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BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and devastating malignancies. Oxaliplatin, a platinum-based chemotherapeutic agent, is approved for the treatment of several malignancies, including HCC. However, its role in HCC is not well established. This study was designed to investigate the potential of oxaliplatin as an immunogenic cell death (ICD) inducer and to explore its regulatory effects on the response of HCC to immune checkpoint blockade therapy. METHODS: Murine and human HCC cells were treated with oxaliplatin, followed by evaluation of the expression of ICD-related biomarkers. Murine HCC cells (H22) were subcutaneously inoculated into mice to establish a syngeneic tumor graft model, after which tumor sizes and in vivo immune cell activation were evaluated. To assess putative synergistic effects of oxaliplatin with anti-PD-1 antibodies on H22 tumors, tumor parameters and secreted cytokines were quantified. RESULTS: ICD-related biomarkers were found to be enhanced after treatment of human and murine HCC cells with oxaliplatin. Additionally, we found that the number of mature dendritic cells (DCs) was increased after immature DCs were cocultured with oxaliplatin-treated H22 cells. The numbers of CD8+ T cells and mature DCs were found to be increased in vivo whereas, in contrast, the number of Treg cells was decreased. The tumor sizes were smaller in the oxaliplatin group than in the control group. In the syngeneic tumor graft model, we found that combination therapy with oxaliplatin and anti-PD-1 antibodies could achieve better outcomes than monotherapy, as indicated by (i) inhibition of tumor growth and TGF-β secretion and (ii) augmentation of inflammatory cytokine secretion. CONCLUSIONS: Our data indicate that oxaliplatin can be used as an inducer of ICD and as a modulator of the tumor immune microenvironment. Combination therapies composed of oxaliplatin and immune checkpoint inhibitors may open up novel avenues for the treatment of HCC. Show less

Bis-ADC complexes cis-[Pd{C(NHC6H4NH2)N(H)R}2]Cl2 (R = Xyl 4a, Cy 4b, C6H4-4-F 4c) and cis-[Pt{C(NHC6H4NH2)N(H)R}2]Cl2 (R = Xyl 5a, Cy 5b, C6H4-4-F 5c) were synthesized via the metal-mediated coupling of two isocyanide ligands in cis-[MCl2(CNR)2] (M = Pd, Pt; R = Xyl, Cy, C6H4-4-F) and 1,2-diaminobenzene. New compounds 4c and 5a–c were characterized by HR ESI+-MS, IR, and 1H, 13C{1H} and 195Pt{1H} NMR spectroscopy; the structures of 4a and 5a were elucidated by single-crystal X-ray diffraction. The stability of the ADC complexes in aqueous media (5 mM NaCl) was monitored by UV absorption spectroscopy, HR ESI+ mass spectrometry, and 195Pt{1H} NMR spectroscopy (for 5a). Molar conductivity measurements in MeOH (ΛM = 167–173 Ω−1 mol−1 cm2) indicate that, in this solvent, the ADC complexes exist as dicationic species of [A][Q]2 type. The ADC complexes binding to CT DNA was investigated by means of spectroscopic and hydrodynamic techniques including UV absorption and circular dichroism spectroscopy, fluorescence spectroscopy, low-gradient viscometry, flow birefringence, and AFM imaging. As a result, complexes 4a and 5a were shown to bind double-stranded DNA predominantly via the formation of monofunctional adducts in the major groove of the macromolecule. Binding of the ADC complexes also provokes the formation of a large number of intermolecular DNA–DNA contacts in solution. The antiproliferative activity of all prepared ADC complexes 4a–c and 5a–c was evaluated in vitro against three human carcinoma cell lines (HT-29, MDA-MB-231, and MCF-7) and two non-tumorigenic cell lines (L929 and RC-124) and compared to that of cisplatin. Among the compounds studied, complexes 4a and 5a appeared to be the most active species with IC50 values in MCF-7 cells of about 10 μM. Show less

Water soluble Pd(ii) and Pt(ii)–ADC species synthesized via the metal-mediated coupling of isocyanides and 1,2-diaminobenzene have demonstrated antitumor potential.

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A new dinuclear Pd(I) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin. Show less

AbstractMetal‐driven self‐assembly is one of the most effective approaches to lucidly design a large range of discrete 2D and 3D coordination architectures/complexes. Palladium(II)‐based self‐assembled coordination architectures are usually prepared by using suitable metal components, in either a partially protected form (PdL′) or typical form (Pd; charges are not shown), and designed ligand components. The self‐assembled molecules prepared by using a metal component and only one type of bi‐ or polydentate ligand (L) can be classified in the homoleptic series of complexes. On the other hand, the less explored heteroleptic series of complexes are obtained by using a metal component and at least two different types of non‐chelating bi‐ or polydentate ligands (such as La and Lb). Methods that allow the controlled generation of single, discrete heteroleptic complexes are less understood. A survey of palladium(II)‐based self‐assembled coordination cages that are heteroleptic has been made. This review article illustrates a systematic collection of such architectures and credible justification of their formation, along with reported functional aspects of the complexes. The collected heteroleptic assemblies are classified here into three sections: 1) [(PdL′)m(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is equal; 2) [(PdL′)m(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is different; and 3) [Pdm(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is equal. Representative examples of some important homoleptic architectures are also provided, wherever possible, to set a background for a better understanding of the related heteroleptic versions. The purpose of this review is to pave the way for the construction of several unique heteroleptic coordination assemblies that might exhibit emergent supramolecular functions. Show less

Four new complexes of Au(III), Pd(II), Ni(II), and Cu(II) ions were synthesized, derived from a novel heterocyclic ligand (L) that has both triazole and tetrazole rings. The ligand synthesis was through successive steps to achieve both heterocyclic rings. The synthesized compounds were characterized using conventional techniques like infrared, ultra violet—visible and proton/carbon nuclear magnetic resonance spectroscopy, metal and thermal analyses, and molar conductivity. All complexes were suggested to have square planar geometry, gold, nickel, and palladium complexes were salts while copper neutral complexes have the chemical formulas; [AuL2]Cl.2H2O, [PdL2]Cl2.2H2O, [NiL2]Cl2.2H2O, and [CuL2]. The cytotoxic effect was studied on breast cancer cell line (MCF‐7 cell line) at different concentrations by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay method, for the ligand (L) and complexes. The results showed that gold(III) and nickel(II) complexes have the highest cytotoxicity among all compounds against cancer cell lines. Show less

A palladium(II)-catalyzed asymmetric 1,2-diamination of 1,3-dienes with readily available dialkylureas was established by using a chiral pyridine-oxazoline ligand. The diamination reaction exclusively occurs at the terminal C-C double bond of the 1,3-dienes to give 4-vinylimidazolidin-2-ones in high yields and with excellent levels of enantioselectivity (up to 99% yield, 97% ee). The reaction could feasibly be applied for gram-scale synthesis with a 1:1 ratio of the diene and the urea. Show less

AbstractThe 2‐(1,2,3‐triazol‐4‐yl)pyridine motif, with its facile “click” synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal‐directed self‐assembly of intricate three‐dimensional structures. Organic ligands that bear two such chelates bridged by flexible hinge moieties readily undergo self‐assembly with metal ions of different coordination geometries to generate a series of topologically diverse metallomacrocycles that can be used for numerous applications. Herein, the synthesis and self‐assembly of one such ligand with zinc(II), copper(II), and palladium(II) ions is reported, and the stability of the resulting metallomacrocycles described. An investigation into the use of these metallomacrocycles for the recognition of both small‐molecule substrates, such as deoxyguanosine monophosphate, and larger biological assemblies, such as DNA and RNA guanine quadruplexes, is also described. Show less

The coupling of bis(xylylisocyanide) complex of Pd(II) with 1,2,4-thiadiazole-5-amines leads to the formation of an equilibrium mixture of the binuclear complexes. In each of the studied cases, one of the formed complexes is the kinetic product, and the other one is the thermodynamic product. The complexes which are thermodynamic products have been isolated in the pure form and characterized by means of high-resolution mass spectrometry, IR and NMR spectroscopy, and X-ray diffraction analysis. NMR study of the regioisomerization in a solution has revealed that the relative stability of the thermodynamic products in comparison with the kinetic ones is higher than for the corresponding regioisomers containing 1,3-thiazole or 1,3,4- thiadiazole fragment. Show less

The reaction of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine with cis-dichlorobis(2,6-dimethylphenyl isocyanide)platinum(II) (cis-[PtCl2(CNXyl)2], Xyl = 2,6-Me2C6H3) gave platinum(II) monocarbene complex whose deprotonation with an organic base generated a nucleophilic species capable of reacting with palladium(II) and platinum(II) bis(isocyanide) complexes to afford homo- and heteronuclear isocyanide/carbene structures. Show less

The main aim of this study is to assess the safety and antitumor efficacy of a palladium(II) (Pd)-saccharinate complex with terpyridine. To characterize the Pd(II) complex in vitro, its cytotoxicity was evaluated using a water-soluble tetrazolium salt cell viability assay and the mechanism of cell death was assessed by DNA fragmentation/condensation and live cell imaging analyses. The antitumor efficacy and safety of the Pd(II) complex in-vivo were examined by analyzing reduction in tumor size, changes in body and organ weight, histopathological analysis of liver, kidney, and tumor sections, and biochemical analysis of serum in C57BL/6 mice. Our results showed that the Pd(II) complex was more cytotoxic to cancer cells than noncancer cell lines and caused cell death through apoptotic pathways. The treatment of the Pd(II) complex in tumor-bearing mice effectively reduced the tumor size at half the dose used for cisplatin. The Pd(II) complex appeared to exert less liver damage than the cisplatin-based complex on changes in the hepatic enzymes levels in the serum. Hence, the complex appears to be a potential chemotherapeutic drug with high antitumor efficacy and fewer hepatotoxic complications, providing an avenue for further studies. Show less

High drug attrition rates remain a critical issue in oncology drug development. A series of steps during drug development must be addressed to better understand the pharmacokinetic (PK) and pharmacodynamic (PD) properties of novel agents and, thus, increase their probability of success. As available data continues to expand in both volume and complexity, comprehensive integration of PK and PD information into a robust mathematical model represents a very useful tool throughout all stages of drug development. During the discovery phase, PK/PD models can be used to identify and select the best drug candidates, which helps characterize the mechanism of action and disease behavior of a given drug, to predict clinical response in humans, and to facilitate a better understanding about the potential clinical relevance of preclinical efficacy data. During early drug development, PK/PD modeling can optimize the design of clinical trials, guide the dose and regimen that should be tested further, help evaluate proof of mechanism in humans, anticipate the effect in certain subpopulations, and better predict drug-drug interactions; all of these effects could lead to a more efficient drug development process. Because of certain peculiarities of immunotherapies, such as PK and PD characteristics, PK/PD modeling could be particularly relevant and thus have an important impact on decision making during the development of these agents. Show less

The solution state of palladium cationic–anionic complexes (AmH n ) k [PdCl4] prepared for the first time, where Am is morpholine, methylmorpholine, aminoethylmorpholine, 5-aminovaleric acid, L-1-phenyl-2-methylaminopropanol, and m-xylilenediamine, has been studied by electronic absorption spectroscopy, NMR, and pH measurements. The agreement of obtained results for the state of the complexes in water and NaCl solutions with IR and X-ray diffraction data for these complexes has allowed us to substantiate the principle for designing patent formulation (C5H12NO)2[PdCl4], a new type of palladium complexes, palladium(II) cationic–anionic complexes showing high antitumor and antimetastatic activity. Crystallographic data for six obtained complexes have been presented. Show less

Palladium(II) carboxylate salts have been shown to catalyze the oxidation of various hydroquinones to benzoquinones in the presence of t-BuOOH. This new catalytic system has been integrated into the oxidative 1,4-functionalization of cyclic 1,3-dienes where the palladium plays a remarkable dual role, catalyzing both the diene oxidation itself and the regeneration of the active quinone oxidant, which is required for diene functionalization. These new conditions offer considerable increases in reaction rate over prior art and allow a significant decrease in the equivalents of the nucleophilic carboxylate required for full conversion. Show less

Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis is becoming an increasingly important tool for the identification and selection of new anticancer agents. There are two important elements of effectively using PK/PD analysis to translate preclinical antitumor efficacy from tumor bearing mice (xenografts and allografts) to cancer patients. These two sometimes overlapping elements are termed translation 'WITHIN' and 'ACROSS' species. Translating 'WITHIN' species refers to the quantitative characterization of drug action and disease behavior within tumor bearing mice using PK/PD modeling in order to use this information to make predictions of drug response in humans. Translating 'ACROSS' species refers to use of PK/PD modeling to quantify species similarities and differences in drug response in order to understand the clinical relevance of preclinical efficacy data. Show less

Much success has been achieved with platinum-based chemotherapeutic agents, i.e. through interactions with DNA. The long-term application of Pt complexes is thwarted by issues, leading scientists to examine other metals such as palladium which could exhibit complementary modes of action (given emphasis wherever known). Over the last 10 years several research groups have focused on the application of an eclectic array of palladium complexes (of the type PdX2L2, palladacycles and related structures) as potential anti-cancer agents. This review therefore provides readers with an up to date account of the advances that have taken place over the past several decades. Show less

Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the late-stage clinical trials. The different questions addressed during each stage of drug R&D has led to the emergence of different modeling methodologies. In the research phase, systems biology couples experimental data with elaborate computational modeling techniques to capture lifecycle and effector cellular functions (e.g. metabolism, signaling, transcription regulation, protein synthesis and interaction) and integrates them in quantitative models. These models are subsequently used in various ways, i.e. to identify new targets, generate testable hypotheses, gain insights on the drug's mode of action (MOA), translate preclinical findings, and assess the potential of clinical drug efficacy and toxicity. In the development phase, pharmacokinetic/pharmacodynamic (PK/PD) modeling is the established way to determine safe and efficacious doses for testing at increasingly larger, and more pertinent to the target indication, cohorts of subjects. First, the relationship between drug input and its concentration in plasma is established. Second, the relationship between this concentration and desired or undesired PD responses is ascertained. Recognizing that the interface of systems biology with PK/PD will facilitate drug development, systems pharmacology came into existence, combining methods from PK/PD modeling and systems engineering explicitly to account for the implicated mechanisms of the target system in the study of drug-target interactions. Herein, a number of popular system biology methodologies are discussed, which could be leveraged within a systems pharmacology framework to address major issues in drug development. Show less

Two series of tetrazole-containing platinum(II) and palladium(II) chlorido complexes, trans-[ML(2)Cl(2)] (M=Pt, Pd) and cis-[PtL(2)Cl(2)]·nH(2)O (n=0, 1), where L is 1- or 2-substituted 5-aminotetrazole, have been synthesized and thoroughly characterized. Configuration of platinum(II) complexes obtained from the reaction of 5-aminotetrazoles with K(2)PtCl(4) has been found to vary depending on the nature of tetrazole derivatives and reaction conditions. According to in vitro cytotoxic evaluation, only platinum complexes display noticeable antiproliferative effect, and their cytotoxicity depends strongly on their geometry and hydrophobicity of the carrier ligands. The most promising complexes are cis-[Pt(1-apt)(2)Cl(2)]·H(2)O and cis-[Pt(2-abt)(2)Cl(2)]·H(2)O, where 1-apt is 5-amino-1-phenyltetrazole and 2-abt is 5-amino-2-tert-butyltetrazole. In comparison with cisplatin, they show comparable cytotoxic potency against cisplatin-sensitive human cancer cell lines, cis-[Pt(2-abt)(2)Cl(2)]·H(2)O performing substantially higher activity against cisplatin-resistant cell lines. Cell cycle studies in H1299 cell line indicated that cis-[Pt(2-abt)(2)Cl(2)]·H(2)O induced apoptosis launched from G2 accumulations. The DNA interaction with cis-[Pt(1-apt)(2)Cl(2)]·H(2)O was followed by UV spectroscopy, circular dichroism, hydrodynamic and electrophoretic mobility studies. Both cis-[Pt(1-apt)(2)Cl(2)]·H(2)O and cis-[Pt(2-abt)(2)Cl(2)]·H(2)O complexes appeared to be significantly less toxic than cisplatin in mice, while only compound cis-[Pt(1-apt)(2)Cl(2)]·H(2)O displayed noticeable efficacy in vivo. Show less

Current precious-metal-containing anticancer agents are mostly chelated with N-containing ligands and function by interacting with DNA. In the present study, Pd(acac)2, a Pd(II) complex containing four O-donor ligands, has been evaluated as an active anticancer agent. Pd(acac)2 showed no interaction with N-ligand-containing DNA and the S-ligand-containing DMSO, probably because of the two six-member chelate rings that limit the release of the central Pd nuclei to bind to other ligands. Importantly, we found that Pd(acac)2 exhibited better growth inhibitory effects than cisplatin in several cancer cells. Treatment with Pd(acac)2 significantly induced apoptosis in H460 cells. Mechanistically, Pd(acac)2 induced the activation of a series of key components in ER stress-mediated apoptotic pathway, followed by caspase cleavage and activation, while cisplatin showed no similar effects. CHOP knockdown by specific siRNA significantly attenuated Pd(acac)2-induced cell apoptosis. Finally, Pd(acac)2 significantly inhibits H460 cell growth in xenograft mouse models. Taken together, these mechanistic insights on Pd(acac)2 provide us with a novel mechanism and strategy for the development of precious-metal-based anticancer drugs. Show less

Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/PD models will become a standard approach for drug discovery and development. Show less