Electrophilic Behavior of the "Nucleophilic" Pyramidane: Reactivity of Ge-Pyramidane towards Organolithium Reagents.

The particular reactivity of the recently discovered class of the main group element polyhedral clusters, pyramidanes, remains largely unexplored. In this communication, we report the reaction of the germapyramidane with tert-butyllithium leading to the rather unusual organogermanium compound [Li+(thf)2]⋅2-, as the product of the formal insertion of a Ge-apex into the C-Li bond. This reactivity mode exemplifies unusual electrophilic behaviour of a pyramidane, which is a priori considered as a nucleophilic reagent. Being highly reactive, [Li+(thf)2]⋅2- readily undergoes reactions with electrophiles (MeI, EtBr), initially forming intermediate germahousenes, which isomerize to the thermodynamically more favourable germoles.

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.

ß-Lactam and penicillin substituted mesoionic metal carbene complexes.

1,2,3-Triazolylidene MIC M-complexes (M = Au, Pd, Pt) having 2-azetidinones and penicillin G substituents at the triazole ring were prepared by CuAAC on 2-azetidinones having a terminal alkyne tethered at N1, followed by alkylation of the 1,2,3-triazole ring and transmetallation [Au(I), Pd(II) and Pt(II)]. The Au-MIC complexes efficiently catalyze the regioselective cycloisomerization of enynes, while the Pt-MIC complexes were efficient catalysts in hydrosilylation reactions.

Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain-like Protease PLpro.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro . In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.

Titanium Germylidenes.

Two novel 18-electron titanium germylene complexes, Cp2 Ti(L)=Ge[Si3 (SiMet Bu2 )4 ] 3 b (L=Me3 P) and 3 c (L=XylNC), were synthesized, isolated, and structurally characterized. The length of the titanium-germanium bonds of 2.5387(3) Šand 2.5276(3) Š(in 3 b and 3 c, respectively) well match those expected for the double bond, which was further supported by the DFT study. Based on their structural characteristics, as well as their atomic charges calculations which revealed Ti(δ+)=Ge(δ-) bond polarization, both 3 b and 3 c are classified as the Schrock-type titanium germylidenes, as the germanium analogues of the widely known titanium alkylidenes. By contrast, germylene complexes of the group 6 metals 8 a (M=Mo) and 8 b (M=W) are better described as Fischer-type germylene complexes.

From a (Silatrigerma)cyclobutenylium Ion to a (Silatrigerma)cyclobutenyl Radical and Back.

(Silatrigerma)cyclobutenylium ion salt 2+·[B(C6F5)4]- was readily prepared by the reaction of cyclotrigermene 1 with an equimolar amount of [Et3Si(benzene)]+·[B(C6F5)4]- in benzene. The homoaromatic nature of 2+ was firmly established by its crystallographic analysis, which revealed a highly folded SiGe3 four-membered ring (40.4°) and a remarkably short transannular Ge-Ge distance of 2.9346(3) Å. The homoaromaticity of 2+ was supported by DFT calculations, which confirmed an extensive transannular bonding orbital interaction. One-electron reduction of 2+·[B(C6F5)4]- with potassium graphite resulted in the selective formation of (silatrigerma)cyclobutenyl free radical 2·, which has an allylic-type structure as confirmed by its X-ray and EPR studies. Cation 2+ and free radical 2· can be readily interconverted, thus constituting a fully reversible redox pair.

Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites.

The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.

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.

Tripyridinophane Platform Containing Three Acetate Pendant Arms: An Attractive Structural Entry for the Development of Neutral Eu(III) and Tb(III) Complexes in Aqueous Solution.

We report a detailed characterization of Eu3+ and Tb3+ complexes derived from a tripyridinophane macrocycle bearing three acetate side arms (H3tpptac). Tpptac3- displays an overall basicity (∑ log KiH) of 24.5, provides the formation of mononuclear ML species, and shows a good binding affinity for Ln3+ (log KLnL = 17.5-18.7). These complexes are also thermodynamically stable at physiological pH (pEu = 18.6, pTb = 18.0). It should be noted that the pGd value of Gd-tpptac (18.4) is only slightly lower than that of commercially available MRI contrast agents such as Gd-dota (pGd = 19.2). Moreover, a very good selectivity for these ions over the endogenous cations (log KCuL = 14.4, log KZnL = 12.9, and log KCaL = 9.3) is observed. The X-ray structure of the terbium complex shows the metal coordinated by the nine N6O3 donor set of the ligand and one inner-sphere water molecule. DFT calculations result in two Eu-tpptac structures with similar bond energies (ΔE = 0.145 eV): one structure in which the water is coordinated to the metal ion and one structure in which the water molecule is farther away from the ion, bound to the ligand with an OH-π bond. By detailed luminescence experiments, we demonstrate that the europium complex in aqueous solution presents a hydration equilibrium between nine-coordinate, dehydrated [Eu-tpptac]0 and ten-coordinate, monohydrated [Eu-tpptac(H2O)]0 species. A similar trend is observed for the terbium complex. Despite the presence of this hydration equilibrium, the H3tpptac ligand sensitizes Eu3+ and Tb3+ luminescence efficiently in buffered water at physiological pH. Particularly, the terbium complex displays a long excited-state lifetime of 2.24 ms and an overall quantum yield of 33% with a brightness of 3600 M-1 cm-1. Such features of Ln3+ complexes of H3tpptac indicate that this platform appears to be particularly appealing for the further development of luminescent lanthanide labels.

Tuning Philicity of Dichlorosilylene: Nucleophilic Behavior of the Dichlorosilylene-NHC Complex Cl2Si-IPr.

Novel unsaturated four-membered ring disilene, 3,3-dichloro-1,2,4,4-tetrakis[di-tert-butyl(methyl)silyl]-1Δ-1,2,3,4-trisilagermetene, was synthesized by the ring expansion reaction of the three-membered ring 1-disilagermirene with the silylene-NHC complex Cl2Si-IPr. The mechanism of the unexpected formation of this compound was verified by high-level density functional theory computations, which revealed nSi:(HOMO)-πSi=Si(LUMO) * as the dominant orbital interaction.

Central (S) to Central (M=Ir, Rh) to Planar (Metallocene, M=Fe, Ru) Chirality Transfer Using Sulfoxide-Substituted Mesoionic Carbene Ligands: Synthesis of Bimetallic Planar Chiral Metallocenes.

Enantiopure bimetallic systems containing three different elements of chirality, namely a main-group-based chiral center (sulfur), a transition-metal chiral center (rhodium or iridium), and a planar chiral element (ferrocene or ruthenocene), have been prepared by a sequence of diastereoselective reactions. The chirality of the chiral sulfur center attached to C-5 of a 1,2,3-triazolylidene mesoionic carbene (MIC) ligand coordinated to a metal (Ir, Rh) was transferred through the formation of bimetallic complexes having a chiral-at-metal center and a planar chiral metallocene by C-H activation of the sandwich moiety (M=Fe, Ru). The sense of the planar chirality formed in this sequence of reactions depended on the nature of the ligands at the metal center of the starting complex. The configurations of these species were assigned on the basis of a combination of X-ray diffraction and CD measurements. An electrochemical study of these bimetallic complexes in coordinating solvents showed an equilibrium between the cationic complexes and the neutral species. The effect of the half-sandwich moiety on the oxidation potentials of the system is remarkable, producing notable cathodic displacements. DFT calculations support these findings.

Arsagermene, a compound with an -As[double bond, length as m-dash]Ge[double bond splayed right] double bond.

The first compound featuring an As[double bond, length as m-dash]Ge double bond, arsagermene Mes*As[double bond, length as m-dash]Ge(SiMetBu2)2, was synthesized, isolated and fully characterized. Crystallographic studies revealed that arsagermene has a planar Ge[double bond, length as m-dash]As bond of 2.2731(8) Å, which is notably shorter than the standard Ge-As single bond. The double bond character of arsagermene was further supported by computational data.

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.

From Borapyramidane to Borole Dianion.

Nonclassical pyramidanes with their inverted tetrahedral configuration of the apical atom are among the most challenging synthetic targets in cluster chemistry. In this Communication, we report on the synthesis and structure of the first representative of pyramidal compounds with the group 13 element at the apex, namely, chloroborapyramidane 2. Reduction of 2 with excess of lithium metal unexpectedly produced the cage-opening product, borole dianion derivative {32-·[Li(thf)+]2}, a 6π-electron aromatic system.

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.

Bis(stibahousene).

Strained hydrocarbons constitute one of the most prominent classes of organic compounds. Among them, bicyclo[2.1.0]pentene ("housene") derivatives represent a highly challenging and very attractive class. Although organic housenes have been known for more than five decades, there are still very few of them containing heavier main group elements. In this paper, we report on the two housene-type structures, novel monomeric stibahousene and dimeric bis(stibahousene). The bonding natures of both compounds were approached from both experimental and computational directions to reveal their peculiar structural features.

Chiral Sulfur Functional Groups as Definers of the Chirality at the Metal in Ir and Rh Half-Sandwich Complexes: A Combined CD/X-ray Study.

Mesoionic carbenes (MICs) derived from triazolium salts that contain chiral sulfoxide or sulfoximine functional groups were used to construct enantiopure chiral-at-metal IrIII and RhIII half-sandwich complexes through the synthetic sequence of MIC complexation/C-H aromatic activation. The process was efficient and diastereoselective for the formation of enantiopure five-membered metallacycles. The use of the enantiomers of the chiral sulfur groups allowed us to prepare complexes that had opposite configurations at the metal center. Complete retention of the configuration at the metal center was observed during the formation of cationic IrIII complexes and upon insertion of alkynes into the IrIII -C bond, as demonstrated by a combined circular dichroism/X-ray study. These results point to a vicinal-assisted SN 1-like mechanism.

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.

"Breathing" Motion of a Modulable Molecular Cavity.

A class of hemicryptophane cages that adopt imploded conformations in solution and in the solid state has been described and studied by NMR spectroscopy and X-ray crystallography. It is reported that the degree of collapse of the molecular cavity can be controlled by changing the stereochemistry of the chiral elements of the hemicryptophanes, leading to a modulation of their physical and chemical properties. Upon the binding of an oxidovanadium unit, the collapsed molecular cavity can inflate to give an expanded conformation. Removal of the vanadium core by an ancillary complexing ligand restores the initial folded structure. Thus, coordination/de-coordination of the metal ion controls the dynamic motions of the cage, leading to a reversible nanomechanical process. This controlled motion between a collapsed and expanded cavity can be seen as that of a breathable molecular cage.