-P = 2.54 Hz), 132.3 (d, C-H, ⁴J_C-P = 3.05 Hz), 129.0 (d, C-H, ³J_C-P = 11.9 Hz), 125.7 (d, C-P, ¹J_C-P = 60.9 Hz), 67.2 (s, -CH₂), 60.1 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 32.06. MS (FAB⁺): 476 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1628 (s, C=N). Elem. Anal. Calcd. for C₂₁H₂₀Cl₂NOPPd: C, 49.39; H, 3.95; N, 2.74. Found: C, 49.29; H, 4.01; N, 2.70.

For 2b: Yield: 82.8 mg (78.87%). M. p. 224 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s, 1H, -CH=N), 7.94 (dd, 1H, CHAr, ³J_H-H = 7.80 Hz, ⁴J_H-H = 4.29 Hz), 7.92 (t, 1H, CHAr, ³J_H-H = 7.54 Hz), 7.79 (t, 1H, CHAr, ³J_H-H = 7.61 Hz), 7.63 (m, 1H, CHAr), 7.53–7.41 (m, 8H, CHAr), 7.14 (dd, 1H, CHAr, ³J_H-H = 10.52 Hz, ³J_H-P = 7.69 Hz), 4.35 (dd, 1H, -CHH, ²J_H-H = 11.48 Hz, ³J_H-H = 3.99 Hz), 4.15 (m, 2H, -CH₂), 4.06 (dd, 1H, -CHH, ²J_H-H = 11.25 Hz, ³J_H-H = 7.23 Hz), 0.91 (d, 3H, -CH₃, ³J_H-H = 5.83 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 166.0 (s, -CH=N, ³J_C-P = 7.95 Hz), 137.4 (d, C-H, ³J_C-P = 8.9 Hz), 136.3 (d, C-H, ²J_C-P = 16.4 Hz), 134.6 (d, C-H, ³J_C-P = 7.8 Hz), 133.6 (d, C-H, ²J_C-P = 11.2 Hz), 133.58 (d, C-H, ²J_C-P = 10.8 Hz), 133.5 (d, C-H, ⁴J_C-P = 2.5 Hz), 133.0 (s, C-H, ³J_C-P = 3.0 Hz), 132.4 (d, C-H, ⁴J_C-P = 2.7 Hz), 132.3 (d, C-H, ⁴J_C-P = 2.8 Hz), 129.1 (d, C-H, ³J_C-P = 11.9 Hz), 129.0 (d, C-H, ³J_C-P = 11.9 Hz), 126.6 (d, C-P, ¹J_C-P = 62.3 Hz), 126.0 (d, C-P, ¹J_C-P = 61.2 Hz), 119.1 (d, C-P, ¹J_C-P = 51.3 Hz), 72.0 (s, -CH₂), 66.3 (s,-CH), 19.8 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 32.58. MS (FAB⁺): 490 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1629 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NOPPd: C, 50.36; H, 4.23; N, 2.67. Found: C, 50.25; H, 4.25; N, 2.66.

For 2c: Yield: 85.6 mg (79.20%). M. p. 240 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (s, 1H, -CH=N), 8.06 (dd, 1H, CHAr, ³J_H-H = 6.90 Hz, ⁴J_H-H = 4.32 Hz), 7.92 (t, 1H, CHAr, ³J_H-H = 7.54 Hz), 7.79 (t, 1H, CHAr, ³J_H-H = 7.61 Hz), 7.65 (m, 1H, CHAr), 7.60–7.40 (m, 8H, CHAr), 7.15 (dd, 1H, CHAr, ³J_H-H = 10.52 Hz, ³J_H-P = 7.64 Hz), 4.63 (m, 1H, -CHH), 4.02 (m, 1H, -CHH), 3.28 (m, 2H, -CH₂), 3.20 (m, 1H, -CH). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 166.2 (s, -CH=N, ³J_C-P = 8.0 Hz), 137.4 (d, C-H, ³J_C-P = 9.2 Hz), 136.4 (d, C-H, ²J_C-P = 16.7 Hz), 134.6 (s, C-H, ³J_C-P = 7.7 Hz), 134.1 (d, C-H, ³J_C-P = 2.1 Hz), 133.7 (d, C-H, ²J_C-P = 11.2 Hz), 133.6–133.5 (m, C-H), 132.5 (d, C-H, ⁴J_C-P = 2.8 Hz), 132.3 (d, C-H, ⁴J_C-P = 2.7 Hz), 129.1 (d, C-H, ³J_C-P = 12.4 Hz), 129.0 (d, C-H, ³J_C-P = 12.5 Hz), 126.6 (d, C-P, ¹J_C-P = 63.3 Hz), 126.0 (d, C-P, ¹J_C-P = 60.7 Hz), 119.2 (d, C-P, ¹J_C-P = 51.0 Hz), 71.0 (s, -CH), 67.9 (s, -CH₂), 62.2 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 37.42. MS (FAB⁺): 506 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1634 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NO₂PPd: C, 48.87; H, 4.10; N, 2.59. Found: C, 48.07; H, 4.05; N, 2.50.

For 2d: Yield: 86.5 mg (82.43%). M. p. 217 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s, 1H, -CH=N), 8.14 (dd, 1H, CHAr, ³J_H-H = 7.77 Hz, ⁴J_H-H = 4.34 Hz), 7.92 (t, 1H, CHAr, ³J_H-H = 7.51 Hz), 7.82 (t, 1H, CHAr, ³J_H-H = 7.59 Hz), 7.64–7.42 (m, 10H, CHAr), 7.20 (dd, 1H, CHAr, ³J_H-H = 10.83 Hz, ³J_H-P = 7.51 Hz), 4.67 (m, 1H, -CH), 3.55 (m, 2H, -CH₂), 1.27 (d, 3H, -CH₃, ³J_H-H = 7.20 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 164.2 (s, -CH=N, ³J_C-P = 6.9 Hz), 137.7 (d, C-H, ³J_C-P = 9.0 Hz), 136.3 (d, C-H, ²J_C-P = 16.5 Hz), 134.9 (s, C-H, ³J_C-P = 8.0 Hz), 133.9 (d, C-H, ³J_C-P = 3.0 Hz), 133.8–133.4 (m, C-H), 133.7 (d, C-H, ²J_C-P = 11.3 Hz), 132.8 (d, C-H, ⁴J_C-P = 2.4 Hz), 132.5 (d, C-H, ⁴J_C-P = 3.2 Hz), 129.5 (d, C-H, ³J_C-P = 11.8 Hz), 129.0 (d, C-H, ³J_C-P = 12.2 Hz), 126.4 (d, C-P, ¹J_C-P = 60.67 Hz), 126.2 (d, C-P, ¹J_C-P = 64.9 Hz), 118.5 (d, C-P, ¹J_C-P = 53.0 Hz), 70.4 (s, -CH), 64.2 (s,-CH₂), 18.57 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 36.05. MS (FAB⁺): 490 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1639 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NOPPd: C, 51.07; H, 4.53; N, 2.55. Found: C, 50.13; H, 4.42; N, 2.50.

For 2e: Yield: 83.7 mg (77.71%). M. p. 215 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 1H, -CH=N), 8.17 (dd, 1H, CHAr, ³J_H-H = 7.65 Hz, ⁴J_H-H = 4.29 Hz), 7.98 (t, 1H, CHAr, ³J_H-H = 7.58 Hz), 7.87 (t, 1H, CHAr, ³J_H-H = 7.60 Hz), 7.75–7.40 (m, 10H, CHAr), 7.23 (dd, 1H, CHAr, ³J_H-H = 11.16 Hz, ³J_H-P = 7.62 Hz), 4.22 (m, 1H, -CH), 1.76 (m, 2H, -CH₂), 1.70 (m, 2H, -CH₂), 0.46 (t, 3H, -CH₃, ³J_H-P = 7.29 Hz). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 164.3 (s, -CH=N, ³J_C-P = 7.95 Hz), 138.0 (d, C-H, ³J_C-P = 9.0 Hz), 135.9 (d, C-H, ²J_C-P = 16.6 Hz), 135.1 (s, C-H, ³J_C-P = 8.3 Hz), 134.1 (d, C-H, ³J_C-P = 3.7 Hz), 133.8–133.3 (m, C-H), 133.6 (d, C-H, ²J_C-P = 12.3 Hz), 133.5 (d, C-H, ²J_C-P = 12.1 Hz), 132.95 (d, C-H, ⁴J_C-P = 3.0 Hz), 132.5 (d, C-H, ⁴J_C-P = 3.2 Hz), 129.6 (d, C-H, ³J_C-P = 11.8 Hz), 128.9 (d, C-H, ³J_C-P = 12.6 Hz), 125.9 (d, C-P, ¹J_C-P = 66.1 Hz), 125.4 (d, C-P, ¹J_C-P = 60.4 Hz), 118.3 (d, C-P, ¹J_C-P = 54.2 Hz), 76.7 (s, -CH), 63.2 (s,-CH₂), 24.9 (s,-CH₂), 9.47 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 37.45. MS (FAB⁺): 504 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1635 (s, C=N). Elem. Anal. Calcd. For C₂₃H₂₄Cl₂NOPPd: C, 51.27; H, 4.49; N, 2.59. Found: C, 50.33; H, 4.68; N, 2.51.

For 2f: Yield: 77.0 mg (71.42%). M. p. 207 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s, 1H, -CH=N), 8.19 (dd, 1H, CHAr, ³J_H-H = 7.73 Hz, ⁴J_H-H = 4.45 Hz), 7.95 (t, 1H, CHAr, ³J_H-H = 7.57 Hz), 7.86 (t, 1H, CHAr, ³J_H-H = 7.57 Hz), 7.70–7.53 (m, 10H, CHAr), 7.39 (dd, 1H, CHAr, ³J_H-H = 10.98 Hz, ³J_H-P = 7.64 Hz), 3.64 (s, 2H, -CH₂), 1.49 (s, 3H, -CH₃). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 161.3 (s, -CH=N, ³J_C-P = 6.0 Hz), 139.2 (d, C-H, ³J_C-P = 9.3 Hz), 136.1 (d, C-H, ²J_C-P = 17.1 Hz), 135.3 (d, C-H, ³J_C-P = 8.4 Hz), 134.1 (s, C-H, ³J_C-P = 3.3 Hz), 133.9–133.5 (m, C-H), 133.6 (d, C-H, ²J_C-P = 11.8 Hz), 132.8 (d, C-H, ⁴J_C-P = 3.1 Hz), 129.3 (d, C-H, ³J_C-P = 12.3 Hz), 126.1 (d, C-P, ¹J_C-P = 64.9 Hz), 117.6 (d, C-P, ¹J_C-P = 54.8 Hz), 74.7 (s, -CC₃), 70.3 (s,-CH₂), 23.18 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 39.77. MS (FAB⁺): 504 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1620 (s, C=N). Elem. Anal. Calcd. for C₂₃H₂₄Cl₂NOPPd: C, 51.93; H, 4.77; N, 2.48. Found: C, 51.60; H, 4.86; N, 2.53.

For 2g: Yield: 78.1 mg (72.22%). M. p. 215 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.93 (s, 1H, -CH=N), 8.19 (dd, 1H, CHAr, ³J_H-H = 7.73 Hz, ⁴J_H-H = 4.45 Hz), 7.95 (t, 1H, CHAr, ³J_H-H = 7.57 Hz), 7.86 (t, 1H, CHAr, ³J_H-H = 7.54 Hz), 7.70–7.53 (m, 10H, CHAr), 7.39 (dd, 1H, CHAr, ³J_H-H = 10.99 Hz, ³J_H-P = 7.68 Hz), 4.35 (m, 1H, -CH), 3.74 (m, 2H, -CH₂). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 165.4 (s, -CH=N, ³J_C-P = 6.7 Hz), 138.3 (d, C-H, ³J_C-P = 9.3 Hz), 135.8 (d, C-H, ²J_C-P = 16.4 Hz), 135.2 (d, C-H, ³J_C-P = 8.0 Hz), 134.3 (s, C-H, ³J_C-P = 3.3 Hz), 133.9–133.5 (m, C-H), 133.7 (d, C-H, ²J_C-P = 11.65 Hz), 132.6 (d, C-H, ⁴J_C-P = 3.1 Hz), 129.2 (d, C-H, ³J_C-P = 12.2 Hz), 126.4 (d, C-P, ¹J_C-P = 64.3 Hz), 118.2 (d, C-P, ¹J_C-P = 55.5 Hz), 76.1 (s, -CH), 61.3 (s, -CH₂). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 37.73. MS (FAB⁺): 506 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1637 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NO₂PPd: C, 49.62; H, 4.40; N, 2.48. Found: C, 49.01; H, 4.39; N, 2.46.

For 2h: Yield: 54.6 mg (49.24%). M. p. 215 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.71 (s, 1H, -CH=N), 8.45 (dd, 1H, CHAr, ³J_H-H = 7.68 Hz, ⁴J_H-H = 4.47 Hz), 7.97 (t, 1H, CHAr, ³J_H-H = 7.61 Hz), 7.88 (t, 1H, CHAr, ³J_H-H = 7.61 Hz), 7.75–7.50 (m, 10H, CHAr), 7.41 (dd, 1H, CHAr, ³J_H-H = 10.99 Hz, ³J_H-P = 7.68 Hz), 3.77 (s, 1H, -CH₂), 1.45 (s, 3H, -CH₃). ¹³C{¹H} NMR (75 MHz, DMSO-d₆) δ 162.9 (s, -CH=N, ³J_C-P = 6.2 Hz), 139.3 (d, C-H, ³J_C-P = 9.5 Hz), 136.0 (d, C-H, ²J_C-P = 17.4 Hz), 135.3 (d, C-H, ³J_C-P = 8.0 Hz), 134.2 (s, C-H, ³J_C-P = 3.5 Hz), 133.9–133.5 (m, C-H), 133.7 (d, C-H, ²J_C-P = 11.5 Hz), 132.6 (d, C-H, ⁴J_C-P = 3.0 Hz), 129.2 (d, C-H, ³J_C-P = 12.2 Hz), 126.5 (d, C-P, ¹J_C-P = 65.2 Hz), 117.4 (d, C-P, ¹J_C-P = 54.7 Hz), 78.3 (s, -CC₃), 65.4 (s,-CH₂), 17.6 (s, -CH₃). ³¹P{¹H} NMR (121.5 MHz, DMSO-d₆): δ 39.16. MS (FAB⁺): 520 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1635 (s, C=N). Elem. Anal. Calcd. for C₂₃H₂₄Cl₂NO₂PPd: C, 49.80; H, 4.36; N, 2.52. Found: C, 49.82; H, 4.34; N, 2.52.

3.3. General Procedure for Synthesis of Pt(II)-Complexes (3a–h)

The corresponding iminophosphine ligand (1a–h, 0.2 mmol) and [Pt(SMe₂)₂Cl₂] (0.2 mmol) were dissolved in 25 mL of THF. The mixture was refluxed for 12 h, and the product was obtained as a yellow-green precipitate. After that, the product (3a–h) was collected by filtration and washed with THF and cold ethyl ether.

For 3a: Yield: 79.7 mg (66.53%). M. p. 260 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H, -CH=N), 7.99 (dd, 1H, CHAr, ³J_H-H = 7.73 Hz, ⁴J_H-H = 4.05 Hz), 7.86 (t, 1H, CHAr, ³J_H-H = 7.57 Hz), 7.80 (t, 1H, CHAr, ³J_H-H = 7.61 Hz), 7.61 (m, 2H, CHAr), 7.53 (dd, 4H, CHAr, ³J_H-H = 7.58 Hz, ³J_H-H = 2.78 Hz), 7.41 (dd, 4H, CHAr, ³J_H-H = 12.81 Hz, ³J_H-P = 7.60 Hz), 7.08 (d, 1H, CHAr, ³J_H-H = 9.07 Hz), 4.55 (m, 2H, -CH₂), 3.59 (m, 2H, -CH₂). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 166.0 (s, -CH=N), 136.7 (d, C-H, ²J_C-P = 13.8 Hz), 136.2 (d, C-H, ³J_C-P = 9.0 Hz), 134.3 (d, C-H, ³J_C-P = 8.13 Hz), 133.5 (d, C-H, ²J_C-P = 11.0 Hz), 132.9 (s, C-H), 131.9 (d, C-H, ⁴J_C-P = 2.8 Hz), 132.8 (s, C-H), 128.7 (d, C-H, ³J_C-P = 11.7 Hz), 125.5 (d, C-P, ¹J_C-P = 68.0 Hz), 120.3 (d, C-P, ¹J_C-P = 59.1 Hz), 68.1 (s, -CH₂), 60.1 (s, -CH₂). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 4.54 (d, P-Pt, ¹J_P-Pt = 1876.77 Hz). MS (FAB⁺): 564 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1632 (s, C=N). Elem. Anal. Calcd. for C₂₁H₂₀Cl₂NOPPt: C, 42.08; H, 3.36; N, 2.33. Found: C, 41.67; H, 3.30; N, 2.39.

For 3b: Yield: 74.8 mg (60.96%). M. p. 259 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H, -CH=N), 8.01 (dd, 1H, CHAr, ³J_H-H = 6.52 Hz, ⁴J_H-H = 3.98 Hz), 7.87 (t, 1H, CHAr, ³J_H-H = 7.55 Hz), 7.81 (t, 1H, CHAr, ³J_H-H = 7.40 Hz), 7.78 (dd, 2H, CHAr, ³J_H-H = 12.44 Hz, ³J_H-P = 7.71 Hz), 7.61 (m, 2H, CHAr), 7.53 (dd, 4H, CHAr, ³J_H-H = 7.63 Hz, ³J_H-H = 2.44 Hz), 7.38 (dd, 2H, CHAr, ³J_H-H = 12.51 Hz, ³J_H-P = 7.46 Hz), 7.13 (s, 1H, CHAr), 4.60 (m, 1H, -CH₂), 4.27 (m, 1H, -CH₂), 4.18 (m, 1H, -CH₂), 0.81 (s, 3H, -CH₃). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 164.9 (s, -CH=N), 136.8–136.5 (m, C-H), 134.3 (d, C-H, ³J_C-P = 8.2 Hz), 133.5 (d, C-H, ²J_C-P = 11.1 Hz), 133.4 (d, C-H, ²J_C-P = 10.9 Hz), 133.2 (s, C-H), 133.1 (s, C-H), 132.0 (d, C-H, ⁴J_C-P = 2.8 Hz), 131.9 (d, C-H, ⁴J_C-P = 2.8 Hz), 128.6 (d, C-H, ³J_C-P = 11.8 Hz), 126.3 (d, C-P, ¹J_C-P = 68.1 Hz), 125.7 (d, C-P, ¹J_C-P = 66.1 Hz), 119.0 (d, C-P, ¹J_C-P = 62.9 Hz), 72.9 (s, -CH₂), 65.7 (s,-CH), 19.9 (s, -CH₃). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 3.73 (d, P-Pt, ¹J_P-Pt = 1890.94 Hz). MS (FAB⁺): 578 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1622 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NOPPt: C, 43.07; H, 3.61; N, 2.28. Found: C, 43.06; H, 3.59; N, 2.21.

For 3c: Yield: 98.4 mg (78.19%). M. p. 265 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H, -CH=N), 8.01 (dd, 1H, CHAr, ³J_H-H = 7.06 Hz, ⁴J_H-H = 4.21 Hz), 7.86 (t, 1H, CHAr, ³J_H-H = 7.50 Hz), 7.80 (t, 1H, CHAr, ³J_H-H = 7.76 Hz), 7.61 (m, 2H, CHAr), 7.70–7.45 (m, 4H, CHAr), 7.13 (d, 1H, CHAr, ³J_H-H = 9.07 Hz), 4.98 (s, 1H, -CHH), 4.10 (dd, 1H, -CHH, ³J_H-H = 11.62 Hz, ³J_H-H = 7.68 Hz), 3.98 (m, 1H, -CH), 3.23 (d, 1H, -CHH, ³J_H-H = 7.95 Hz), 3.11 (s, 1H, -CHH). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 165.1 (s, -CH=N), 136.7–136.5 (m, C-H), 134.2 (d, C-H, ³J_C-P = 8.0 Hz), 133.5 (d, C-H, ²J_C-P = 11.1 Hz), 133.5 (d, C-H, ²J_C-P = 11.0 Hz), 133.1 (s, C-H), 133.0 (s, C-H), 132.0 (s, C-H), 131.8 (s, C-H), 128.8 (d, C-H, ³J_C-P = 11.8 Hz), 128.6 (d, C-H, ³J_C-P = 11.7 Hz), 126.2 (d, C-P, ¹J_C-P = 66.9 Hz), 125.9 (d, C-P, ¹J_C-P = 69.8 Hz), 119.9 (d, C-P, ¹J_C-P = 59.2 Hz), 70.5 (s, -CH), 68.8 (s, -CH₂), 62.0 (s, -CH₂). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 3.90 (d, P-Pt, ¹J_P-Pt = 1894.99 Hz). MS (FAB⁺): 594 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1634 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NO₂PPt: C, 41.98; H, 3.52; N, 2.22. Found: C, 41.57; H, 3.46; N, 2.20.

For 3d: Yield: 89.8 mg (73.21%). M. p. 256 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H, -CH=N), 8.10 (m, 1H, CHAr), 7.86 (t, 1H, CHAr, ³J_H-H = 6.78 Hz), 7.81 (m, 1H, CHAr), 7.70–7.29 (m, 6H, CHAr), 7.07 (m, 1H, CHAr), 5.20 (s, 1H, -CH), 3.50–3.30 (m, 2H, -CH₂), 1.28 (s 3H, -CH₃). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 163.1 (s, -CH=N), 137.4–136.0 (m, C-H), 134.2 (d, C-H, ³J_C-P = 8.0 Hz), 134.0–132.0 (m, C-H), 133.5 (d, C-H, ²J_C-P = 13.6 Hz), 133.5 (d, C-H, ²J_C-P = 11.7 Hz), 132.4 (s, C-H), 132.1 (s, C-H), 129.0 (d, C-H, ³J_C-P = 12.2 Hz), 128.7 (d, C-H, ³J_C-P = 11.3 Hz), 125.1 (d, C-P, ¹J_C-P = 58.7 Hz), 120.1 (s, C-P), 133.0 (s, C-H), 69.6 (s, -CH), 63.8 (s, -CH₂), 18.5 (s, -CH₃). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 5.77 (d, P-Pt, ¹J_P-Pt = 1864.66 Hz). MS (FAB⁺): 578 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1614 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NOPPt: C, 43.07; H, 3.61; N, 2.28. Found: C, 42.98; H, 3.55; N, 2.17.

For 3e: Yield: 104.8 mg (83.54%). M. p. 256–259 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H, -CH=N), 8.20–8.06 (m, 1H, CHAr), 7.98–7.82 (m, 2H, CHAr), 7.70–7.40 (m, 6H, CHAr), 7.36 (m, 1H, CHAr), 4.20–3.60 (m, 3H, -CH, -CH₂), 1.80 (m, 2H, -CH₂), 0.60 (t, 3H, -CH₃, ³J_H-H = 7.36 Hz). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 163.0 (s, -CH=N), 138.2 (s, C-H), 135.3 (s, C-H), 133.8 (d, C-H, ²J_C-P = 11.1 Hz), 133.6 (d, C-H, ²J_C-P = 11.3 Hz), 132.8 (s, C-H), 132.5 (s, C-H), 129.5 (d, C-H, ⁴J_C-P = 7.6 Hz), 129.0 (d, C-H, ³J_C-P = 12.2 Hz), 125.7 (d, C-P, ¹J_C-P = 73.8 Hz), 118.3 (s, C-P), 79.1 (s, -CH), 65.9 (s, -CH₂), 25.6 (s, -CH₂), 9.6 (s, -CH₃). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 4.33 (d, P-Pt, ¹J_P-Pt = 2040.80 Hz). MS (FAB⁺): 592 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1614 (s, C=N). Elem. Anal. Calcd. for C₂₃H₂₄Cl₂NOPPt: C, 44.03; H, 3.85; N, 2.23. Found: C, 44.13; H, 3.94; N, 2.11.

For 3f: Yield: 82.2 mg (65.54%). M. p. 263–264 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (s, 1H, -CH=N), 8.40 (m, 1H, CHAr), 8.04–7.85 (m, 2H, CHAr), 7.70–7.62 (m, 4H, CHAr), 7.61–7.52 (m, 2H, CHAr), 7.48 (m, 1H, CHAr), 3.72 (s, 2H, -CH₂), 1.58 (m, 6H, -CH₃). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 160.1 (s, -CH=N, ³J_C-P = 4.6 Hz), 138.9 (d, C-H, ³J_C-P = 9.3 Hz), 136.3 (d, C-H, ²J_C-P = 14.2 Hz), 135.2 (d, C-H, ³J_C-P = 8.7 Hz), 133.6 (s, C-H), 133.5 (d, C-H, ²J_C-P = 11.5 Hz), 132.4 (d, C-H, ⁴J_C-P = 3.0 Hz), 129.1 (d, C-H, ³J_C-P = 12.1 Hz), 126.4 (d, C-P, ¹J_C-P = 72.3 Hz), 116.9 (d, C-P, ¹J_C-P = 64.2 Hz), 76.3 (s, -CH₂), 71.9 (s, -CC), 23.3 (s, -CH₃). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 4.22 (d, P-Pt, ¹J_P-Pt = 2034.69 Hz). MS (FAB⁺): 592 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1620 (s, C=N). Elem. Anal. Calcd. for C₂₃H₂₄Cl₂NOPPt: C, 44.03; H, 3.86; N, 2.23. Found: C, 43.95; H, 3.87; N, 2.23.

For 3g: Yield: 80.9 mg (64.30%). M. p. 232–234 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.83 (s, 1H, -CH=N), 8.33 (m, 1H, CHAr), 7.87–7.84 (m, 2H, CHAr), 7.60–7.40 (m, 7H, CHAr), 3.90–3.70 (m, 2H, -CH₂), 3.69 (dd, 1H, -CH, ²J_H-H = 11.29 Hz, ³J_H-H = 5.05 Hz), 3.53 (dd, 1H, -CH, ²J_H-H = 11.35 Hz, ³J_H-H = 6.06 Hz), 3.07 (tt, 1H, -CH, ³J_H-H = 5.56 Hz, ³J_H-H = 5.46 Hz). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 162.4 (s, -CH=N), 137.8 (s, C-H), 136.7 (d, C-H, ²J_C-P = 11.6 Hz), 134.8 (s, C-H), 134.1 (s, C-H), 133.3 (s, C-H), 133.6 (d, C-H, ²J_C-P = 11.2 Hz), 131.9 (s, C-H), 128.9 (d, C-H, ³J_C-P = 11.7 Hz), 118.5 (d, C-P, ¹J_C-P = 58.8 Hz), 58.5 (s, -CH₂), 54.2 (s, -CH). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 2.90 (d, P-Pt, ¹J_P-Pt = 1876.80 Hz). MS (FAB⁺): 594 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1628 (s, C=N). Elem. Anal. Calcd. for C₂₂H₂₂Cl₂NO₂PPt: C, 41.98; H, 3.52; N, 2.23. Found: C, 42.18; H, 3.54; N, 2.24.

For 3h: Yield: 47.7 mg (37.05%). M. p. 172–176 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H, -CH=N), 8.15 (m, 1H, CHAr), 7.91–7.87 (m, 2H, CHAr), 7.70–7.30 (m, 7H, CHAr), 3.84 (d, 1H, -CH, ²J_H-H = 10.00 Hz), 3.76 (d, 1H, -CH, ²J_H-H = 10.99 Hz), 3.47 (d, 1H, -CH, ²J_H-H = 11.26 Hz), 3.41 (d, 1H, -CH, ²J_H-H = 11.21 Hz), 1.49 (s, 3H, -CH₃). ¹³C{¹H} NMR (125.76 MHz, DMSO-d₆) δ 160.3 (s, -CH=N, ³J_C-P = 4.2 Hz), 138.5 (d, C-H, ³J_C-P = 9.2 Hz), 136.8 (d, C-H, ²J_C-P = 15.2 Hz), 134.5 (d, C-H, ³J_C-P = 8.0 Hz), 133.7 (s, C-H), 133.5 (d, C-H, ²J_C-P = 11.2 Hz), 133.0 (m, C-H), 131.6 (s, C-H), 128.6 (d, C-H, ³J_C-P = 11.7 Hz), 128.0 (d, C-P, ¹J_C-P = 69.2 Hz), 117.6 (d, C-P, ¹J_C-P = 60.4 Hz), 62.7 (s, -CH₂), 57.9 (s, -CH), 17.4 (s, -CH₃). ³¹P{¹H} NMR (202.45 MHz, DMSO-d₆): δ 3.52 (d, P-Pt, ¹J_P-Pt = 1878.80 Hz). MS (FAB⁺): 608 m/z [M-Cl]⁺. IR (ATR, cm⁻¹): 1635 (s, C=N). Elem. Anal. Calcd. for C₂₃H₂₄Cl₂NO₂PPt: C, 42.93; H, 3.75; N, 2.17. Found: C, 43.77; H, 4.07; N, 2.12.

3.4. Cytotoxic Evaluation

The compounds were screened in vitro against human cell lines: HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), K562 (human chronic myelogenous leukaemia), U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and COS-7 (cell line monkey African green kidney). The cell lines were supplied by the National Cancer Institute (USA) and were donated by the Cancer Institute of Mexico. The cell lines were cultured in RPMI-1640 medium supplemented with 10% foetal bovine serum, 2 mM L-glutamine, 25 μg/mL amphotericin B (Gibco) and 1% non-essential amino acids (Gibco). They were maintained at 37 °C in a humidified atmosphere with 5% CO₂.

Cytotoxic activity was determined using the protein-binding dye sulforhodamine B (SRB) in a microculture assay to measure cell growth [33]. The cultures were exposed for 48 h to the compound at concentrations of 25 μM. DMSO was employed as the solvent. After incubation, cells were fixed to the plastic substratum by adding 50 μL of cold 50% aqueous trichloroacetic acid. The plates were incubated at 4 °C for 1 h, washed with tap H₂O, and air-dried. The trichloroacetic acid fixed cells were stained by adding 0.4% SRB. The free SRB solution was removed by washing with 1% aqueous acetic acid. The plates were then air-dried, and the bound dye was solubilised by adding 10 mM unbuffered Tris-base (100 μL). The plates were placed on and shaken for 10 min, and the absorption was determined at 515 nm using an ELISA plate reader (Bio-Tex Instruments). The inhibitory concentration 50 (IC₅₀) values were calculated on extrapolated fit curves based on doses/response data analysed in triplicate for each compound through linear regression analysis [42].

3.5. Data Collection and Refinement for Crystalline Compounds

1d, 1e, 2d, and 3d crystals were grown by slow evaporation in DMSO, and 3e in MeOH. Suitable monocrystals were analysed on a Bruker Smart Apex II diffractometer with a Mo-target X-ray source (λ = 0.71073 Å). The detector was placed 5.0 cm from the crystals, and frames were collected with a scan width of 0.5 cm in ω and an exposure time of 10 s/frame. Frames were integrated with the Bruker SAINT software package using a narrow-frame integration algorithm [43]. Systematic absences and intensity statistics were used in orthorhombic space group determination for 1d, 1e, and 3e and the triclinic space group for 2d and 3d. The structures were solved using Patterson methods using the SHELXS-2014/7 programme [44]. The remaining atoms were located via a few cycles of least-squares refinements and difference Fourier maps. Hydrogen atoms were input at calculated positions and allowed to ride on the atoms to which they were attached. Thermal parameters were refined for hydrogen atoms on the phenyl groups using a Ueq = 1.2 Å to precedent atom [45]. The final refinement cycles were carried out on all non-zero data using SHELXL-2014/7 [44]. Absorption corrections were applied using the SADABS programme [46]. The Hirshfeld surfaces were calculated considering the disordered parts; however, the major occupancy of disordered atoms was considered when analysing non-covalent interactions.

3.6. Computational Details

Before molecular docking simulations, electronic structure calculations were performed using the crystal geometrical data of complexes 2d and 3d as a starting point for modelling the other complexes without a crystal structure. The geometry optimisation of all platinum and palladium complexes was carried out utilising the B3LYP functional and the Pople 6-31 + g (d,p) basis set, which accounted for light atoms such as N, O, P, H, Cl, and C. For the metal centres of palladium and platinum, the LanL2DZ pseudo-potential was employed [46]. Hessian matrix calculations were performed to verify the presence of stationary points and ensure the validity of the geometrical structure obtained from the electronic structure calculation. The resulting geometrical data were then compared to those reported by X-ray experiments. Furthermore, single-point calculations were conducted to evaluate the impact of water as a solvent, utilising the SMD implicit solvent method [47]. The NPA3 natural atomic population scheme determined the atomic charges, which proved valuable for subsequent molecular docking studies [48]. All calculations were performed using the Gaussian 16 suite of programmes [49].

Autodock Tools was employed as the interface for the molecular docking simulations to generate the necessary input files. Subsequently, Autodock 4 was utilised to execute the docking simulations between the DNA model and the platinum and palladium complexes [50]. The hydrogen atoms, except the polar ones, were systematically removed to facilitate the molecular docking simulations. Additionally, the NPA charges obtained from the electronic structure calculations were incorporated to further enhance the precision and validity of the simulations.

The DNA model used in this study was obtained from the Protein Data Bank (PDB) with the code 1AIO [51], as it is co-crystallised with cisplatin. This choice served as a reliable reference for our research. For this model, all polar hydrogens were added and the Gasteiger charges were calculated [52]. To explore all the possible binding sites of the complexes to DNA, blind molecular docking simulations were performed over the entire DNA space using the Lamarkian genetic algorithm. Chimera, Pymol, and Maestro Schrödinger programmes were employed to describe the interactions between palladium-platinum complexes and DNA [53,54,55].

4. Conclusions

New Pd(II) and Pt(II) complexes have been synthesised bearing PN ligands derived from aminoalcohols. Additionally, previously reported Pd(II) complexes 2a, 2f, and 2h were also synthesised, but changing their application from cross-coupling catalysis to cytotoxic activity. Molecular structures of 1b, 1d, 2d, 3d, and 3e compounds were unequivocally determined by single-crystal X-ray diffraction (SC-DRX). Pd(II) and Pt(II) complexes (2d, 3d, and 3e) were obtained with a distorted square-planar geometry. Supramolecular analysis of close contacts revealed hydrogen-halogen bonds due to Cl∙∙∙H/H∙∙∙Cl contacts in Hirshfeld surfaces in about 20 per cent. These interactions were slightly less than those generated by C∙∙∙H/H∙∙∙C contacts, indicating that they play an essential role in the stabilisation of crystalline packing.

The best antiproliferative activity was obtained for complexes 2e, 2f and 3b, being selective against the K562 cancer cell line with IC₅₀ values of 7.73 ± 1.4, 8.53 ± 1.9 and 8.83 ± 1.5 µM, respectively. Although those values are higher than those of cisplatin, further studies should be made to increase the cytotoxic activity of these selective complexes. This study’s DNA model and computational methods corroborate the experimental findings, revealing a consistent trend like the cisplatin standard. Furthermore, the investigation of interactions involving molecules 2e, 2f, and 3b highlighted the substantial impact of altering the metal or amino group on the binding modes.