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Research Article
ARTICLE IN PRESS
doi:
10.25259/JKSUS_82_2025

Synthesis of new bis(triethylphosphine)platinum(II) complexes containing heterocyclic selenones as potential inhibitors of human cancer: Experimental and theoretical investigations

, , , , , , , , ,
aDepartment of Environmental, Health and Safety, King Fahd University of Petroleum and Minerals, Dhahran, 31261, Saudi Arabia
bDepartment of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, 31261, Saudi Arabia
cDepartment of Biochemistry, Pt. Jawaharlal Nehru Government Medical College& Hospital (H.P)-176310, Chamba, Himachal Pradesh, India
dDepartment of matter Sciences, University Mohamed Khider, BP, 145 RP; (07000), Biskra, Algeria
eDepartment of Chemistry, College of Science, Qassim University, Qassim, 51452, Saudi Arabia

*Corresponding author: E-mail address: mu.alrasheedi@qu.edu.sa (M Alrasheedi)

Received: , Accepted: ,
© 2026 Journal of King Saud University – Science - Published by Scientific Scholar
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Today, there is a significant demand for a new generation category of metal-based medicines capable of minimizing side effects while simultaneously improving efficacy against cancers that have acquired resistance to cisplatin. Seven new complexes of platinum(II) (1-7) derived from bis(triethylphosphine) and selenone ligands with the general the formulas [Pt(Et3P)2(Selenone)2]Cl2 for complexes (1, 2, and 7), and [Pt(Et3P)2(Selenone)2](PF6)2 for complexes (3-6) have been synthesized. Where formulas of selenones are (1,3-Imidazolidine-2-selenone (ImSe); N-methyl-1,3-Imidazolidine-2-selenone (MeImSe); N-ethyl-1,3-Imidazolidine-2-selenone (EtImSe), N-i-propyl-1,3-Imidazolidine-2-selenone (i-prImSe); 1,3-Diazinane-2-selenone (DiazSe); 1,3-Diazepane-2-selenone (DiapSe)). These complexes were comprehensively characterized by elemental analysis, fourier-transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy, including 1H, 13C, 31P, and 77Se nuclei, which confirmed their structural composition. The crystal structures of complexes 3 and 5 were further elucidated using single crystal X-ray diffraction, which revealed a deformed square planar arrangement around the platinum center due to the coordination of selenone and platinum(II) ion. This configuration aligns with the expected geometry for platinum(II) complexes, enhancing stability and potential reactivity.The cytotoxic effects of the synthesized complexes, alongside cisplatin as a control, were evaluated in vitro against three human cancer cell lines: HeLa (cervical cancer), HCT-15 (colon adenocarcinoma), and MG-63 (osteosarcoma). Results from IC50calculations showed that these complexes exhibited cytotoxic effects ranging from promising to moderate. Notably, complexes 3 and 4 demonstrated higher efficacy compared to cisplatin, suggesting their potential as more effective anti-cancer agents. Molecular docking studies further investigated this potential, as all complexes displayed stronger binding affinity and lower inhibition constants within the target DNA binding pocket than cisplatin, indicating a superior docking profile. ADME-Tox predictions were conducted to assess drug-likeness and pharmacokinetic properties, revealing that complex 4 met all criteria of the Lipinski and Egan rules without violations. This favorable ADME-Tox profile highlighted complex 4 as a promising candidate for drug development.

Keywords

ADME-Tox prediction
Cell line
Molecular docking
Platinum(II) complexes
Selenones

1. Introduction

Platinum(II) complexes, especially cisplatin, have been critically important in cancer treatment owing to their notable anti-tumor efficacy. They are employed in the treatment of several malignancies, such as lung, testicular, ovarian, and bladder cancer (Shen et al., 2024; Kazimir et al., 2023; Mustafa et al., 2014; Zhang et al., 2023). Platinum(II) complexes have a unique mechanism of action and are effective in causing damage to cancer cells, making them essential in oncology (Jin et al., 2024; Rossi et al., 2024; Wang et al., 2024; Štarha, 2024). After being licensed in 1978 to treat cancer, cisplatin was later analogued with carboplatin (Harrap, 1985) and oxaliplatin (Kidani et al., 1978) for use in the US in 1989 and 2002 to treat solid tumors. In clinical practice, platinum-based chemotherapy is often employed; nonetheless, a considerable fraction of tumors show resistance, either innate or acquired (Wang and Lippard, 2005; Galluzzi et al., 2012) Metal complexes, due to their unique properties such as lipophilicity, geometries, accessible redox states, coordination numbers, and thermodynamic and kinetic features, are gaining interest in cancer treatments (Rodríguez-Rodríguez et al., 2012; Barton et al., 2011). The existence of inorganic or organic ligands affects these compounds’ pharmacological characteristics (Zhang et al., 2022).

For more than 40 years, cisplatin has been the anti-cancer medication most frequently utilized in the treatment of cancer (Rosenberg et al., 1965; Sigel et al., 2018; Kelland, 2007). Certain adducts that platinum complexes produce with DNA include bidentate of 1,2-intrastrand cross-link, which results in double helix deformation in biological proteins. Platinated adducts alter cell transcription machinery, leading to cancer cell death due to their impact (Ang et al., 2010). Drugs based on platinum have detrimental effects on the kidney, liver, inner ear, peripheral nerves, and nephrotoxicity, neurotoxicity, hepatotoxicity, and ototoxicity (Kelland, 2000). Because currently available platinum-based drugs have limitations, researchers are continuously searching for new platinum complexes with superior pharmacological features (Johnstone et al., 2016; Kenny and Marmion, 2019; Štarha et al., 2019). Metal-based anti-cancer medicines must have high stability under physiological circumstances in order to be transported and distributed to tumor cells. Studies have shown that the biological activity of metal complexes may be markedly changed by adjusting the coordinated ligands of metal centers, which may have an impact on the pharmacological effectiveness of these therapies (Karaca et al., 2017; Liu and Gust, 2013).

The use of chelating ligands including phosphine in metal-based anti-cancer complexes has opened up new possibilities for altering the chemical and biological characteristics of metal complexes (Gorbachuk et al., 2020). Studies indicate that the insertion of phosphine ligands may improve the anti-cancer complexes’ lipophilicity and membrane permeability, which would raise their cytotoxicity (Gandin et al., 2010). Because phosphine ligands have soft donor atoms, they are very good at stabilizing many types of metal centers (Komarnicka et al., 2021). N-heterocyclic carbenes (NHCs) are considered to be a class of ligands that show great potential for metal-based drug development due to their exceptional coordination ability and therapeutic qualities (Singh and Lown, 2000).

It has been discovered that compounds containing selenium, particularly organo-selenium, are less dangerous (Radhakrishna et al., 2010). Because selenium compounds have been proven to decrease the activity of the enzyme thioredoxin reductase, which contains selenocysteine, researchers are investigating the biological potential of selenium compounds (Villavicencio et al., 2014). The bioavailability as well as the release of selenium compounds at the target organism are critical factors that impact their usefulness as therapeutics. These properties may be modified by carefully choosing the appropriate ligand, which can also impact lipophilicity and delivery mode (Prast-Nielsen et al., 2010). In this respect, platinum(II) complexes containing selenone ligands are of particular interest owing to their distinctive structural features and promising cytotoxic potential for chemotherapeutic applications (Hayat et al., 2021). The structural characteristics and cytotoxicity of platinum(II) complexes of selenones are of great interest due to their potential chemotherapeutic applications (Misra et al., 2015; Zeng et al., 2014).

The study aims to evaluate the in vitro cytotoxicity of novel Pt (II) complexes containing phosphine and selenone ligands against human osteosarcoma MG-63, human cervical cancer cell lines (HeLa), and human colon adenocarcinoma (HCT-15). The structures of the synthesized complexes are depicted in Scheme 1.

Structures of synthesized platinum (II) complexes (1-7), and platinum (II) precursor (0).
Scheme 1.
Structures of synthesized platinum (II) complexes (1-7), and platinum (II) precursor (0).

2. Materials and Methods

Solvents and chemicals were analytical grade and were used without additional purification. 1,1-Dimethyl-2-selenourea, ethanol, acetonitrile, dichloromethane, (C2H5)2O, and AgPF6 were acquired from Sigma-Aldrich in St. Louis, Missouri, USA. Cis-dichloridobis(triethylphosphine)platinum(II) was bought from Strem Chemicals located in Massachusetts, USA. The following compounds were synthesised: 1,3-Imidazolidine-2-selenone (ImSe), N-methyl-1,3-Imidazolidine-2-selenone (MeImSe), N-ethyl-1,3-Imidazolidine-2-selenone (EtImSe), N-i-propyl-1,3-Imidazolidine-2-selenone (i-prImSe), 1,3-Diazinane-2-selenone (DiazSe), and 1,3-Diazepane-2-selenone (DiapSe) were synthesized as described (Wazeer et al., 2003).

Analyzer 2400 (Perkin Elmer Series 11(CHNS/O)) was used to perform the elemental analyses. The PerkineElmer FTIR 180 spectrophotometer was used to record the solid state fourier-transform infrared spectroscopy (FTIR) spectra using KBr pellets across the range 4000-400 cm-1 at resolution 4.00 cm-1. 1H (500.01 MHz), 13C (125.65 MHz), 31P (200.0 MHz) and 77Se(95.35 MHz) nuclear magnetic resonance (NMR) spectra were recorded on a LAMBDA Jeol 500.01 MHz NMR spectrophotometer at 297 K. The spectral conditions for 1H NMR were; 32 K data points, 0.963 s acquisition time, 2.5 s pulse delay, and a 5.12 µs pulse width, while for 13C NMR they were; 32 K data points, 0.963 s acquisition time, 3.2 s pulse delay, and a 5.75 µs pulse width. The chemical shifts were measured relative to tetramethylsilane (TMS). The 77Se NMR chemical shifts were recorded at 95.35 MHz using 2.0 s pulse delay and 0.311 s acquisition time. TMS is used as an internal reference for the chemical changes (1H and 13C), H3PO4 as external (31P) at 0.0 ppm and NaHSeO3 as external for (77Se) at 1308 ppm. Melting points were recorded on Stuart melting point SMP30 apparatus.

2.1 Synthesis of the Pt(II) complexes

2.1.1 Synthesis of [Pt{(Et)3P}2(Selenone)2](Cl)2 (1, 2 and 7)

A(0.251 g, 0.500 mmol) cis-dichloridobis(triethylphosphine)platinum(II) [Bis-{(Et)3P}2PtCl2] in 20.0 mL dichloromethane was added to selenone ligands (1.00 mmol) in 5.0 mL ethanol. The mixture was stirred for three hours at ambient room temperature (25°C), filtered, and extracted from a clear yellow solution. After five to six days, the products were cleaned three times with (5.0 mL) diethyl ether and recrystallized from acetonitrile/ethanol. The complexes 1, 2, and 7 were obtained as distinct yellow solids.

Cis-[Pt{(Et)3P}2(N,N’-Me2Seu)2](Cl)2 (1). Calc. for C18H46Cl2N4P2PtSe2, Mw = (804.45 g/mol): C, 26.87; H,5.76; N, 6.96. Found: C, 26.69; H, 5.84; N, 6.81. Yield = (0.276 g, 68.6%).

Cis-[Pt{(Et)3P}2(ImSe)2](Cl)2 (2). Calc. for C18H42Cl2N4P2PtSe2, Mw = 800.42 g/mol: C, 27.01; H,5.28; N, 6.99. Found: C, 27.20; H, 4.35; N, 5.23. Yield = (0.250 g, 62.5%). M.P = 208─210°C.

Cis-[Pt{(Et)3P}2(DiazSe)2](Cl)2 (7). Calc. for C20H46Cl2N4P2PtSe2, Mw = 828.47 g/mol: C, 28.99; H, 5.59; N, 6.76. Found: C, 28.81; H, 5.85; N, 6.34. Yield = (0.270 g, 65.2%). M.P = 210─213°C.

2.1.2 Synthesis of [Pt{(Et)3P}2(Selenone)2] (PF6)2 (3-6)

A (0.253 g, 1.00 mmol) AgPF6in 5.0 mL of ethanol was added to cis-dichloridobis(triethylphosphine) platinum(II), [Bis-{(Et)3P}2PtCl2] (0.251 g, 0.500 mmol) in 20.0 mL dichloromethane. After two hours of stirring at room temperature, the liquid was filtered out to remove the silver chloride’s white precipitate. (1.00 mmol) selenone was added to the filtrate and the mixture was stirred for three hours at ambient room temperature (25°C), then the clear yellow solution was filtered, and after five days, yellow products were produced, cleaned three times with diethyl ether, and recrystallized from acetonitrile/ethanol.

Cis-[Pt{(Et)3P}2(MImSe)2](PF6)2(3).Calc.for C20H46Cl0.5(PF6)1.5N4P2PtSe2, Mw = 992.73 g/mol: C, 24.19; H, 4.67; N, 5.64. Found: C, 23.97; H, 4.66; N, 5.24. Yield = (0.365 g, 73.6%). M.P = 148─151°C.

Cis-[Pt{(Et)3P}2(i-prImSe)2](PF6)2 (4). Calc. C24H54F12N4P4PtSe2, Mw = 1103.60 g/mol: C, 26.11; H, 4.93; N, 5.07. Found: C, 26.46; H, 4.63; N, 5.39. Yield = (0.397 g, 72.1%). M.P = 109─112°C.

Cis-[Pt{(Et)3P}2(EtImSe)2](PF6)2 (5). Calc. for C22H50Cl0.5(PF6)1.5N4P2PtSe2, Mw = 1020.78 g/mol: C, 26.09; H, 4.93; N, 5.48. Found: C, 26.02; H, 4.29; N, 5.39. Yield = (0.381 g, 74.7%). M.P = 113─116°C.

Cis-[Pt{(Et)3P}2(DiapSe)2](PF6)2 (6). Calc. for C22H50F12N4P4PtSe2, Mw = 1075.55 g/mol: C, 24.56; H, 4.68; N, 5.20. Found: C, 24.92; H, 4.48; N, 5.65. Yield = (0.412 g, 76.7%). M.P = 110─113°C.

2.2 MTT assay for invitro cytotoxicity of Pt(II) complexes

The study investigated the cytotoxic effects of platinum(II) complexes and cisplatin on three distinct cell lines (MG-63, HCT-15, and HeLa), using a previously published method (Altaf et al., 2015). The cells were planted at a density of 3 x 103 cells/well in a 96-well tissue culture plate with 100 μL of DMEM 10% FBS. The plate was then incubated for 72 hours at 37°C, 5% CO2, and 90% relative humidity. After that, they were incubated in DMEM with cisplatin and platinum(II) complexes. Following the removal of the medium, 100 μL of DMEM containing 0.5 mg/ml of MTT was added, and the mixture was incubated at 37°C for four hours in a CO2 incubator. The purple formazan from the cells crystallized as black crystals, and 100 μL of DMSO was injected to keep the monolayer intact. An entirely dissolved formazan crystal produced a purple solution. Using a LabSystemsMultiskan EX ELISA reader, the absorbance of 96 well-plates was recorded at 570 nm. Three duplicate experiments were used to calculate the IC50 of each drug’s 50% cell growth inhibition.

2.3 X-ray structure analysis of complexes 3 and 5

A Bruker AXS D8 Quest diffractometer was used to gather the intensity data for Complexes 3 and 5, using MoK (λ = 0.71073 Å) radiation from an Iμs microfocus tube. The data was collected using a Bruker AXS PHOTON II CPAD detector at 298 K using ω- and φ-scans. The data was processed using the APEX3 Crystal Structure Analysis Package (Bruker AXS). APEX3 data extraction (Bruker, 2017) Cell refinement: SAINT (Bruker, 2017) compression of data: SAINT (Bruker, 2017) Direct methods (SHELXT-2014) for the structural solution and SADABS (Sheldrick, 2017) for absorption correction (Sheldrick, 2015) additional structure refinement process involved full-matrix least-squares technique on F2 (Sheldrick, 2015) and molecular graphics using program XP, part of the SHELXT 6.14 program library. Table S1 provides an overview of crystal data, data collection specifics, and complexes 3 and 5 refining.

Supplementary Material

2.4 Computational methodologies

2.4.1 DFT calculations

Using the PBEPBE functional in GAUSSIAN 16 in the gas phase without any constraints, the analysis comprised DFT-based geometry optimization for each structure and the LAN2DZ double-ζ basis set for atom description. All optimization geometries in DMSO solvent were assessed using the conductor-like polarizable continuum model (CPCM), which took D3 dispersion correction into account. Frequency calculations were then performed to verify the minimal structures, all of which are >0 frequencies.

2.4.2 Molecular docking protocol and validation

For docking studies, this work chose an active docking complex that exhibited potency against three cancer cell lines (Hela, HTC-15, and MG-63).MG-63 (PDB ID: 6T2W) (Goldberg et al., 2020), HTC-15 (PDB ID: 4RA4) (George et al., 2015), and Hela (PDB ID: 3F81) (Wu et al., 2009) are examples of proteins. The Protein Data Bank (http://www.rcsb.org/pdb/) provided the X-ray crystal structures, which were used to determine the interactions between drugs (Chemical Computing Group, 2014) and the targets’ active sites. The study simplified the crystal structures of proteins by eliminating cofactors, ions, and water molecules, and then adding missing hydrogen atoms, as shown in Table 1.

Table 1. Summary of the most important information related to the selected targets.
Targets PDB Methods Organism Chains Sequence length Resolution (Å) Native ligand
3F81 X-ray diffraction Homo sapiens A, B 183 1.90 STT
4RA4 X-ray diffraction Homo sapiens A 355 2.63 3KZ
6T2W X-ray diffraction Homo sapiens A 332 1.70 M9T

The native ligand of 3F81 is STT: 2-[(5∼{E})-5-[[3-[4-(2-fluoranylphenoxy)phenyl]-1-phenyl-pyrazol-4-yl]methylidene]-4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-3-yl]ethanesulfonic acid (C27 H20 F N3 O5 S3), The native ligand of 4RA4 is 3KZ: (1R)-9-[(3S,4S)-1,3-dimethylpiperidin-4-yl]-8-(2-fluorophenyl)-1-methyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one (C24H27F N4O2), The native ligand of 6T2W is M9T: 2-[(4-methoxy-2-methyl-phenyl)amino]-7-methyl-9-(4-oxidanylcyclohexyl)purin-8-one (C20H25N5O3).

The Molecular Operating Environment (MOE) 2014.09 software helped conduct the docking calculations on selected targets (Chemical Computing Group, 2014), with a detailed protocol described in previous research (Daoud et al., 2018; Toumi et al., 2021). The molecular docking approach’s high accuracy was confirmed by re-docking crystallized ligands in receptors and computing the RMSD value, which falls between 1 and 2 Å (Bajda et al., 2013).

2.4.3 ADME-tox prediction

The number of hydrogen bond acceptors, hydrogen bond donors, TPSA, nROT, MW, and LogP were predicted using SwissADME web server (http://www.swissadme.ch/; accessed on 01 January 2025). The ADME-T parameters (Absorption, Distribution, Metabolism, Excretion, and Toxicity) were calculated using pkCSM server http://biosig.unimelb.edu.au/pkcsm/prediction; accessed on 01 January 2025)). The data was accessed on April 1, 2024 (Daina et al., 2017; Pires et al., 2015).

3. Results and Discussion

3.1 Spectroscopic characterization

Using the corresponding selenone, [Bis-{(Et)3P}2PtCl2] was used to synthesize complexes (1–7). The IR measurements for free ligands and their platinum(II) complexes demonstrate a considerable change between the free ligands and their complexes, as presented in Table S2. As in other Pt(II) complexes of selenones, the low frequency shift suggests a reduction in the double character of the C=Se bond owing to complexation (Ahmad and Isab, 2003; Alhoshani et al., 2019). The increased C-N π bond character in complexes caused the stretching bands of v(N─H) to be moved to a higher frequency region in comparison to the free ligands (Seliman et al., 2017).

The 1H and 13C NMR chemical shifts of the complexes are given in Tables S3 and S4 respectively. 1H NMR spectra of complexes 1-7 (shown in Figs. S1-S7, Supplementary Material). The values for N-H resonance are presented for comparison. The N-H resonance of the complexes (1-7) shifted downfield by about (1.0-4.0) ppm compared to their value in the free ligand. In 13C NMR of complexes (1-7), the selenone carbon (C=Se) resonance appeared upfield shift by (7.6-29.3) ppm compared to that in uncoordinated ligands as observed earlier (Alhoshani et al., 2019; Fettouhi et al., 2004). The 1H and 13C resonances of the (cis-(Et3P)2) moiety exhibited a downfield shift in almost all complexes as compared to the precursor. The precursor [cis-(Et3P)2PtCl2] has a coupling constant of (J(C─P)Hz) 19.72 Hz, whereas the coupling constant of carbon-phosphorus for the complexes (J(C─P)Hz) ranges from 15.57 to 17.13 Hz, except for complex 7, which has a coupling value of 65.39 Hz. This value is attributed to the larger ring size of DiapSe, which suggests that out of all the complexes, complex 7 is the most stable.13C NMR spectra of complexes 1-7 (shown in Figs. S8-S13, Supplementary Material).

The 31P and 77Se NMR chemical shifts of free ligands and complexes (1-7) are given in Table S5. In 31P NMR of complexes (1-7), the phosphorus resonance appeared downfield shift by (0.73-3.68) ppm compared to that in uncoordinated ligands as observed earlier (Ahmad and Isab, 2003). 31P NMR spectra of complexes 1-7 (shown in Figs. S14-S20, Supplementary Material).

The precursor [cis-(Et3P)2PtCl2] has a coupling constant of (J(P─Pt) Hz) 1750.49Hz, whereas the coupling constant of (J(P─Pt)Hz) for the complexes ranges from 538.33to 1147.46 Hz. The peak of 31P NMR in [cis-(Et3P)2PtCl2] appeared as a singlet, whereas, in all complexes (1-7), it appeared as a triplet due to its splitting by the Pt and Se atoms.

77Se NMR of complexes showed that the selenium signal shifts significantly upfield by (27.00, 24.85, 35.00, 41.84, 51.37,86.15, and 28.84) ppm. Pt(II) binding to the selenium ligands appears to be the cause of this extremely significant shielding, which is consistent with our previous studies (Ahmad and Isab, 2003; Ahmad et al., 2002).77Se NMR spectra of complexes 1-7 (shown in Figs. S21-S26, Supplementary Material).

3.2 Crystal structure description

The molecular structures of [Pt{(Et)3P}2(MImSe)2](PF6)2 (3) and [Pt{(Et)3P}2(EtImSe)2](PF6)2 (5) are shown in Figs. 1 and 2. When both complexes crystallized, they were composed of ionic species: [Pt{(Et)3P}2(Selenone)]2+ and 2PF6- ions. In the complexes’ ions, the platinum atom is bound to two P atoms of (Et)3P and two selenium atoms of MImSe and EtImSe at the cis position. The geometry at platinum for complexes 3 and 5 is nearly planar with the cis angles around platinum of (86.25(5)°, 87.67(5)°, 90.15(5)°, and 94.26(5)°) Vs complex 3 along with (87.03(3)°, 87.79(3)°, 90.13(3)°, and 94.12(3)°) Vs complex 5. While the linear angles of Se1—Pt1—Se2 and P1—Pt1—P2 are 163.0(3)°, 171.2(6)°, 163.5(2)°, and 174.0(3)° for complexes 3 and 5, respectively. The inversion center at the Pt atom causes the PtL4 coordination unit to be certainly planar. The Pt-P1, Pt-P2, Pt-Se1 and Pt-Se2 bond distances for complex 3 are of 2.333(2), 2.343(2), 2.417(1), and 2.424(9) Ǻ respectively, where the Pt-P1, Pt-P2, Pt-Se1 and Pt-Se2 bond distances for complex 5 are 2.3481(8), 2.3334(8), 2.4371(6), and 2.4414(5) Ǻ respectively. These values agree with the reported for similar complexes (Alhoshani et al., 2019; Seliman et al., 2017; Chopade et al., 2015; Altoum et al., 2017). Around selenium, the connecting bond is V-shaped (Pt—Se—C) of 106.2(2)° or 107.0(2)o) for complex 3, whereas for complex 5, it is 106.7(1)° and 107.2(1)°.The bond angles around carbon atoms >C=Se and carbene in a trigonal planar environment indicate electrostatic interactions establishing a connection between complex cations and PF6- anions.

Crystal structure of complex (3)[Pt((Et)3P)2(N-MeImSe)2](PF6)2, with partial labeling atoms.
Fig. 1.
Crystal structure of complex (3)[Pt((Et)3P)2(N-MeImSe)2](PF6)2, with partial labeling atoms.
Crystal structure of complex (5), [Pt((Et)3P)2(N-EtImSe)2](PF6)2, with partial labeling atoms.
Fig. 2.
Crystal structure of complex (5), [Pt((Et)3P)2(N-EtImSe)2](PF6)2, with partial labeling atoms.

3.3 In vitro cytotoxicity investigation

The study evaluated the in vitro cytotoxicity of prepared complexes and cisplatin (1-7) in DMSO against three human cancer cells: HeLa, MG-63, and HCT-15. Results are expressed in terms of IC50 value as given in Table 2 and showed that complexes 1, 3, and 4 had better cytotoxicity than cisplatin for MG-63 cells. For HeLa cells, all complexes had less activity than cisplatin. The impact of the concentration of complexes (1-7) and cisplatin on the percentage viability of the three cell lines is illustrated in Figs. 3-5. Complex 4 of the present series showed the highest activity against HTC-15 and MG-63 cancer cells. The study also reported the anti-cancer properties of other pt(II) complexes of heterocyclic selenones (Alhoshani et al., 2019; Alotaibi et al., 2019; Altoum et al., 2017). DFT molecular geometry optimization and score energy studies revealed that complex 4 has potent anti-tumor properties due to strong hydrogen bonds with LEU785, LEU588, and TYR665 protein residues of three cancer cells, and the lowest HOMO–LUMO gap value.

Table 2. IC50 values (μM) of cisplatin and platinum(II) complexes (1-7) against HCT-15, MG-63, and HeLa cancer cell lines.
Complex IC50 (μM)
HCT-15 MG-63 HeLa
1 64.02(±0.05) 9.65(±0.02) 111.03(±1.02)
2 215.55(>100) 110.5(>100) 142.55(>100)
3 13.84(±0.05) 22.57(±0.04) 49.97(±0.06)
4 7.96(±0.05) 17.16(±0.06) 36.59(±0.07)
5 20.59(±0.05) 47.65(±0.04) 42.17(±0.04)
6 48.31(±0.05) 72.43(±0.02) 179.73(±0.84)
7 151.31(±1.25) 88.46(±1.20) 151.83(±1.22
0 387.07(>100) 277.56(>100) 330.00(>100)
Cisplatin 30.2 (±0.02) 33.58(±0.03) 20.55(±0.05)
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage viability of HCT-15 colon adenocarcinoma cells.
Fig. 3.
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage viability of HCT-15 colon adenocarcinoma cells.
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage viability of MG-63 osteosarcoma cells.
Fig. 4.
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage viability of MG-63 osteosarcoma cells.
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage of viability of HeLa cervical cancer cells.
Fig. 5.
Effect of different concentrations of platinum(II) complexes (0-7) and cisplatin on the percentage of viability of HeLa cervical cancer cells.

3.4 DFT molecular geometry optimization

The crystal X-ray structures provided the initial geometries for Compounds 3 and 5’s DFT geometry optimization. Fig. 6 displays the optimized geometries of compounds 3 and 5. These were visualized using the Gauss-View tool.

The optimized molecular geometries of Complexes 3, 4 and 5. Pt, Sky blue; Se, yellow; C, grey; N, blue; P, orange; H, white sphere.
Fig. 6.
The optimized molecular geometries of Complexes 3, 4 and 5. Pt, Sky blue; Se, yellow; C, grey; N, blue; P, orange; H, white sphere.

To validate the calculation methodology, it is interesting to compare the computational results with those obtained experimentally. The PBEPBE-D3/LAN2DZ calculated parameters are in good accord with the findings of the results. The optimized structural parameters are on average less than 3.6% and 3.1% different from the experimental data for complexes 3 and 5 respectively. Indeed, the optimized Pt1—Se1, Pt1—P1and Se1—C1 bonds lengths (2.54 Å, 2.42 Å and 1.92 Å) on complex 3 are at most 5.1%, 3.6% and 5.7% larger than those given by XRD (2.42 Å, 2.33 Å and 1.81 Å). The same findings are obtained for complex 5 (Table 3). The optimized Se1—Pt1—Se2, Se1—Pt1—P1 and Se2—Pt1—P2 bonds angles (168.8˚, 91.7˚ and 87.7˚) in complex 3 is at most 3.5%, 1.7% and 0% larger than those given by XRD (163.3˚, 90.15˚ and 87.67˚). Therefore, from a structural point of view, the systems examined in this paper are well described by the PBEPBE-D3/LAN2DZ technique, which will be used for additional compounds, especially for complex 4 which was not characterized by XRD.

Table 3. Calculated and experimental geometric parameters (Bond length (Å) and Bond angles (˚)) of compounds 3, 4 and 5.
Complex 3
 Complex 5
 Complex 4
Bond length(Å) XRD DFT Relative error (%) XRD DFT Relative error % DFT
Pt1—Se1 2.42(1) 2.54 5.1 2.44(6) 2.54 4.3 2.54
Pt1—Se2 2.42(9) 2.55 5.4 2.44 (5) 2.55 4.4 2.55
Pt1—P1 2.33(2) 2.42 3.6 2.35(8) 2.43 3.3 2.42
Pt1—P2 2.34(2) 2.43 3.5 2.33 (8) 2.42 3.8 2.43
Se1—C1 1.81(7) 1.92 5.7 1.87 (3) 1.92 2.6 1.92
Se2—C6(11) 1.82(6) 1.92 5.7 1.87(3) 1.92 2.9 1.92
Bond angles (˚)
Se1—Pt1—Se2 163.03(3) 168.81 3.5 163.50(2) 170.34 4.2 169.62
Se1—Pt1—P1 90.15(5) 91.70 1.7 94.12(3) 92.39 1.9 91.54
Se1—Pt1—P2 94.26(5) 91.87 2.6 90.13(3) 90.40 0.3 91.91
Se2—Pt1—P1 86.25(5) 87.42 1.3 87.79(3) 90.02 2.5 87.20
Se2—Pt1—P2 87.67(5) 87.79 0.0 87.04(3) 86.87 0.3 88.96
P1—Pt1—P2 171.26(6) 175.73 2.6 174.24(1) 175.75 0.8 175.63
C1—Se1—Pt1 106.2(2) 101.16 4.8 106.71(1) 98.81 7.4 99.10
C6(11)—Se2—Pt1 107.01(2) 101.58 5.1 107.23(1) 102.63 4.3 101.34

The optimized angles and bond lengths obtained for the complex 4 are presented in Table 3. The optimized structures and atom numbering scheme are given in Fig. 6. The molecule has the C1 point group. In this complex, the bond distances of Pt1—Se1, Pt1—Se2, Pt1—P1, Pt1—P2, Se1—C1 and Se2—C6 were calculated to respectively be 2.54 Å, 2.55 Å, 2.42 Å, 2.43 Å, 1.92 Å and 1.92 Å. The bond angles of Se1—Pt1—Se2, Se1—Pt1—P1, Se1—Pt1—P2, Se2—Pt1—P1, Se2—Pt1—P2, P1—Pt1—P2, C1—Se1—Pt1 and C6—Se2—Pt1 were calculated to be 169.6, 91.5, 91.9, 87.2, 88.9, 175.6, 99.1 and 101.3, respectively.

The geometric parameters of complex 4 are very similar to those obtained for complex 3 and 5 (Table 3). In conclusion, the modification of the branching of the imidazole moiety does not influence the geometric parameters of the complex.

Fig. 7 displays the quantum physicochemical characteristics of the complexes under study, which were estimated at the PBEPBE-D3/LAN2DZ level of theory. These values include the energies of the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), and the HOMO–LUMO gap. The energy gap between complexes 3, 4, and 5’s lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) energies are 2.63 eV, 2.62 eV and 2.66 eV, respectively. The three compounds are good semiconductors. Complex 4 has the lowest value of the HOMO–LUMO gap, which suggests heightened reactivity and increased electronic conductivity.

Frontier molecular orbitals and HOMO–LUMO gaps of complexes 3, 4 and 5.
Fig. 7.
Frontier molecular orbitals and HOMO–LUMO gaps of complexes 3, 4 and 5.

3.5 Score energy and best poses analysis

Complex 4, the most active substance in the experiment, exhibited strong cytotoxicity against two cancer cell lines (MG-63 and HTC-15). The best poses obtained from docking simulation for complex 4 with the pocket of Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) proteins have been listed in Table S6.

With the aid of the free BIOVIA DS visualization program (Dassault Systems BIOVIA, Discovery Studio modelling environment, 2020), 3D and 2D diagrams of the interactions between complex 4 and the receptors under study were visualized. According to Table S6, we found that complex 4 fits well in the binding site of the Hela (PDB ID: 3F81) and it is located in the same region of the native ligand (STT). Besides, the 3F81@4complex has the lowest negative score energy value (-5.595 kcal/mol) compared to the native ligand with the value (-4.658 kcal/mol) (Table S6). After docking complex 4 in the active site residues Hela (PDB ID: 3F81) target, we found that this complex was making one strong hydrogen bond (Imberty et al., 1991; Wade and Goodford, 1989) with residue ASP92 (at bond distances =2.62 Å). Furthermore, five hydrophobic interactions (two alkyl types and three Pi-Alkyl types) are established between complex 4 and the following residues: LEU25, TYR23, and TYR128 (Table S6+ Figs. 7 and 8). On the other hand, many recent studies (Belkadi et al., 2021; Morales-Salazar et al., 2023) confirmed that residues: ASP92, and TYR128play important roles in inhibiting Hela (PDB ID: 3F81). However, the results confirmed that the residues that in the case of complex 4 and the residues forming the bond are almost the same as those of the native ligand.

3D and 2D diagrams of interactions between compound 4 and the active site residues of Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) targets.
Fig. 8.
3D and 2D diagrams of interactions between compound 4 and the active site residues of Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) targets.

As shown in Table S6, complex 4 has high affinity for HCT-15(PDB ID: 4RA4). Moreover, the score energy of the complex formed by complex 4 was found to be -6.780 kcal/mol, which is slightly closer to that of the native ligand (3KZ) (score energy = -7.554 kcal/mol). In addition, we found that complex 4 formed strong hydrogen bond with LYS347 (Imberty et al., 1991; Wade and Goodford, 1989) (distance: 2.80 Å). While this complex formed 10 hydrophobic interactions (9 alkyl types and 1 Pi-Alkyl type) with residues: ALA366, ALA480, LEU345, VAL353, MET470, MET417, and PHE350 (Table 3+ Figs. 7 and 8). Furthermore, the current results are supported by previous studies (Wong et al., 2017; Wang et al., 2022), indicating that residues VAL353, PHE350, and MET470 are important inhibit HCT-15 (PDB ID:4RA4). Similarly, molecular docking simulation results indicate that complex 4 has a slightly different type of interaction with HCT-15 (PDB ID: 4RA4) compared to the native ligand, which is justified by the presence of common residues.

Based on the score energy value, complex4exhibits high affinity for MG-63 (PDB ID: 6T2W). It was observed that the complex formed by this compound has a lower energy value of -6.844 Kcal/mol, which is very close to the energy value of the native ligand (M9T)(-7.709kcal/mol) (Table S6). On the other hand, we found that complex 4 forms two strong hydrogen bonds (Imberty et al., 1991; Wade and Goodford, 1989) with residues LEU588 and ASP670 (distance = 2.89 and 2.69 Å, respectively). Furthermore, five hydrophobic interactions (four alkyl types and one Pi-Alkyl type) appear to be formed between this compound and residues: LEU785, LEU588, and TYR665 (Figs. 8 and 9). The 6T2W-AD126 complex shares the most common residues with the native ligand. Several recent studies have shown that residues LEU785, LEU588, and TYR665 play important roles in the inhibition of MG-63 (PDB ID: 6T2W) (Aarhus et al., 2023; Liu et al., 2022).

3D and 2D diagrams of interactions between native ligands and the active site residues of Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) targets.
Fig. 9.
3D and 2D diagrams of interactions between native ligands and the active site residues of Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) targets.

3.6 Physicochemical parameters and ADME-Tox prediction

The drug-likeness evaluation of complex 4 was conducted using ADME-T predictions and physicochemical properties calculations, with all results listed in Table 4.

Table 4. ADME-Tox and drug-likeness properties of the compound 4
Entry

TPSA

(Å2)

 n-ROTB

MW

(g/mol)

 MLog P

n-ON

acceptors

n-OHNH

donors

Lipinski’s

violations

Egan

violations
<140 <11 <500 ≤5 <10 <5 ≤1 ≤1
4 217.645 12 817.702 3.09 4 2 Accepted Accepted
ADME-T Absorption Distribution Metabolism Excretion Toxicity

Caco2

(10-6 cm/s)

 HIA % CNS (log PS)

BBB

(log BB)

 CYP1A2 inhibitor CYP2C19 inhibitor CYP2D6 substrate Renal OCT2 substrate Total Clearance(mL/min/kg) AMES toxicity Hepatotoxicity
4 1.14 92.76 -1.23 0.869 NO NO YES NO -1.368 NO NO

Caco-2: Colon adeno carcinoma, HIA: Human intestinal absorption, CNS: Central Nervous System permeability, BBB: Blood–Brain Barrier permeability. Renal OCT2 substrate: Organic cation transporter 2.

According to the data in Table 3, we found that the TPSA value ​​of complex4 is greater than 140 Å. Additionally, this complex has n-OHNH donors<5 and n-ON acceptors<10. Alternatively, complex4 has a molecular weight value greater than 500 g/mol, and MLogP value less than 5. Besides, we found that nROTB value is >11. The study found that complex 4 met drug-likeness criteria without violating Lipinski and Egan rules.

The results in Table 3 show that: (i) The Caco-2 value of studied complex is greater than -5.15 cm/s), indicated that it has a good permeability. Also, the HIA value of this complex (92.76%) is greater than 30%, which confirmed that complex 4 can be easily absorbed orally in the gastrointestinal system. (ii) The logPS value of the complexation the range of -3<logPS<-2, indicating that it can penetrate the CNS. In addition, the logBB value of complex 4was: 0.869, which confirmed that the complex was (logBB<-1) distributed poorly in the brain. (iii) The results in the above table indicate that complex4is not CYP1A2 and CYP2C19 inhibitors and it is CYP2D6 substrate. Furthermore, it can clearly be noted that complex 4 is not likely to be OCT2 substrate. The complex also exhibited an average excretion clearance of less than 5 ml/min/kg. Also, complex4didnot show AMES toxicity and did not pose a risk of Hepatotoxicity (Table S6).

4. Conclusions

The study provides the spectral and structural characterization of a new platinum(II) complexes containing triethyl phosphine and heterocyclic selenones ligands. The complexes were fully characterized by variety of spectroscopic techniques. The crystal structure analysis of complexes 3 and 5 revealed that the complexes adopt a distorted square planar geometry at the platinum(II) atoms. The growth inhibitory effects of synthesized complexes (1-7) assessed via MTT assay. The IC50 values showed promising to moderate cytotoxicity for the prepared platinum(II) complexes. The present study has revealed that the most active complex 4 can be considered as a leading candidate for the inhibition of HCT-15 (human colon adenocarcinoma). The molecular docking simulation and ADME-Tox properties were successfully used to investigate and predict the characteristic manner of complex 4. The molecular docking results proved that compound 4 has high binding affinity against Hela (PDB ID: 3F81), HTC-15 (PDB ID: 4RA4), and MG-63 (PDB ID: 6T2W) receptors, confirming low negative energy values. Additionally, complex 4 established many interactions with the active site residues of receptor targets. ADME-TOX properties were estimated for this candidate to validate its pharmacodynamics and pharmacokinetics, as well as to ensure compliance with the Lipinski and Egan protocols. We found that complex 4 did not exhibit AMES toxicity and did not pose a risk of hepatotoxicity.

Acknowledgement

The Researchers would like to thank the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2026).

CRediT authorship contribution statement

Adam A. A. Sulaiman: Investigation, methodology, writing, review and editing. Gaurav Bhatia: Methodology and formal analysis. Mohammed Fettouhi: Methodology and formal analysis. Ismail Daoud: Software and formal analysis. Ridha Ben Said: Software and formal analysis. Seyfeddine Rahali: Software and formal analysis. Mariam Fraghaly: Formal analysis and writing original draft. Ard Elshifa Mohammed: Methodology and data acquisition. Muneera Alrasheedi: Investigation, formal analysis and data acquisition. Anvarhusein Isab: Project administration and supervision

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Supplementary Material

Supplementary material to this article can be found online at https://dx.doi.org/10.25259/JKSUS_82_2025.

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