N-Heterocyclic Carbene-Iridium Complexes as Photosensitizers for In Vitro Photodynamic Therapy to Trigger Non-Apoptotic Cell Death in Cancer Cells.

A series of seven novel iridium complexes were synthetized and characterized as potential photosensitizers for photodynamic therapy (PDT) applications. Among them, four complexes were evaluated in vitro for their anti-proliferative activity with and without irradiation on a panel of five cancer cell lines, namely PC-3 (prostate cancer), T24 (bladder cancer), MCF7 (breast cancer), A549 (lung cancer) and HeLa (cervix cancer), and two non-cancerous cell models (NIH-3T3 fibroblasts and MC3T3 osteoblasts). After irradiation at 458 nm, all tested complexes showed a strong selectivity against cancer cells, with a selectivity index (SI) ranging from 8 to 34 compared with non-cancerous cells. The cytotoxic effect of all these complexes was found to be independent of the anti-apoptotic protein Bcl-xL. The compound exhibiting the best selectivity, complex 4a, was selected for further investigations. Complex 4a was mainly localized in the mitochondria. We found that the loss of cell viability and the decrease in ATP and GSH content induced by complex 4a were independent of both Bcl-xL and caspase activation, leading to a non-apoptotic cell death. By counteracting the intrinsic or acquired resistance to apoptosis associated with cancer, complex 4a could be an interesting therapeutic alternative to be studied in preclinical models.

An Artemisinin-Derivative-(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity.

A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single-crystal X-ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF-κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.

Pharmacomodulation on Gold-NHC complexes for anticancer applications - is lipophilicity the key point?

A series of four new mononuclear cationic gold(I) complexes containing nitrogen functionalized N-heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of three complexes are presented. These lipophilic gold(I) complexes originate from a pharmacomodulation of previously described gold(I)-NHC complexes, by replacing an aliphatic spacer with an aromatic one. The Log P values of the resulting complexes increased by 0.7-1.5, depending on the substituents in comparison to the aliphatic-linker systems. The new series of complexes has been investigated in vitro for their anti-cancer activities in PC-3 (prostate cancer) and T24 (bladder cancer) cell lines and in the non-cancerous MC3T3 (osteoblast) cell line. All tested complexes show high activities against the cancer cell lines with GI50 values lower than 500 nM. One complex (11) has been selected for further investigations. It has been tested in vitro in six cancer cell lines from different origins (prostate, bladder, lung, bone, liver and breast) and two non-cancerous cell lines (osteoblasts, fibroblasts). Moreover, cellular uptake measurements were indicative of a good bioavailability. By various biochemical assays, this complex was found to effectively inhibit the thioredoxin reductase (TrxR) and its cytotoxicity towards prostate PC-3, bladder T24 and liver HepG2 cells was found to be ROS-dependent.

Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation.

A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.

Synthesis, characterization, and antileishmanial activity of neutral N-heterocyclic carbenes gold(I) complexes.

A series of five new mononuclear neutral gold(I) complexes containing N-heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of four complexes are presented. These gold(I) complexes together with four other neutral gold(I)-NHC complexes previously described were evaluated in vitro against Leishmania infantum promastigotes and axenic amastigotes. Moreover, their cytotoxicity was assessed on the murine macrophages J774A.1. Except one complex (10), eight gold(I)-NHC-Cl complexes show potent activity against the pathological relevant form of L. infantum amastigote with IC50 in the low micromolar and submicromolar range and five of them exhibit a SI close to 10. The lead-complex 11 displays a very high and selective activity (IC50 = 190 nM, SI = 40.29) and constitutes the best promising gold(I)-based drug of this series.

Gold(I)-Catalyzed Cycloisomerization-Dimerization Cascade of Benzene-Tethered 1,6-Enynes.

An unprecedented stereoselective domino reaction of 1,6-enynes with an aryl ring at C3-C4 in the presence of gold(I) catalysts at low temperature is described. This process involves a novel 5-exo-dig cycloisomerization-dimerization sequence to afford formal Diels-Alder adducts that undergo a smooth gold-catalyzed double bond migration at room temperature. In addition, the first examples of the gold mesoionic carbene mediated [2+2+2] cycloaddition of these enynes with benzaldehyde are reported.

Luminescent bioactive NHC-metal complexes to bring light into cells.

Organometallic complexes are mostly used in catalytic applications and nowadays they are attracting more and more attention for biomedical applications. Until the last decade, research in the latter area was focused on screening of complexes against cancer cell lines, bacteria or parasites. For a couple of years mechanistic studies have helped in elucidating the mode of action of such complexes, one of the applied methods consists of studying cell uptake and intracellular distribution of luminescent bioactive complexes, in order to identify the main targets. This perspective summarizes the results obtained with luminescent bioactive NHC-metal complexes in this field of research.

Synthesis, characterization, and antileishmanial activities of gold(I) complexes involving quinoline functionalized N-heterocyclic carbenes.

A series of new mononuclear cationic or neutral gold(I) complexes containing quinoline functionalized N-heterocyclic carbene(s) (NHC(s)) were synthesized and fully characterized by spectroscopic methods. The X-ray structures of two key compounds are presented. Proligands and their corresponding gold(I) complexes together with previously described silver(I) and gold(I) bis(NHC-quinoline) and gold(I) bis(NHC-methylbipyridine) complexes were evaluated in vitro towards Leishmania infantum. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine macrophages J774A.1. All gold(I) compounds show potent antileishmanial activity against L. infantum promastigotes and three of them are also efficient against L. infantum intracellular amastigotes. Structure-activity and toxicity relationships enables to evidence a lead-compound (6) displaying both a high activity and a good selectivity index.

Synthesis, structures, and selective toxicity to cancer cells of gold(I) complexes involving N-heterocyclic carbene ligands.

New gold(I) complexes containing two 1-[2-(diethylamino)ethyl]imidazolydene ligands have been synthesized and characterized. The X-ray structures of two key compounds are presented. All complexes have been tested for their antiproliferative activities in prostate cancer cell line PC-3. Lipophilicity (Log P) has been determined for these complexes. The most active complex has been tested for the cytotoxic activities in five human cancer cell lines and primary endothelial cells. The most active complex demonstrated a potent selectivity for cancer cells.

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles.

We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6ß-epoxy-cholesterol (5,6ß-EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6ß-EC remains unreactive whereas 5,6α-EC gives cholestan-3ß,5α-diol-6ß-substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6α-EC.

Synthesis of ferulic ester dimers, functionalisation and biological evaluation as potential antiatherogenic and antiplasmodial agents.

Oxidative dimerization of ferulic acid methyl ester afforded dihydrobenzofuran derivative and new linear compound identified by X-ray crystallography. The gallate derivatized dihydrobenzofuran analogue was obtained and all compounds were evaluated for potential antiatherogenic, antiplasmodial (best IC(50)=0.8 microM) and cytotoxic activities.

A Stable (Amino)(Phosphino)Carbene as bidentate ligand for Palladium and Nickel Complexes: Synthesis, Structure, and Catalytic Activity.

Two original complexes featuring an (amino)(phosphino)carbene η(2)-bonded to the metal have been obtained in 60 and 80 % yields, by addition of the corresponding stable carbene to PdCl(2)(cod) and NiCl(2)(PPh(3))(2), respectively. Both complexes have been fully characterized including X-ray diffraction studies. The catalytic activity of the palladium complex has been evaluated for aryl amination reactions.