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Purpose:Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability.Patients and Methods:We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2.Results:This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively.Conclusions:The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases.See related commentary by de Jong et al., p. 1830

Mean concentration-time profiles of pressurized intraperitoneal aerosol chemotherapy (PIPAC) oxaliplatin (n = 14) in plasmatot (A) and ultrafiltrate (B)

The area under the curve(AUC) ratio (Ultrafiltrate(UF) vs Plasmatot) at different dose levels

Study timeline

Supplementary tables and figures

Indolo[2,3-d]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their RuII and OsII complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (1H NMR and UV–vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by 1H and 13C NMR and UV–vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine., Several synthesized indololatonduine derivatives and their RuII and OsII complexes were investigated for their microtubule-targeting properties in comparison with paclitaxel and colchicine. Fluorescence staining and in vitro tubulin polymerization assays indicate excellent microtubule-destabilizing activity. The compounds were even more potent than the well-known microtubule-destabilizing agent colchicine.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

P53 plays a key role in protecting the human genome from DNA-related mutations; however, it is one of the most frequently mutated genes in cancer. The P53 family members p63 and p73 were also shown to play important roles in cancer development and progression. Currently, there are various organic molecules from different structural classes of compounds that could reactivate the function of wild-type p53, degrade or inhibit mutant p53, etc. It was shown that: (1) the function of the wild-type p53 protein was dependent on the presence of Zn atoms, and (2) Zn supplementation restored the altered conformation of the mutant p53 protein. This prompted us to question whether the dependence of p53 on Zn and other metals might be used as a cancer vulnerability. This review article focuses on the role of different metals in the structure and function of p53, as well as discusses the effects of metal complexes based on Zn, Cu, Fe, Ru, Au, Ag, Pd, Pt, Ir, V, Mo, Bi and Sn on the p53 protein and p53-associated signaling.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

Improvements in the diagnosis and treatment of systemic breast cancer have led to a prolongation in patient survival. Unfortunately, these advances are also associated with an increased incidence of brain metastases (BM), with the result that many patients succumb due to BM treatment failure. Intracranial delivery of many chemotherapeutic agents and other therapeutics is hindered by the presence of an impermeable blood-brain barrier (BBB) designed to protect the brain from harmful substances. The formation of BM compromises the integrity of the BBB, resulting in a highly heterogeneous blood-tumor barrier (BTB) with varying degrees of vascular permeability. Here, we discuss how blood vessels play an important role in the formation of brain micrometastases as well as in the transformation from poorly permeable BM to highly permeable BM. We then review the role of BTB vascular permeability in the diagnostics and the choice of treatment regimens for breast cancer brain metastases (BCBM) and discuss whether the vasculature of primary breast cancers can serve as a biomarker for BM. Specifically, we examine the association between the vascular permeability of BCBM and their accumulation of large molecules such as antibodies, which remains largely unexplored.

A series of heteroleptic square-planar Pt and Pd complexes with bis(diisopropylphenyl) iminoacenaphtene (dpp-Bian) and Cl, 1,3-dithia-2-thione-4,5-dithiolate (dmit), or 1,3-dithia-2-thione-4,5-diselenolate (dsit) ligands have been prepared and characterized by spectroscopic techniques, elemental analysis, X-ray diffraction analysis, and cyclic voltammetry (CV). The intermolecular noncovalent interactions in the crystal structures were assessed by density functional theory (DFT) calculations. The anticancer activity of Pd complexes in breast cancer cell lines was limited by their solubility. Pd(dpp-Bian) complexes with dmit and dsit ligands as well as an uncoordinated dpp-Bian ligand were devoid of cytotoxicity, while the [Pd(dpp-Bian)Cl

Annexin A1 (ANXA1) is an endogenous protein, which plays a central function in the modulation of inflammation. While the functions of ANXA1 and its exogenous peptidomimetics, N-Acetyl 2-26 ANXA1-derived peptide (ANXA1Ac2-26), in the modulation of immunological responses of neutrophils and monocytes have been investigated in detail, their effects on the modulation of platelet reactivity, haemostasis, thrombosis, and platelet-mediated inflammation remain largely unknown. Here, we demonstrate that the deletion of Anxa1 in mice upregulates the expression of its receptor, formyl peptide receptor 2/3 (Fpr2/3, orthologue of human FPR2/ALX). As a result, the addition of ANXA1Ac2-26 to platelets exerts an activatory role in platelets, as characterised by its ability to increase the levels of fibrinogen binding and the exposure of P-selectin on the surface. Moreover, ANXA1Ac2-26 increased the development of platelet-leukocyte aggregates in whole blood. The experiments carried out using a pharmacological inhibitor (WRW4) for FPR2/ALX, and platelets isolated from Fpr2/3-deficient mice ascertained that the actions of ANXA1Ac2-26 are largely mediated through Fpr2/3 in platelets. Together, this study demonstrates that in addition to its ability to modulate inflammatory responses via leukocytes, ANXA1 modulates platelet function, which may influence thrombosis, haemostasis, and platelet-mediated inflammation under various pathophysiological settings.

The biosynthetic gene cluster of fungal bioactive sesterterpenoids, variecolin (1) and variecolactone (2), was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues, one of which exhibited potent anticancer activity comparable to that of 1.

Synthesis of novel (+)-sclareolide-based homodrimane sesquiterpenoids bearing hydrazinecarbothioamide or N-substituted 1,2,4-triazole unit has been reported. These heterocyclic compounds demonstrate promising in vitro antifungal and antibacterial activities toward fungal species Aspergillus niger, Fusarium solani, Penicillium chrysogenum, Penicillium frequentans, and Alternaria alternata and bacteria strains Bacillus sp. and Pseudomonas aeruginosa at minimum inhibitory concentration level of μg/ml. In addition, two homodrimane sesquiterpenoids with hydrazinecarbothioamide fragment show cytotoxicity toward human ovarian carcinoma cells A2780 and A2780cis with half maximal inhibitory concentration values in range of 9–15 μM.

A novel proligand HLH has been prepared from 2-pyridinamidrazone and 6-(morpholinomethyl)pyridine-2-carboxaldehyde. Subsequently, starting from HLH and CuCl2·2H2O in the presence of triethylamine, a series of homo- and heterometallic complexes with [CuICl2]− as counteranion, namely mononuclear complex [CuIICl(HLOMe)][CuICl2] (1), dinuclear Ru(II)–Cu(II) complex [CuIIRuII(η6-p-cymene)Cl2(LH)][CuICl2]·1.5H2O (2·1.5H2O), Os(II)–Cu(II) complex [CuIIOsII(η6-p-cymene)Cl2(LH)][CuICl2]·H2O (3·H2O), and tetranuclear complex [CuII4(L1)2(L2)2Cl2]·5MeOH (4·5MeOH), where HLOMe, L1, and L2 are Schiff base ligands derived from HLH, were synthesized. The structures of metal complexes were established by X-ray diffraction. Complexes 1–3 demonstrated quasireversible one-electron reduction of Cu(II) in complex cations and one-electron oxidation of [CuICl2]− counterion, confirmed by UV–vis and EPR spectroelectrochemical measurements. They exhibited moderate antiproliferative activity against ovarian carcinoma and cervical ad...

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. Ministry of Education (MOE) Accepted version G.P. acknowledges the National University of Singapore (NUS) for financial support (grant C-141-000-097-001). W.H.A. acknowledges the Ministry of Education Singapore (MOE) for financial support (grant R143000680114). D.G acknowledges the support of the Israel Science Foundation (grant 1611/14) and the support of the Alex Grass Center for Drug Design and Synthesis.Y.Z. acknowledges the Depart- ment of Pharmacy (NUS) and Hebrew University of Jerusa- lem (HUJ) for the research scholarship for ajoint PhD degree.M.V.B.acknowledges E. Fasolko and T. Hajsz for generating the artwork.

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death which can improve clinical outcomes of chemo-immunotherapeutic combination regimens by the establishment of a long-term cancer immunity. None of the clinically used DNA-binding Pt II complexes is considered a Type II ICD inducer. We generated a series of Pt II -carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt-NHC and compared their efficiencies in triggering ICD-related cellular responses and phagocytosis. We successfully identified PlatinER , a novel highly potent Pt II drug candidate with superior ICD properties. Crucially, the magnitude of ICD-associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER-localized reactive oxygen species (ROS) generation, which underpinned their mechanisms of action and provided a feasible approach for the design of more effective Type II ICD inducers.

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses. We hypothesized that Au complexes that induce severe ER stress might counteract pro-survival cellular attempts leading to the ER stress-mediated apoptosis and reduced platinum resistance. In this work, we prepared a series of highly cytotoxic AuI-dialkyldithiocarbamate complexes and investigated their anticancer potential in ovarian cancer cells. Complexes demonstrated surprisingly low stability in chloroform, resulting in the formation of an Au chain polymer, which also displayed excellent cytotoxicity. Lead complex 2 induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly, 2 caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response.

The in-gel detection of proteins for various proteomic experiments is commonly done with the fluorescent Ru-II tris(bathophenanthroline disulfonate) complex (Ru(BPS)(3)), which is more cost-effective compared to commercial Ru-based formulations but requires tedious procedures for its preparation and strongly acidic staining conditions. Herein, we report the synthesis and characterization of heteroleptic Ru-II complexes Ru(BPS)(2)(BP) and Ru(BPS)(BP)(2) containing bathophenanthroline (BP) and bathophenanthroline disulfonate disodium salt (BPS) in comparison with Ru(BPS)(3). It was shown by fluorescent and UV-vis measurements that novel Ru-II complexes were excitable in both UV and visible light, close to emission bands of classical lasers, which is important for successful in-gel protein detection. Novel fluorescent dyes demonstrated improved protein detection in comparison with commercially available SYPRO Ruby staining solution. In addition, unlike commonly used staining protocols, staining with Ru(BPS)(BP)(2) can be performed at nearly neutral pH, thereby reducing artificial post-translational modifications (PTMs).

International audience; The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.

International audience; With the aim of enhancing the biological activity of ruthenium−nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind) 4 (NO)]Cl 2 •H 2 O ([3]Cl 2 •H 2 O) and trans-[RuOH(Hind) 4 (NO)]Cl 2 •H 2 O ([4]Cl 2 •H 2 O), have been prepared from trans-[Ru(NO 2) 2 (Hind) 4 ] ([2]). When the pH-dependent solution behavior of [3]Cl 2 •H 2 O and [4]Cl 2 • H 2 O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind) 2 (Hind) 2 (NO)] ([5]) and [RuOH(ind) 2 (Hind) 2 (NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV−vis, 1 H NMR) techniques. Compound [2], as well as [3]Cl 2 •2(CH 3) 2 CO, [4]Cl 2 •2(CH 3) 2 CO, and [5]•0.8CH 2 Cl 2 , the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl 2 and [4]Cl 2 was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3−6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump−probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl 2 and [4]Cl 2 showed considerable antiproliferative activity in human cancer cell lines with IC 50 values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru−NO complexes [3]Cl 2 and [4]Cl 2 was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.

N -[1-Alkylpyridin-4(1 H )-ylidene]amides (PYAs), also known as pyridinium amidates, are a class of recently introduced ligands for transition metal ions. Herein we report the synthesis of the Pt(PYA) complexes [PtCl(DMSO)(HL)]Cl 2 ( 1 ), [Pt(CH 3 )(DMSO)(L)]Cl ( 2 ) and [Pt(CH 3 )(PPh 3 )(L)]Cl ( 3 ) (L = N -(1-benzylpyridin-4(1 H )-ylidene)picolinamide). L and [HL] + act as bidentate ligands coordinating through the pendant pyridine and either the amidate oxygen or nitrogen atoms to give the corresponding N , O or N , N linkage isomers. DFT calculations were carried out to determine the most energetically favorable isomeric forms of these compounds. For 1 the N , O coordination mode was lower in energy, while for 2 and 3 hardly any difference was found. In vitro cytotoxicity studies of [HL]Cl and 1 in human colorectal carcinoma HCT116, non-small cell lung carcinoma NCI-H460, and cervical carcinoma SiHa cells showed that both compounds are cytotoxic in the low μM range.

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3−6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.

Six morpholine-(iso)thiosemicarbazone hybrids HL1–HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1–6)Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

N -[1-Alkylpyridin-4(1 H )-ylidene]amides (PYAs), also known as pyridinium amidates, are a class of recently introduced ligands for transition metal ions. Herein we report the synthesis of the Pt(PYA) complexes [PtCl(DMSO)(HL)]Cl 2 ( 1 ), [Pt(CH 3 )(DMSO)(L)]Cl ( 2 ) and [Pt(CH 3 )(PPh 3 )(L)]Cl ( 3 ) (L = N -(1-benzylpyridin-4(1 H )-ylidene)picolinamide). L and [HL] + act as bidentate ligands coordinating through the pendant pyridine and either the amidate oxygen or nitrogen atoms to give the corresponding N , O or N , N linkage isomers. DFT calculations were carried out to determine the most energetically favorable isomeric forms of these compounds. For 1 the N , O coordination mode was lower in energy, while for 2 and 3 hardly any difference was found. In vitro cytotoxicity studies of [HL]Cl and 1 in human colorectal carcinoma HCT116, non-small cell lung carcinoma NCI-H460, and cervical carcinoma SiHa cells showed that both compounds are cytotoxic in the low μM range.

International audience; p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity.

We thank Prof. Markus Galanski for providing Pt precursors.; International audience; Platinum-based anticancer coordination compounds are widely used in the treatment of many tumor types, where they are very effective but also cause severe side effects. Organoplatinum compounds are significantly less investigated than the analogous coordination compounds. We report here rollover cyclometalated Pt compounds based on 2,2'-bipyridine which are demonstrated to be potent antitumor agents both in vitro and in vivo. Variation of the co-ligands on the Pt(2,2'-bipyridine) backbone resulted in the establishment of structure-activity relationships. They showed that the biological activity was in general inversely correlated with the reaction kinetics to biomolecules as shown for amino acids, proteins, and DNA. The less stable compounds caused higher reactivity with biomolecules and were shown to induce p53-dependent DNA damage. In contrast, the presence of bulky PTA and PPh3 ligands was demonstrated to cause lower reactivity and increased antineoplastic activity. Such compounds were devoid of DNA-damaging activity and induced ATF4, a component of the endoplasmic reticulum (ER) stress pathway. The lead complex inhibited tumor growth similar to oxaliplatin while showing no signs of toxicity in test mice. Therefore, we demonstrated that it is possible to fine-tune rollover-cyclometalated Pt(II) compounds to target different cancer pathways and be a means to overcome the side effects associated with cisplatin and analogous compounds in cancer chemotherapy.

There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes.

There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes.

The development of new methods to synthesize nanometric metal catalysts has always been an important and prerequisite step in advanced catalysis. Herein, we design a stable nitrogen ligated Pt complex for the straightforward synthesis by carbonization of uniformly sized atomic and sub-nanometric Pt catalysts supported on mesoporous silica. During the carbonization of the Pt precursor into active Pt species, the nitrogen-containing ligand directed the decomposition in a controlled fashion to maintain uniform sizes of the Pt species. The nitrogen ligand had a key role to stabilize the single Pt atoms on a weak anchoring support like silica. The Pt catalysts exhibited remarkable activities in the hydrogenation of common organic functional groups with turnover frequencies higher than in previous studies. By a simple post-synthetic treatment, we could selectively remove the Pt nanoparticles to obtain a mixture of single atoms and nanoclusters, extending the applicability of the present method.

The monomeric (PdL·2H

The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibito r. A Pt-lV­ EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a Pt-li species to exert a synergistic cytotoxic effect. ln this study, a redesigned Pt-IV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic Pt-li species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (approximate to 80%) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.

International audience; Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds.