Carrier Ligand Research Articles

IN VITRO CYTOTOXIC ACTIVITIES OF PLATINUM(II) COMPLEXES CONTAINING 1H-BENZO[d]IMIDAZOLE AND 1H-1,3-DIAZOLE DERIVATIVES

Objective: This study aimed to synthesize and evaluate the cytotoxic activities of four platinum(II) complexes with 2-substituted or nonsubstituted 1H-benzo[d]imidazole and 1H-1,3-diazole derivatives as carrier ligands (L1-L4), which may have potent cytotoxic activity and low side effects. Material and Method: K1-K4 complexes were synthesized by heating and mixing K2PtCl4 and the appropriate L1-L4. The chemical structures of K1-K4 were elucidated by Infrared and 1H Nuclear Magnetic Resonance spectroscopic methods. In vitro, cytotoxic effects of K1-K4 complexes against prostate (DU-145), endometrial adenocarcinoma (Ishikawa), and breast cancer (MCF-7) cell lines were tested by the MTT method. Result and Discussion: According to the IC50 values of the tested cell lines, K1 and K2 derivatives bearing unsubstituted 1H-benzo[d]imidazole (L1) and 1H-1,3-diazole (L2) were found to be the most effective compounds among these synthesized complexes.

Interactions with DNA Models of the Oxaliplatin Analog (cis-1,3-DACH)PtCl2.

It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis-1,3-diaminocyclohexane (cis-1,3-DACH) upon formation, stability, and stereochemistry of the (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis-1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (cis-1,3-DACH)Pt(5'GMP)2 and (cis-1,3-DACH)Pt(3'GMP)2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis-1,3-DACH derivatives with respect to the analogous cis-(NH3)2 species could be a consequence of the greater bite angle of the cis-1,3-DACH carrier ligand with respect to cis-(NH3)2. Finally, the (cis-1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.

Antitumor active trans‑platinum complexes through metabolic stability and enhanced cellular accumulation

Utilizing isoquinoline as a carrier ligand, we have evaluated the reactivity of selected trans‑platinum planar amine (TPA) carboxylate compounds by varying the leaving carboxylate group (acetate, hydroxyacetate, and lactate) in an effort to optimize the cytotoxic and metabolic efficiency. To measure the pharmacological properties of these compounds, a combination of systematic biophysical and biological studies were carried out mainly involving substitution reaction with NAM (N-acetyl-methionine), effects on DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects. TPA compounds showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum, while displaying a distinct micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle. Monitoring the TPA compounds with NAM suggests the following trend for the reactivity: hydroxyacetate > lactate > acetate. The same trend was seen for the cytotoxicity in tumor cells and DNA binding, while the rate of drug inactivation/protein binding in cells was not significantly different among these leaving groups. Thus, our results show superior cellular efficacy of TPA compounds and distinct micromolar cytotoxic activities different than cisplatin. Moreover, we found the TPA compounds had prolonged survival and decreased tumor burden compared to the control mice in a relevant human ovarian cancer mouse model with A2780 cells expressing luciferase. Therefore, we propose that further optimization of the basic TPA structure can give further enhanced in vivo activity and may eventually be translated into the development of clinically relevant non-traditional platinum drugs.

Synthesis, characterization and in vitro cytotoxic activity of platinum(II) oxalato complexes involving 2-substitutedimidazole or 2-substitutedbenzimidazole derivatives as carrier ligands

Synthesis, characterization and in vitro cytotoxic activity of platinum(II) oxalato complexes involving 2-substitutedimidazole or 2-substitutedbenzimidazole derivatives as carrier ligands

Complexes of N, N- and N, N, N- Sulfonamide Ligands as Therapeutic and Diagnostic Agents

Ethylenediamine, diethylenetriamine and dipicolylamine have been used as the carrier ligands to synthesize bidentate (N,N) or tridentate (N,N,N) chelate systems that coordinate with metal centers. The terminal amine groups of ethylenediamine and diethylenetriamine and the central amine group of dipicolylamine can be easily substituted to give sulfonamide ligands having bulky aromatic fragments. In the formation of metal sulfonamides, the sulfonamide nitrogens of primary or secondary sulfonamidesdeprotonate and coordinate with metal centers forming M-N bonds while the free amines coordinate to metal centers through lone pairs. The reported synthetic approaches and the properties of these complexes and ligands are discussed in this review. The bulky sulfonamide moieties bring about unique biological features to the ligand system while enhancing the fluorescent properties of the ligand. The metal center itself incorporates interesting biological features to the complex. These properties of the metal center andthe ligand show a synergistic effect in the complexes that may come in handy when designing therapeutic or diagnostic agents. The increased lipophilicity of the ligands and thereby the complexes will ensure better uptake by target cells making them ideal candidates for biological applications.
 Keywords: Sulfonamide, ethylenediamine, diethylenetriamine, dipicolylamine

Structural changes in DNA by binding mitochondrion-targeted monofunctional platinum(II) complexes using molecular dynamics simulation study

Triphenylphosphonium (Ph3P+, TPP) is a highly effective mitochondrial targeting group, an example of using which on mitochondrion-targeted monofunctional platinum(II) agent as anticancer drug was OPT, with the –CH2Ph3P+ group at ortho position of the pyriplatin pyridine ring. To study how carrier ligands might affect the efficacy of OPT, we constructed two platinum(II) agents with bulky bidentate ligands based on OPT. DNA structural changes caused by these three platinum(II) agents using molecular dynamics simulations were analysed. Data regarding DNA conformational changes including helical parameter, base stacking, average structure, and principal component analyses has been obtained. We found that TPP-based monofunctional platinum(II) complexes with bulky carrier ligands may induce more significant DNA conformational changes. These results are beneficial for developing highly efficient mitochondrion-targeted platinum anticancer drugs with carrier ligands of different steric hindrance.

Pd(II) based anticancer drug candidates with 1,2-Aminoethyl piperidine scaffold and sulfur donor ancillary: Their in vitro bio-activity, molecular docking and DFT study

A series of Pd(II) complexes Pd-1 to Pd-6; out of these [Pd(PIEAM)(LC)]+; Pd-3, [Pd(PIEAM)(NALC)]; Pd-4, [Pd(PIEAM)(GSH)]; Pd-5 and [Pd(PIEAM)(DL-meth)]2+; Pd-6 have been synthesized from water soluble stable diaqua complex [Pd(PIEAM)(OH2)2](NO3)2; Pd-2. The Pd-2 complex was obtained from hydrolysis of [Pd(PIEAM)Cl2]; Pd-1 (where, PIEAM = 1,2-Aminoethyl piperidine, a bidentate carrier ligand and with ancillary groups like; LC = L-cysteine, NALC = N-acetyl-L-cysteine, GSH = Glutathione, DL-meth = DL-methionine). All these Pd-1-Pd-6 complexes were characterized by different spectroscopic studies, like; UV–Vis, FT-IR, 1H NMR, and ESI Mass analyses. The bioactivity and drug-likeness properties of the complexes were assessed by PASS and ADME prediction software. The bioactivity of the complexes was experimentally investigated on DNA binding properties by gel electrophoresis, electronic, fluorescence, and viscometric methods. The binding constant values of Pd-3 complex with CT DNA bining in both absorption (Kb = 7.50 × 104M−1)and fluorosence titration (KSV = 35.10 × 103 M−1) was found greater than other Pd-1, Pd-2, Pd-4-Pd-6 complexes (Kb = (4.25–0.64) × 104 M−1; KSV = (13.57–1.11) × 103 M−1). The comparison in BSA bining of Pd(II) complexes also suggested the higher binding constant of Pd-3 complex in both spectroscopic method (Kb = 32 × 103M−1; KSV = 2.32 × 104 M−1) than other Pd(II) complexes (Kb = 16–2.4 × 103M−1; KSV = 1.99–1.53 × 104 M−1). A theoretical investigation of the structural property and TD-DFT of the complexes was executed by DFT calculations. The detailed BSA binding activity of the complexes was performed by fluorescence quenching, synchronous, and 3D-fluorescence spectroscopic methods. Molecular docking of the complexes with DNA and BSA was under study for their binding mode and different weak forces. Their cytotoxic behaviors, like; anticancer activity by MTT assay and ROS (Reactive Oxygen Species) generation by NBT (Nitro Blue Tetrazolium) assay, were investigated. The cytotoxicity of the complexes was under investigation on human lung adenocarcinoma cell A549, colorectal carcinoma cell HCT 116, and normal human embryonic kidney cell HEK 293.

Photophysical study on DNA & BSA binding and cytotoxic behaviour of piperidine-Pt(II) complexes: Their kinetics & mechanism and molecular docking

For the development of Pt(II) based anticancer drug candidates, carrier ligand 2-(Piperidine-1-yl)ethylamine (PIEAM) was used as a bidentate chelator to synthesize dichloro complex [Pt(PIEAM)Cl2] C-1 and its diaqua [Pt(PIEAM)(OH2)2](X)2 (C-2). The diaqua complex C-2 was further used to synthesize thiol substituted Pt(II)-sulfur complexes with l-cysteine (LC) and N-acetyl-l-cysteine (NAC). The Pt(II) complexes were characterized by multi spectroscopic methods and thermal analysis. The role of electronic and steric factors of carrier ligand PIEAM on substitution reactions of C-2 with LC and NAC was studied in aqueous medium at pH 4.0 under pseudo first-order kinetics and rate constant, equilibrium constant and thermodynamic parameters were calculated. The DNA binding activity and binding mode were confirmed by gel electrophoresis and viscosity measurement. The binding activity of Pt(II) complexes with DNA and BSA was explored by absorption and fluorometric titration methods. In vitro MTT assay of Pt(II) complexes were tested on different cancer cell lines like; MCF 7, A549, HCT 116 and also on normal human embryonic kidney cell HEK 293. The cell cycle arrest of MCF 7 cell growth and also the oxidative stress level (ROS) after treating with Pt(II) complexes were analysed. The structural optimization for molecular docking of Pt(II) complexes at B3LYP functional level were performed to correlate the experimental findings. The antineoplastic activity and drug likeness behaviour of Pt(II) complexes were further supported by PASS prediction and in silico ADME analysis.

Cis-(3-benzyloxy-1,1-cyclobutanedicarboxylato κ2O,O′)bis(1-methyl-1H-pyrazole)platinum(II)

A huge variety of types of cancer makes it necessary to search for new effective drugs with a defined molecular target. Modification of substituents in ligands based on 3-hydroxy-1,1-cyclobutanedicarboxylic acid are one of the effective directions to design a better version of carboplatin. In the present study, we combined in one molecule a derivative of 3-hydroxycyclobutane-1,1-dicarboxylic acid and N-methylpyrazole as a carrier ligand. The antiproliferative of the novel complex Pt(II) was established for cell lines HCT116, MCF7, A549, and WI38 by means of a standard MTT colorimetric assay.

Diglycolamides as highly efficient carrier ligands for actinide transport in supported liquid membranes

Diglycolamides as highly efficient carrier ligands for actinide transport in supported liquid membranes

Brief Research on the Biophysical Study and Anticancer Behavior of Pt(II) Complexes: Their DNA/BSA Binding, Molecular Docking, and Cytotoxic Property.

The potent bidentate carrier ligand 2-picolylamine (pic) has been used to synthesize Pt(II) complexes to know their bioactivity and anticancer property as reflected by PASS prediction software. The dichloro Pt(II) complex [Pt(pic)Cl2], Pt-1, and its hydrolyzed diaqua complex [Pt(pic)(OH2)2]2+, Pt-2, were synthesized. The thiol-containing Pt(II) complexes [Pt(pic)(l-cys)]+, Pt-3, and [Pt(pic)(L-ac-l-cy)]+, Pt-4, were synthesized from Pt-2, which was obtained from hydrolysis of Pt-1. Their biomolecular interactions with BSA and DNA were executed by spectroscopic methods, and their cytototoxic property was tested by the MTT assay. In vitro biomolecular interactions of Pt(II) complexes with BSA and DNA were investigated by different spectroscopic and viscosity measurement methods for their pharmacokinetic and pharmacodynamic importance. The conformational change of BSA in the presence of a drug candidate was studied by Förster resonance energy transfer calculation and synchronous and three-dimensional fluorescence spectroscopic studies. A theoretical approach on optimization structures, highest occupied molecular orbital-lowest unoccupied molecular orbital energy, global reactivity parameters, time-dependent density functional theory, and molecular docking with BSA and DNA was executed to strengthen and support the experimental observations. In vitro cytotoxic profiles of the complexes like the anticancer activity and their level of reactive oxygen species production were brought under consideration on A549 cancer cells and the normal human embryonic kidney cell line HEK-293. The cytotoxic property was compared with that of the recognized anticancer drug cisplatin.

Highly selective carrier mediated transport of plutonium(IV) across a supported liquid membrane using two substituted tripodal amides

ABSTRACT Plutonium-specific supported liquid membranes were developed and reported for the first time. The studies included in this paper are on the supported liquid membrane transport behavior of Pu(IV), Am(III) and U(VI) investigated using two tripodal amides viz. N,N,N,’N,’N,”N”-hexa-n-octylnitrilotriacetamide (HONTA) and N,N,N,’N,’N,”N”-hexa-n-dodecylnitrilotriacetamide (HDDNTA). The feed phase consisted of 3 M HNO3 while 0.5 M oxalic acid +0.5 M HNO3 was used as the strip phase. The SLM studies indicated 78.2% and 86.2% transport of plutonium(IV) after 4 h using 0.08 M concentrations of HONTA and HDDNTA, respectively, and the transport of Am(III) and U(VI) was <1% under identical feed acid conditions indicating a possible highly selective separation of Pu(IV) using HONTA as the carrier ligand from a mixture of Pu(IV), Am(III) and U(VI). The stability of the membrane was reasonably good up to 9 days. The activation energy of the transport process was determined using temperature variation studies with HONTA and HDDNTA indicating the transport process being kinetically as well as diffusion controlled. This work is highly relevant for the separation of Pu from radioactive feeds containing other actinide elements such as U and Am.

Single and selective transport of Zr(IV) ions with trioctyl amine dissolved in kerosene using a multidropped liquid membrane technique.

It is very important to develop a process for selectively extracting Zr(IV) ions from the solution medium to produce zirconium metal used in industry and nuclear reactors. In this study, the parameters affecting the extraction of Zr(IV) ions were investigated using a multidropped liquid membrane (MDLM) system. Trioctyl amine (TOA) dissolved in kerosene was used as a carrier ligand in the extraction of Zr(IV) ions by the MDLM technique. The effect of carrier concentration and stripping solution concentration, pH, and the temperature in the donor phase on the transport of Zr(IV) were investigated. The optimum condition for the transportation of Zr(IV) was a 0.50 M H2SO4 solution as donor phase, 0.10 molL-1 TOA as a carrier, and 0.10 M Na2CO3 as acceptor phase. The transport percentage of Zr(IV) was increased up to >99% and the calculated activation energy which is 6.36 kcal mol-1 indicated that the process was diffusion controlled by Zr(IV) ions. The results showed that the MDLM system, which resembles a bulky membrane system in shape, is a promising technique for the extraction of Zr(IV) ions from an acidic solution. It is more practical and effective than bulk, supported, or inclusion, and emulsion liquid membrane techniques.

Unique Eu(III) transport selectivity seen using a supported liquid membrane containing a diglycolamide dendrimer ligand

ABSTRACT Dendrimers are exotic multi-functional ligands and are expected to give rise to better extraction/transport results as compared to the mono-functional ligands. Diglycolamide (DGA) based dendrimers are scarcely reported and literature on their transport studies are very limited. Transport of Am(III) and Eu(III) across a PTFE (polytetrafluoroethylene) based flat sheet supported liquid membrane containing a generation 1 dendrimer of tris(2-aminoethyl)amine (TREN), containing six diglycolamide (DGA) pendent arms (termed as TREN-G1-DenDGA) was investigated from nitric acid feed solutions. The transport studies involved 5.75 × 10−4 M ligand solution in 5% isodecanol modified n-dodecane. Am(III) transport was slower than that of Eu(III) under identical conditions. The transport of both Am(III) and Eu(III) increased with increasing nitric acid concentration from 1 to 6 M HNO3 suggesting a solvation extraction mechanism with nitrate ions playing a significant role. A unique preferential Eu(III) transport over Am(III) was seen at 3 M HNO3 with a transport selectivity factor (ratio of permeability coefficient values) of 6.2 which decreased upon changing the acid concentration. Carrier ligand concentration also played a significant role in transport selectivity. Membrane parameters such as permeability coefficient and effective diffusion coefficient (D eff) values were determined experimentally. The liquid membrane stability studies were also carried out.

Interaction of Copper Trafficking Proteins with the Platinum Anticancer Drug Kiteplatin.

The interaction of metallodrugs with proteins influences their mechanism of action and side effects. In the case of platinum drugs, copper transporters modulate sensitivity and resistance to these anticancer agents. To deepen the knowledge of the structural properties underlying the reactivity of platinum drugs with copper transporters, we studied the interaction of kiteplatin and two of its derivatives with the methionine‐rich motif of copper importer Ctr1 and with the dithiol motif of the first domain of Menkes ATPase. Furthermore, cellular uptake and cytotoxicity of the three complexes were evaluated in cisplatin‐sensitive and ‐resistant ovarian cancer cells, comparing the data with those of clinically relevant drugs. Reactivity depends on the tightness of the chelate ring formed by the carrier ligands and the nature of the leaving and entering groups. The results highlight the importance of subtle changes in the platinum coordination sphere that affect drug absorption and intracellular fate.

Rational design of ASCT2 inhibitors using an integrated experimental-computational approach

ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.

Front Cover: Metal‐ligand cooperative activation of HX (X=H, Br, OR) bond on Mn based pincer complexes (14/2021)

The spaceship on the cover picture depicts a pincer complex browsing a vast space of different functionalization groups. The spaceship carries the reactive manganese site, whose properties can be tuned by changing the functional groups on the specific “docking sites” of the carrier ligand. Herein we present an automated high-throughput computational study of how ligand functionalization affects the reactivity and catalytic behaviour of metal-ligand cooperative Mn(I) pincer complexes. The study included DFT and DFTB calculations to analyze the stability of different adducts relevant to (de)hydrogenation catalytic chemistry (https://doi.org/10.1002/zaac.202100078).

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity.

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

Selective permeation of 90Y from a mixture of 90Y/90Sr through diglycolamide impregnated supported liquid membranes

An attempt was made in this work to evaluate a simple flat sheet supported liquid membrane technique for the separation of carrier free 90Y from 90Sr using two diglycolamide carrier ligands, (i) N,N,N′,N′-tetra-n-octyl-diglycolamide (TODGA), and (ii) N,N,N′,N′-tetra-(2-ethylhexyl)-diglycolamide (TEHDGA). Various experimental parameters were optimized to get selective transport of 90Y over 90Sr. At 6 M HNO3 feed acidity, >95% 90Y could be recovered selectively in just 4 h with both the ligands. Under identical experimental conditions, about 0.1% transport of Sr was also recorded which could be completely removed by passing through a Sr selective column to get medical grade 90Y pure product. A mathematical model equation was also derived and experimentally validated for predicting the transport of 90Y through membrane.

Americium pertraction across supported liquid membranes containing multiple diglycolamide ligands: Role of alkyl substitution and spacer length in carrier ligands

Liquid–liquid extraction and subsequent supported liquid membrane (SLM) transport studies involving Am3+ ion were carried out from nitric acid feed solutions using three N-pivot tripodal diglycolamide (DGA) ligands with varying substituent at the inner carboxamide N atom and spacer length. The ligand with an isopropyl substituent and with C2 spacer is termed as iPr3-TREN-DGA, while the one without alkyl substituent is termed as TREN-DGA. The third ligand with no substituent but a C3 spacer is termed as TRPN-DGA. The trend of metal ion extraction was iPr3-TREN-DGA > TRPN-DGA > TREN-DGA when solutions of ca. 1.0×10−3 M ligand in 95% n-dodecane+5% isodecanol were used. Stripping studies were carried out using 0.01M HNO3, 0.01M EDTA (at pH 3.0) and 1M α-HIBA (α-hydroxyisobutyric acid) The extraction and stripping kinetics studies suggested attainment of equilibrium in about 30minutes. The SLM studies were carried out in a two-compartment cell with 20mL feed as well as receiver phase volumes and PTFE (polytetrafluoroethylene) flat sheets as the solid support. The transport rates followed the same trend as that of the metal ion extraction study, suggesting comparable diffusion coefficients of the complexes (obtained by the lag-time method). Membrane stability studies indicated the best stability for the TRPN-DGA ligand.