Dithienylethene-Based Photoswitchable Phosphines for the Palladium-Catalyzed Stille Coupling Reaction.

Homogeneous transition metal catalysis is a constantly developing field in chemical sciences. A growing interest in this area is photoswitchable catalysis, which pursues in situ modulation of catalyst activity through noninvasive light irradiation. Phosphorus ligands are excellent targets to accomplish this goal by introducing photoswitchable moieties; however, only a limited number of examples have been reported so far. In this work, we have developed a series of palladium complexes capable of catalyzing the Stille coupling reaction that contain photoisomerizable phosphine ligands based on dithienylethene switches. Incorporation of electron-withdrawing substituents into these dithienylethene moieties allows variation of the electron density on the phosphorus atom of the ligands upon light irradiation, which in turn leads to a modulation of the catalytic properties of the formed complexes and their activity in a model Stille coupling reaction. These results are supported by theoretical computations, which show that the energy barriers for the rate-determining steps of the catalytic cycle decrease when the photoswitchable phosphine ligands are converted to their closed state.

Exploring Raloxifene-based Metallodrugs: A Versatile Vector Combined with Pt(II), Palladium(II) and Nickel(II) Dichlorides and Carborates against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene-based hybrid drug bearing a 2,2'-bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complex 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexes 4 and 5 exhibited various cytotoxic behavior towards different types of hormone-receptor positive (HR+) cancer and TNBC cell lines. The replacement of the two chlorido ligands in 3‒5 with a dicarbollide (carborate) ion [C2B9H11]2- resulted in reduced activity of compounds 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence-associated phenotype of TNBC cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC.

Carboranylphosphines: B9-Substituted Derivatives with Enhanced Reactivity for Anchoring to Dendrimers.

Invited for the cover of this issue are the groups and colleagues of Anne-Marie Caminade at the CNRS and University of Toulouse, Evamarie Hey-Hawkins at Leipzig University, and Agustí Lledós from the Autonomous University of Barcelona. The image depicts birds crowned by a carborane competing for access to food, to illustrate the steric hindrance encountered when grafting carboranes to dendrimers (artwork by Dr. Christoph Selg). Read the full text of the article at 10.1002/chem.202303867.

Carboranylphosphines: B9-Substituted Derivatives with Enhanced Reactivity for the Anchoring to Dendrimers.

Several ortho-carboranes bearing a phenoxy or a phenylamino group in the B9 position were prepared employing various protection and deprotection strategies. Following established protocols, dendritic compounds were synthesized from a hexachlorocyclotriphosphazene or thiophosphoryl chloride core, and possible anchoring options for the B9-substituted ortho-carboranes were investigated experimentally and theoretically (DFT). Furthermore, 1- or 1,2-phosphanyl-substituted carborane derivatives were obtained. The resulting diethyl-, diisopropyl-, di-tert-butyl-, diphenyl- or diethoxyphosphines bearing a tunable ortho-carborane moiety are intriguing ligands for future applications in homogeneous catalysis or the medicinal sector.

Enhanced reversal of ABCG2-mediated drug resistance by replacing a phenyl ring in baicalein with a meta-carborane.

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5-year survival rate of human patients. Co-treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron-based clusters as meta-carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta-carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2-mediated efflux and caused a fivefold increase in mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7-trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 µm without reversing mitoxantrone resistance, its carborane analogue 5,6,7-trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 µm) and caused a stronger increase in mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta-carborane and three methoxy substituents leads to an enhanced reversal of ABCG2-mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors.

Exploring the potential of tamoxifen-based copper(ii) dichloride in breast cancer therapy.

For decades, tamoxifen-based hormone therapy has effectively addressed oestrogen receptor positive (ER+) luminal A breast cancer. Nonetheless, the emergence of tamoxifen resistance required innovative approaches, leading to hybrid metallodrugs with several therapeutic effects besides the inhibition of oestrogen receptor α (ERα). Drawing inspiration from tamoxifen metabolite structures (4-hydroxytamoxifen and 4,4'-dihyroxytamoxifen), a phenyl ring was replaced by a bidentate 2,2'-bipyridine donor moiety to give 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (L), enabling coordination of bioactive transition metal compounds such as copper(ii) dichloride, yielding [CuCl(µ-Cl)(L-κ2N,N')]2 (1). Notably, copper(ii) complex 1 exhibited remarkable activity within the low micromolar concentration range against ER+ human glioblastoma U251, as well as breast carcinomas MDA-MB-361 and MCF-7, surpassing the efficacy of previously reported palladium(ii) and platinum(ii) dichloride analogs against these cell lines. The pronounced efficacy of complex 1 against triple-negative MDA-MB-231 cells highlights its potential multitherapeutic approach, evident through induction of apoptosis and antioxidant activity. This study evaluates the potential of copper-tamoxifen hybrid complex 1 as a potent therapeutic candidate, highlighting its diverse mechanism of action against challenging breast cancer subtypes.

Synthesis of P-stereogenic 1-phosphanorbornane-derived phosphine-phosphite ligands and application in asymmetric catalysis.

A convenient synthesis of enantiopure mixed donor phosphine-phosphite ligands has been developed incorporating P-stereogenic phosphanorbornane and axially chiral bisnaphthols into one ligand structure. The ligands were applied in Pd-catalyzed asymmetric allylic substitution of diphenylallyl acetate, Rh-catalyzed asymmetric hydroformylation of styrene and Rh-catalyzed asymmetric hydrogenation of an acetylated dehydroamino ester. Excellent branched selectivity was observed in the hydroformylation although low ee was found. Moderate ee's of up to 60% in allylic substitution and 50% in hydrogenation were obtained using bisnaphthol-derived ligands.

Ring-Opening Reaction of 1-Phospha-2-Azanorbornenes via P-N Bond Cleavage and Reversibility Studies.

The reactive P-N bond in 1-phospha-2-azanorbornenes is readily cleaved by simple alcohols to afford P-chiral 2,3-dihydrophosphole derivatives as a racemic mixture. The isolation of the products was not possible due to the reversibility of the reaction, which could, however, be stopped by sulfurization of the phosphorus atom, thus efficiently blocking the lone pair of electrons, as exemplified for 6b yielding structurally characterized 8b. Additionally, the influence of the substituent in the α position to the phosphorus atom (H, Ph, 2-py, CN) on the reversibility of the reaction was studied. Extensive theoretical calculations for understanding the ring-closing mechanism suggested that a multi-step reaction with one or more intermediates was most probable.

Access to Enantiomerically Pure P-Chiral 1-Phosphanorbornane Silyl Ethers.

Sulfur-protected enantiopure P-chiral 1-phosphanorbornane silyl ethers 5a,b are obtained in high yields via the reaction of the hydroxy group of P-chiral 1-phosphanorbornane alcohol 4 with tert-butyldimethylsilyl chloride (TBDMSCl) and triphenylsilyl chloride (TPSCl). The corresponding optically pure silyl ethers 5a,b are purified via crystallization and fully structurally characterized. Desulfurization with excess Raney nickel gives access to bulky monodentate enantiopure phosphorus(III) 1-phosphanorbornane silyl ethers 6a,b which are subsequently applied as ligands in iridium-catalyzed asymmetric hydrogenation of a prochiral ketone and enamide. Better activity and selectivity were observed in the latter case.

Modular Synthesis of Phosphino Hydrazones and Their Use as Ligands in a Palladium-Catalysed Cu-Free Sonogashira Cross-Coupling Reaction.

Invited for this month's cover is the group of Evamarie Hey-Hawkins at Leipzig University. The cover picture shows the three different bonding modes (mono-, bi- and tridentate) of the modular ligand towards palladium(II) or platinum(II), illustrated with Winston who kindly served as the model. The cat has three binding sites (mouth, front paws and hind paws = P, N and pyridine) to bind the metal dichloride fragment. When all three are used in a tridentate bonding mode, one chlorido ligand is cleaved off. Cover design by Dr. Christoph Selg. More information can be found in the Research Article by Evamarie Hey-Hawkins and co-workers.

Stronger Together! Mechanistic Investigation into Synergistic Effects during Homogeneous Carbon Dioxide Hydrogenation Using a Heterobimetallic Catalyst.

A series of group 6 heterobimetallic complexes [M0;IrIII] (M = Cr, Mo, W) were synthesized and fully characterized, and the catalytic behavior was studied. The heterobimetallic complex [Mo0;IrIII] (C1) was by far the most active and has shown a considerable synergistic effect, with both metals actively participating in homogeneous carbon dioxide hydrogenation, leading to formate salts. Based on theoretical calculations, the synergistic interaction is due to Pauli repulsion, lowering the transition state and thus enabling higher catalytic activity. The mechanism of both the hydrogenation itself and the synergistic interaction was studied by NMR spectroscopy, kinetic measurements, and theoretical calculations. The homogeneous nature of the reaction was proven using in situ high-pressure (HP) NMR experiments. The same experiments also showed that the octahedral Mo(CO)3P3 moiety of the complex is stable under the reaction conditions. The hydride complex is the resting state because the hydride transfer is the rate-determining step. This is supported by kinetic measurements, in situ HP NMR experiments, and theoretical calculations and is in contrast to the monometallic IrIII counterpart of C1.

Facile Synthesis of Enantiomerically Pure P-Chiral 1-Alkoxy-2,3-dihydrophospholes via Nucleophilic P-N Bond Cleavage of a 1-Phospha-2-azanorbornene.

Invited for the cover of this issue is the group of Prof. Evamarie Hey-Hawkins at Leipzig University. The image depicts a deer with diastereomeric antlers. Read the full text of the article at 10.1002/chem.202300790.

Correction: Kazimir et al. Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes. Pharmaceutics 2023, 15, 682.

In the original publication [...].

Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs.

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

Modular Synthesis of Phosphino Hydrazones and Their Use as Ligands in a Palladium-Catalysed Cu-Free Sonogashira Cross-Coupling Reaction.

Phosphino hydrazones represent a versatile class of nitrogen-containing phosphine ligands. Herein, we report a modular synthesis of phosphino hydrazone ligands by hydrazone condensation reaction of three different aryl hydrazines with 3-(diphenylphosphino)propanal (PCHO). Complexation reactions of these phosphino hydrazone ligands with palladium(II) and platinum(II) were investigated and the catalytic activity of the palladium(II) complexes was explored in a Cu-free Sonogashira cross-coupling reaction achieving yields up to 96 %. Additionally it was shown that the catalytically active species is homogeneous.

Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro.

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.

Facile Synthesis of Enantiomerically Pure P-Chiral 1-Alkoxy-2,3-dihydrophospholes via Nucleophilic P-N Bond Cleavage of a 1-Phospha-2-azanorbornene.

The reactive P-N bond in a racemic mixture of endo-1-phospha-2-azanorbornene (PAN) (RP /SP )-endo-1 is readily cleaved with enantiomerically pure lithium alkoxides followed by protonation to afford diastereomeric mixtures of P-chiral 1-alkoxy-2,3-dihydrophosphole derivatives. The isolation of these compounds is rather challenging due to the reversibility of the reaction (elimination of alcohols). However, methylation of the sulfonamide moiety of the intermediate lithium salts and sulfur protection of the phosphorus atom prevent the elimination reaction. The resulting air-stable P-chiral diastereomeric 1-alkoxy-2,3-dihydrophosphole sulfide mixtures can be readily isolated and fully characterized. The diastereomers can be separated by crystallization. The 1-alkoxy-2,3-dihydrophosphole sulfides are readily reduced with Raney nickel to afford phosphorus(III) P-stereogenic 1-alkoxy-2,3-dihydrophospholes with potential use in asymmetric homogeneous transition metal catalysis.

Triphenyltin(IV) Carboxylates with Exceptionally High Cytotoxicity against Different Breast Cancer Cell Lines.

Organotin(IV) carboxylates are a class of compounds explored as alternatives to platinum-containing chemotherapeutics due to propitious in vitro and in vivo results, and distinct mechanisms of action. In this study, triphenyltin(IV) derivatives of non-steroidal anti-inflammatory drugs (indomethacin (HIND) and flurbiprofen (HFBP)) are synthesized and characterized, namely [Ph3Sn(IND)] and [Ph3Sn(FBP)]. The crystal structure of [Ph3Sn(IND)] reveals penta-coordination of the central tin atom with almost perfect trigonal bipyramidal geometry with phenyl groups in the equatorial positions and two axially located oxygen atoms belonging to two distinct carboxylato (IND) ligands leading to formation of a coordination polymer with bridging carboxylato ligands. Employing MTT and CV probes, the antiproliferative effects of both organotin(IV) complexes, indomethacin, and flurbiprofen were evaluated on different breast carcinoma cells (BT-474, MDA-MB-468, MCF-7 and HCC1937). [Ph3Sn(IND)] and [Ph3Sn(FBP)], unlike the inactive ligand precursors, were found extremely active towards all examined cell lines, demonstrating IC50 concentrations in the range of 0.076-0.200 µM. Flow cytometry was employed to examine the mode of action showing that neither apoptotic nor autophagic mechanisms were triggered within the first 48 h of treatment. However, both tin(IV) complexes inhibited cell proliferation potentially related to the dramatic reduction in NO production, resulting from downregulation of nitric oxide synthase (iNOS) enzyme expression.

Metal phosphine aldehyde complexes and their application in Cu-free Sonogashira and Suzuki-Miyaura cross-coupling reactions.

Transition metal coordination chemistry and catalysis are rife with phosphine ligands. One of the rather less studied members of the phosphine ligand family are phosphine aldehydes. We have synthesised 3-(diphenylphosphino)propanal (PCHO) with a slight modification of the known procedure and studied its complexation behaviour with palladium(II) and platinum(II). The catalytic activity of the palladium(II) phosphine aldehyde complexes was investigated in Cu-free Sonogashira and Suzuki-Miyaura cross-coupling reactions. Furthermore, the homogeneous nature of the catalytically active species was confirmed.

Synergistic Catalysis in Heterobimetallic Complexes for Homogeneous Carbon Dioxide Hydrogenation.

Two heterobimetallic Mo,M' complexes (M' = IrIII, RhIII) were synthesized and fully characterized. Their catalytic activity in homogeneous carbon dioxide hydrogenation to formate was studied. A pronounced synergistic effect between the two metals was found, most notably between Mo and Ir, leading to a fourfold increase in activity compared with a binary mixture of the two monometallic counterparts. This synergism can be attributed to spatial proximity of the two metals rather than electronic interactions. To further understand the nature of this interaction, the mechanism of the CO2 hydrogenation to formate by a monometallic IrIII catalyst was studied using computational and spectroscopic methods. The resting state of the reaction was found to be the metal-base adduct, whereas the rate-determining step is the inner-sphere hydride transfer to CO2. Based on these findings, the synergism in the heterobimetallic complex is beneficial in this key step, most likely by further activating the CO2.