Trans-platinum Complexes Research Articles

Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells.

Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans-[Pt(amine)Cl2(PPh3)], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.

Synthesis and structure of two novel trans-platinum complexes.

Here for the first time the synthesis and characterization of two new trans-platinum complexes, trans-[PtCl2{HN=C(OH)C6H5}2] (compound 1) and trans-[PtCl4(NH3){HN=C(OH)tBu}] (compound 2) [with tBu = C(CH3)3] are described. The structures have been characterized using nuclear magnetic resonance spectroscopy and X-ray single-crystal diffraction. In compound 1 the platinum cation, at the inversion center, is in the expected square-planar coordination geometry. It is coordinated to two chloride anions, trans to each other, and two nitrogen atoms from the benzamide ligands. The van der Waals interactions between the molecules produce extended two-dimensional layers that are linked into a three-dimensional structure through π...π intermolecular interactions. In compound 2 the platinum cation is octahedrally coordinated by four chloride anions and two nitrogen atoms from the pivalamide and ammine ligands, in trans configuration. The molecular packing is governed by intermolecular hydrogen bonds and van der Waals interactions.

Wavelength and solvent controlled energy and charge transfer in donor-acceptor substituted platinum acetylide complexes

• Photophysics of a Donor-Acceptor substituted Pt(II) Complex are studied. • Complex displays wavelength and solvent tuned photophysics. • Ultrafast spectroscopy reveals the existence of ultrafast energy and charge transfer. An electron donor-acceptor platinum complex trans -Pt(PBu 3 ) 2 (C≡C-T 4 )(C≡C-TBT) (Pt(T 4 )(TBT)) incorporating (3,3'''-dihexyl-2,2':5',2'':5'',2'''-quaterthiophene, T 4 ) as donor and (4,7-bis(2-thienyl)-2,1,3-benzothiadiazole, TBT) as acceptor has been synthesized and fully characterized. Model complexes trans -Pt(PBu 3 ) 2 (C≡C-T 4 ) 2 and trans -Pt(PBu 3 ) 2 (C≡CTBT) 2 featuring only donor or acceptor moieties were synthesized for reference. Steady state absorption, fluorescence, and ultrafast visible-near infrared transient absorption spectroscopy were applied to evaluate intracomplex energy and charge transfer in different solvents and by using selective excitation wavelengths corresponding to T 4 or TBT units. The fluorescence spectrum of Pt(T 4 )(TBT) is red-shifted with increasing solvent polarity, consistent with the existence of a charge transfer excited state. Detailed solvent and excitation wavelength dependent ultrafast transient absorption experiments were carried out on all of the complexes. For Pt(T 4 )(TBT) in non-polar solution excitation of T 4 leads to ultrafast (∼200 fs) T 4 to TBT energy transfer. However, in more polar solvents, T 4 excitation gives rise to an ultrafast T 4 to TBT electron transfer affording a “ligand to ligand” charge transfer excited state. The results provide insight into the existence of donor-acceptor interactions between weakly coupled π-conjugated units that are separated by a metal center.

An account of noncovalent interactions in homoleptic palladium(II) and platinum(II) complexes within the DFT framework: A correlation between geometries, energy components of symmetry-adapted perturbation theory and NCI descriptors

The present work addresses the underlying nature of weak noncovalent interactions (NCIs) in the self-assembled dimers of two square planar palladium(II) and platinum(II) complexes trans-[Pd(Hida)2] (1) and trans-[Pt(Hida)2] (2) (Hida = monoprotonated iminodiacetate) within the framework of density functional theory (DFT) in gas phase. Initial geometries of the dimers in different spatial orientations were extracted from the X-ray crystal structures, reported earlier, and optimized with three dispersion-corrected functionals that are frequently used to explore NCIs. The BP86-D3, M062X-D3 and ωB97X-D3 functionals have been used to test their performances over the present systems. The SARC-ZORA-TZVP and ZORA-def2-TZVP basis sets were applied for the metals and the remaining elements, respectively. The optimizations resulted in equilibrium geometries where the monomers are self-assembled through NCIs to form dimers in a cyclic fashion. This type of structural pattern is absent in the crystal structures of both 1 and 2. Physical components of interaction energies were investigated by symmetry-adapted perturbation theory (SAPT). The UV-Vis absorption spectra of the dimers are described by time-dependent density functional theory (TD-DFT). Global reactivity parameters for the dimers have been computed within the framework of conceptual density functional theory (CDFT). Detailed investigations on NCIs were performed for all dimer geometries. Simulated IR and 1H NMR spectra, charge transfer, QTAIM, NCI-RGD, IGM, ETS-NOCV and ELF studies confirmed the presence of intermolecular hydrogen bonds (HBs) and weak van der Waals interactions. Energies of the hydrogen bonds and associated orbital interaction energies were computed by QTAIM and ETS-NOCV methods, respectively.

Thioredoxin reductase inhibition by new trans-platinum(II) complexes elicit cytotoxicity in cisplatin resistant ovarian cancer cells

Thioredoxin reductase inhibition by new trans-platinum(II) complexes elicit cytotoxicity in cisplatin resistant ovarian cancer cells

Photo-Triggered Chiroptical Switching of Platinum Complexes Bearing Azobenzene Moieties

l-Alanine-derived optically active trans-platinum complexes bearing azobenzene moieties, l-trans-Pt[P(Ph)2-1,4-C6H4-CONH-C*H(CH3)-CONH-1,4-C6H4-N═N-Ph]2(C≡CPh)2 (L-2a-5t) and l-cis-Pt[P(Ph)2-1,4-C6H4-CONH-C*H(CH2Ph)-CONH-1,4-C6H4-N═N-Ph]2(C≡CPh)2 (L-2a-5c) were synthesized by the ligand exchange reaction of trans-Pt(PPh3)2(C≡CPh)2 and cis-Pt(cod)(C≡CPh)2, respectively, with l-P(Ph)2-1,4-C6H4-CONH-C*H(CH2Ph)-CONH-1,4-C6H4-N═N-Ph. The trans-azobenzene moieties of the complexes isomerized to the cis form upon UV-light irradiation and returned to the trans form upon visible-light irradiation. L-2a-5t displayed weak circular dichroism (CD) signals irrespective of the trans and cis forms of the azobenzene moieties. On the other hand, L-2a-5c with trans-azobenzene moieties displayed strong CD signals, whose intensity decreased upon UV-light irradiation, accompanied by an increase in CD signals based on cis-azobenzene moieties. DFT calculations of the complexes indicated that intramolecular hydrogen bonds form between the amide moieties of two ligands in the cis-platinum complexes, resulting in retention of conformation. A noncovalent interaction plot analysis also indicated that the π–π interaction between the benzene rings of the ligands also contributes to conformational maintenance. The d-alanine-derived counterparts, D-2a-5t and D-2a-5c, exhibited mirror-image CD spectroscopic patterns in comparison to those of L-2a-5t and L-2a-5c. Solution-state IR absorption spectroscopic peaks of C═O stretching and N–H bending vibrations of L-2a-5c were observed broadly at ca. 10 cm–1 lower and higher than those of P(Ph)2-1,4-C6H4-CONH-C*H(CH3)-CONH-1,4-C6H4-N═N-Ph (L-2a), respectively, thus supporting the formation of intramolecular hydrogen bonding at the amide groups.

Understanding the role of flexible alkyl-α,ω-diamine linkers on the substitution behaviour of dinuclear trans-platinum(II) complexes: A kinetic and mechanistic study

An investigation of the role of flexible alkyl-α,ω-diamine linkers on the substitution behaviour of dinuclear trans-platinum(II) complexes. The substitution reactions of four dinuclear trans-platinum(II) complexes viz. [PtNH3Cl2]2-µ-NH2(CH2)2NH2] (P12), [PtNH3Cl2]2-µ-NH2(CH2)3NH2] (P13), [PtNH3Cl2]2-µ-NH2(CH2)4NH2] (P14) and [PtNH3Cl2]2-µ-NH2(CH2)5NH2] (P15) with three neutral thiourea-based nucleophiles specifically: thiourea (TU), N-methyl-2-thiourea (MTU) and N,N-dimethyl-2-thiourea (DMTU) were studied quantitatively under pseudo-first-order condition as function of concentration and temperature by conventional UV–Visible and stopped-flow spectrophotometers. The ligand substitution reaction of the complexes proceeds in veritably three consecutive steps. Each step follows first-order kinetics with the respective complex and nucleophile. The pseudo first order rate constants, kobs(1/2/3), for sequential substitution of the chlorido ligands, the ammine, and subsequent displacement of the linker obeyed the rate law: kobs(1/2/3) = k(1/2/3)[NU]. The ligand substitution reactions were driven by both electronic and steric factors. However, our findings revealed that upon the substitution of the chlorido ligands by the nucleophiles at the platinum centres, the σ-donor capacity via inductive effect of these electron-rich nucleophiles over compensate the steric strain imposed by the nucleophiles and by the alkanediamine linker at the substitution sites. Consequently, electronic factors governed the overall reaction pattern of these complexes. 195Pt NMR results confirmed the simultaneous substitution of all the chlorido ligands by thiourea-based nucleophiles, followed by the subsequent but successive displacement of the ammine groups and the flexible alkanediamine linker from the metal centres. The order of reactivity of the nucleophiles with the complexes decreases with the increase in steric bulk in the nucleophiles: TU > MTU > DMTU. The small positive enthalpy and the large but negative entropy confirm the associative mode of activation for all the studied complexes. Computational modelling using density functional theory (DFT) calculations was employed to rationalise the kinetic trends.

Synthesis, Characterization and Antiproliferative Evaluation of Pt(II) and Pd(II) Complexes with a Thiazine-Pyridine Derivative Ligand.

Chemical, pharmacological, and clinical research on anticancer coordination complexes has led to noteworthy anticancer drugs such as cisplatin, carboplatin and oxaliplatin. Although these compounds are effective chemotherapeutic agents in the treatment of different tumors, they are associated with high toxicity and numerous side effects. Several studies have shown that the range of platinum complexes with antitumor activity is not limited to structural analogs of cisplatin. Therefore, the development of convenient anticancer drugs that can be effectively used for the treatment of human tumors has become the main goal of most research groups in this field. In this sense, active platinum complexes without NH groups, transplatinum complexes, multinuclear complexes, cationic complexes, and several classes of palladium(II) complexes have emerged. Herein, the synthesis and characterization of two Pt(II) or Pd(II) complexes with PyTz (2-(2-pyridyl)iminotetrahydro-1,3-thiazine), a thiazine derivative ligand, with the formula [MCl2(PyTz)]·C2H6O (M = Pt(II) or Pd(II)) were reported. The potential anticancer ability of both complexes was evaluated in epithelial cervix carcinoma HeLa, human ovary adenocarcinoma SK-OV-3, human histiocytic lymphoma U-937, and human promyelocytic leukemia HL-60 cell lines. Interestingly, the Pt(II) complex showed great cytotoxic potential against all tumor cell lines tested, whereas the Pd(II) complex displayed slight antitumor actions.

The effect of charge on the uptake and resistance to reduction of platinum(IV) complexes in human serum and whole blood models.

cis- and trans-Platinum(iv) complexes with diaminetetracarboxylate coordination spheres possess the highly desirable property of exhibiting unusual resistance to reduction by blood serum components and endogenous reductants such as ascorbate. At the same time they are rapidly reduced in the intracellular environment of cancer cells. Consequently, they can potentially be tuned to remain intact in vivo until arrival at the tumour target where they are rapidly reduced to yield the active platinum(ii) species. However, in order to achieve this, uptake must be largely restricted to tumour cells and therefore uptake by healthy cells including red blood cells must be prevented. In this proof of concept study, we report on the effect of net charge as a means of controlling the uptake by red blood cells. Using 1H NMR spectroscopy we found that modifying the net charge of the complex does not influence the rate of reduction of the complexes by an excess of ascorbate. Using XANES spectroscopy we found that modifying the net charge of the platinum(iv) complexes decreased the extent of reduction in whole blood, although probably not to the degree needed for the optimal delivery to tumours. Therefore, it is likely to be necessary to adopt higher charges and/or additional strategies to keep platinum(iv) prodrugs out of blood cells.

Correction to: A kinetic investigation of mononuclear trans-platinum(II) complexes with mixed amine ligands

The article “A kinetic investigation of mononuclear trans-platinum(II) complexes with mixed amine ligands”, written by “Moses Ariyo Olusegun, Desigan Reddy and Deogratius Jaganyi”.

A kinetic investigation of mononuclear trans-platinum(II) complexes with mixed amine ligands

This study was aimed at investigating the substitution behaviour of mononuclear trans-platinum(II) complexes with mixed amine ligands. The rate of substitution of the chloride moieties from the complexes trans-Pt(NH3)(NH2C2H5)Cl2 (tPt2), trans-Pt(NH3)(NH2C3H7)Cl2 (tPt3), trans-Pt(NH3)(NH2C4H9)Cl2 (tPt4) and trans-Pt(NH3)(NH2C5H11)Cl2 (tPt5), by three nucleophiles, viz. thiourea (TU), 1-methyl-2-thiourea (MTU) and 1,3-dimethyl-2-thiourea (DMTU), was studied by stopped-flow spectrophotometry using a large excess of nucleophile. Pseudo-first-order rate constants (kobs) were measured as a function of nucleophile concentration and temperature. Reactions were first order in both [complex] and [nucleophile] and therefore second-order overall (rate = kobs[complex] where kobs = k2[nucleophile]). The kinetics are consistent with a stepwise mechanism involving rate determining substitution of the first chloride followed by a fast second substitution step, with no intermediates being detected. The reactivity of the complexes was largely dependent on the length of the alkyl chain of the alkylamine moiety of the complexes. Computational modelling using density functional theory calculations showed that an increase in chain length by a methylene unit has no direct electronic consequence on the metal centre but did, however, pose significant steric hindrance on the substitution sites due to the flexibility of the alkyl chains and thus governed the overall reaction pattern. 195Pt NMR kinetic studies established that the mixed amine ligands remain coordinated to the metal centre in the final kinetic product. This implies that mononuclear trans-platinum(II) complexes are resistant to complete substitution of ligands by the incoming thiourea nucleophiles at the reaction sites. The reactions follow an associative mechanism of substitution.

Platinum(II) and copper(II) complexes of 7-azaindole-3-carboxaldehyde: crystal structures, IR and Raman spectra, DFT calculations and in vitro antiproliferative activity of the platinum(II) complex

Pt(II) and Cu(II) complexes, trans-[PtCl2(7AI3CAH)2] and [CuBr2(7AI3CAH)2]n, containing 7-azaindole-3-carboxaldehyde (7AI3CAH) have been synthesized and investigated by a single crystal X-ray diffraction, vibrational spectroscopy and DFT calculations. In the platinum(II) complex two pyridine nitrogen atoms of the 7AI3CAH ligands and two chloride ligands are coordinated to the central metal atom, in a square-planar trans arrangement. In the polymeric copper(II) complex the coordination geometry is a tetragonal bipyramid (4 + 2), where the in-plane ligands are two pyridine nitrogen atoms of two organic ligands and two trans-bromide ligands. The apical positions of bipyramid are occupied by the two Br ligands from the neighboring units. Thus, the CuBrBrCu double bridge system is formed. Detailed vibrational assignments of the IR and Raman spectra of the Pt(II) and Cu(II) complexes have been made on the basis of the calculated potential energy distributions (PEDs) using B3LYP method. The in vitro antiproliferative activity of trans-[PtCl2(7AI3CAH)2] was studied against different human cancer cell lines. The results have shown that this complex is comparably cytotoxic with cisplatin at the LoVo (colon cancer) and MCF7 (breast cancer) cells, whilst its cytotoxicity is significantly lower against the A549 cells (lung cancer) as compared to cisplatin. However, it is about 8-fold less toxic than cisplatin against a normal fibroblast cell line (BALB/3T3). A study on stability of trans-[PtCl2(7AI3CAH)2] in DMSO solution has been performed by FT-IR (ATR) spectroscopy to predict a possible binding mode of trans-platinum(II) complex with DNA.

Four-component relativistic 31P NMR calculations for trans-platinum(ii) complexes: importance of the solvent and dynamics in spectral simulations.

We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(ii) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complexes. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functionals, dynamical averaging, and solvation effects. Snapshots obtained from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by using the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules.

Synthesis, Reactivity Studies, and Cytotoxicity of Two trans-Iodidoplatinum(II) Complexes. Does Photoactivation Work?

trans-Platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes signaled a new turning point in the platinum drug design field when their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodidoplatinum complexes trans-[PtI2(amine)(pyridine)] bearing aliphatic amines (isopropylamine and methylamine) and pyridines in trans configuration. X-ray diffraction data support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D, and HCT116. Moreover, we report their solution behavior and reactivity with biological models. Ultraviolet-a (UVA) irradiation induces an increase in their reactivity towards model nucleobase 5′-GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.

A Computational Approach for Hydrolysis of the Third-Generation Anticancer Drug: Trans-Platinum(Ii) Complex of 3-Aminoflavone

In this study, hydrolysis of the anticancer drug trans-bis-(3-amino-flavone)dichloridoplatinum(II) (trans- Pt(3-af)2Cl2; TCAP) in gas and solution phases is studied. With the polarizable continuum model (PCM) model the complex computational study is performed in an aqueous solvent. Before the complex interaction with the target biomolecules, two typical reactions involved in the complex hydrolysis include the first and second hydrolysis processes. Thermodynamic and kinetic parameters of the hydrolysis reactions are analyzed. The variations of two structural parameters of the reaction are discussed.

PtII versus PdII-assisted [2 + 3] cycloadditions of nitriles and nitrone. Synthesis of nitrile-derived arylamido platinum(II) and Δ4-1,2,4-oxadiazoline palladium(II) complexes

The reactions of bis(organonitrile) platinum(II) complexes trans-[PtCl2(NCR)2] (R = C6H4(p-HCO), CH2C6H4(p-CH3)) with pyrroline N-oxide −O+NCHCH2CH2CMe2 afford arylamido platinum(II) complexes trans-[PtCl2{(OCR)NCCH2CH2CMe2NH}2] (R = C6H4(p-HCO) (1), CH2C6H4(p-CH3) (2)). The spectral data of 1 and 2 show that the oxadiazoline rings in both cases have opened by a spontaneous NO bond cleavage to form (Z)-p-formyl-N-(5,5-dimethylpyrrolidin-2-ylidene)benzamide or (Z)-N-(5,5-dimethylpyrrolidin-2-ylidene)-2-p-tolylacetamide ligands, respectively, where the N-atoms of the benzamide or acetamide moieties coordinate to platinum(II) metal centre in trans positions. However, the reactions of bis(organonitrile) palladium(II) complexes trans-[PdCl2(NCR)2] with pyrroline N-oxide furnish Δ4-1,2,4-oxadiazoline palladium(II) complexes trans-[PdCl2{NC(R)ONC(H)CH2CH2CMe2}2] (R = C6H4(p-HCO) (3), CH2C6H4(p-CH3) (4)) as the exclusive detected products. Compounds 1–4 have been characterized by IR, 1H, 13C NMR spectroscopy, elemental analyses, ESI+-MS and also, in the case of 1, by single crystal X-ray diffraction analysis.

Synthesis, X-ray structure and in vitro cytotoxicity of trans-diammineplatinum(II) complexes of selenones, trans-[Pt(NH3)2(selenone)2](NO3)2

Seven trans platinum(II) complexes of selenones having the general formula, trans-[Pt(NH3)2(selenone)2](NO3)2 have been synthesized and characterized using elemental analysis, IR, and NMR (1H &13C &77Se) spectroscopy. The crystal structure of one of them, trans-[Pt(NH3)2(PrImSe)2](NO3)2 (5) was determined by single crystal X-ray diffraction analysis. The platinum atom in the complex cation adopts a distorted square planar geometry. The spectroscopic data particularly, a significant upfield shift in 77Se NMR indicated the coordination of selenone ligands to platinum(II). The in vitro cytotoxicity of these complexes as well as of cisplatin was investigated using MTT assay against two human cancer cell lines, HeLa (cervical cancer cells) and MDA-231 (human breast cancer cells). The IC50 values showed promising cytotoxicity for the prepared platinum(II) complexes, which in the case of 1, 4 and 6 is higher as compared to cisplatin.

Assessing the Ligand Properties of NHC-Stabilised Phosphorus(I) Cations.

The isolation and full characterisation of a series of cationic metal-carbonyl complexes bearing an N-heterocyclic carbene stabilised phosphorus(I) ligand are reported. Specifically, the mononuclear coordination complexes [LM(CO)5 ][BPh4 ] (M=Cr, Mo, W), [LFe(CO)4 ][BPh4 ] and the dinuclear complexes [LMn2 (CO)8 ][BPh4 ] and [LCo2 (CO)6 ][BPh4 ], in which L=[bis(1,3,4,5-tetramethylimidazol-2-ylidene)phosphanide]+ , have all been isolated in the solid state and structurally confirmed by single-crystal X-ray diffraction. The dicationic platinum complex trans-[L2 PtCl2 ][BPh4 ]2 is also reported and fully characterised. The donor ability of [L]+ has been assessed by IR spectroscopy of its metal-carbonyl complexes and by using DFT calculations. The results suggest that [L]+ is a weak π-acceptor with moderate donor strength and thus it bridges the gap that exists between phosphines and amines in terms of ligand properties. Collectively, these molecules represent the first crystallographically characterised cationic metal-carbonyl derivatives of a PI -centred ligand and are a rare collection of cationic metal-carbonyl complexes.

A computational approach for hydrolysis of the third-generation anticancer drug trans-platinum(II) complex of 3-aminoflavone

A computational approach for hydrolysis of the third-generation anticancer drug trans-platinum(II) complex of 3-aminoflavone

A fluorescent probe for investigating metabolic stability of active transplatin analogues

Selective fluorescent probes enable unprecedented studies of metals, with sensitivity not only to identify the metal, but also to discern its oxidation state and coordination environment. Recent work has highlighted the potential of fluorescent probes for specific platinum species in understanding the activity of platinum anticancer agents. Here we report a rhodamine-based probe that selectively responds to aryl-bearing trans-platinum complexes, which represent an important class of potential anticancer agents. We subsequently demonstrate the utility of this probe for studying the rate of metabolism of these types of complexes.