Organometallic Analogues Research Articles

Organometallic analogs of chloroquine: Challenges and perspectives as anti‐malarial agents

Organometallic analogs of chloroquine: Challenges and perspectives as anti‐malarial agents

Synthesis, structural characterization and antitrypanosomal activity of ferrocenyl-based imines with (2 or 4)-nitrophenyl-2-furan group

Two new metallocene complexes with formulation [Fe(η5-C5H5){(η5-C5H4)-NCH-2-C4H2O-(5-C6H4-2-NO2)}] (3) and [Fe(η5-C5H5){(η5-C5H4)-NCH-2-C4H2O-(5-C6H4-4-NO2)}] (4) have been synthesized and their antitrypanosomal activity has been evaluated. Complexes 3 and 4 were obtained by condensation reaction of ferrocenylamine (1) with respective 5-(2-nitrophenyl)-2-furancarboxaldehyde (2a) or 5-(4-nitrophenyl)-2-furancarboxaldehyde (2b). The complexes were fully characterized by spectroscopic techniques (FT-IR, 1H and 13C{1H} NMR, and HRMS), which confirm their correct obtainment. The crystal structures of 3 and 4 were also determined by single crystal X-ray diffraction. Furthermore, UV–visible studies revealed that compounds 3 and 4 exhibited suitable stability in DMSO:HEPES buffer solution (80:20) throughout 24 h. The in vitro antiparasitic activities of ferrocenyl imine derivatives 3 and 4 were assessed against two species of parasites, Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei). The obtained results revealed that compound 3 (EC50 = 0.44 μM) exhibited nearly a 40-fold greater efficacy as an anti-T. brucei agent compared to derivative 4 (EC50 = 16.0 μM). Moreover, compound 3 demonstrated superior potency when compared with its organometallic analogs (EC50 = 2.42–13.3 μM), which were previously reported by our research group. Interestingly, the EC50 value of 3 was found to be 8 times greater than that of nifurtimox (EC50 = 3.56 μM). The cytotoxicity of the ferrocenyl imines was also evaluated on the L6 rat skeletal myoblast cell line.

A General Concept for the Electronic and Steric Modification of 1-Metallacyclobuta-2,3-dienes: A Case Study of Group 4 Metallocene Complexes.

The synthesis of group 4 metal 1-metallacyclobuta-2,3-dienes as organometallic analogues of elusive 1,2-cyclobutadiene has so far been limited to SiMe3 substituted examples. We present the synthesis of two Ph substituted dilithiated ligand precursors for the preparation of four new 1-metallacyclobuta-2,3-dienes [rac-(ebthi)M] (M=Ti, Zr; ebthi=1,2-ethylene-1,10-bis(η5-tetrahydroindenyl)). The organolithium compounds [Li2(RC3Ph)] (1 b: R=Ph, 1 c: R=SiMe3) as well as the metallacycles of the general formula [rac-(ebthi)M(R1C3R2)] (2 b: M=Ti, R1=R2=Ph, 2 c: M=Ti, R1=Ph, R2=SiMe3; 3 b: M=Zr, R1=R2=Ph; 3 c: M=Zr, R1=Ph, R2=SiMe3) were fully characterised. Single crystal X-ray diffraction and quantum chemical bond analysis of the Ti and Zr complexes reveal ligand influence on the biradicaloid character of the titanocene complexes. X-band EPR spectroscopy of structurally similar Ti complexes [rac-(ebthi)Ti(Me3SiC3SiMe3)] (2 a), 2 b, and 2 c was carried out to evaluate the accessibility of an EPR active triplet state. Cyclic voltammetry shows that introduction of Ph groups renders the complexes easier to reduce. 13C CPMAS NMR analysis provides insights into the cause of the low field shift of the resonances of metal-bonded carbon atoms and provides evidence of the absence of the β-C-Ti interaction.

Synthesis and reactivity of Pd(II) imidoyl complexes obtained by insertion of isocyanoferrocene into the Pd-C bonds of orthopalladated precursors.

While the multifaceted reactivity of organic isocyanides has been extensively demonstrated, that of their organometallic analogue, isocyanoferrocene (FcNC; Fc = ferrocenyl), has not yet been adequately explored. This contribution describes the syntheses of novel chelating Pd(II) imidoyl complexes, [(YCH2C6H4C(NFc)-κ2Y,C)PdCl(PR3)], by insertion of FcNC into the Pd-C bond of cyclopalladated precursors [(YCH2C6H4-κ2Y,C)PdCl(PR3)] (Y = Me2N, MeS, R = Ph, Me). The imidoyl complexes underwent facile alkylation with [Me3O][BF4] to produce the cationic aminocarbene complexes [{YCH2C6H4C(N(Me)Fc)-κ2Y,C}PdCl(PR3)][BF4]. All compounds were fully characterised using a combination of spectroscopic methods (NMR, FTIR and ESI MS), cyclic voltammetry and single-crystal X-ray crystallography. In addition, DFT calculations were used to describe the bonding in the two compound families. Analyses with intrinsic bond orbitals (IBOs) and the quantum theory of atoms in molecules (QTAIM) consistently pointed to the transformation of an X-type imidoyl C-ligand (σ-organyl) into an L-type carbene donor upon alkylation, which has only a minor structural consequence. Also reported is the unexpected conversion of the imidoyl complex [(Me2NCH2C6H4C(NFc)-κ2N,C)PdCl(PPh3)] into (Z)-2,2-dimethyl-1-(ferrocenylimino)isoindolin-2-ium tetrafluoroborate as a reductive elimination product, which was induced by Lewis and Brønsted acids.

Inorganometallic allenes [(Mn(η5-C5H5)(CO)2)2(μ-E)] (E = Si-Pb): bis-allylic anionic delocalisation similar to organometallic allene but differential σ-donation and π-backdonation.

The chemistry of heavy group-14 tetrel atoms is known to diverge from that of the lighter congener carbon. Here, we report the structure and bonding in inorganometallic allenes [(MnCp(CO)2)2(μ-E)] (2E, E = Si-Pb; Cp = η5-C5H5). These inorganometallic allenes are structurally similar to the lighter organometallic analog [(MnCp(CO)2)2(μ-C)] (2C). The bonding analysis of these compounds at the M06/def2-TZVPP//BP86/def2-SVP level of theory identifies a linear Mn-E-Mn spine with delocalised, mutually orthogonal π-systems across this back-bone. This results in a bis-allylic anionic bonding scenario. However, the strength of the Mn-E bonding is found to be weaker in these inorganometallic allenes. The energy decomposition analysis at the BP86/TZ2P//BP86/def2-SVP level of theory further reveals that the bonding in these compounds cannot be represented by one unique heuristic bonding model, but multiple bonding models. For all 2E (E = C-Pb), the Dewar-Chatt-Duncanson bonding model is one of the best bonding representations, where the central tetrel atom acts as a 4e- σ-donor and 4e- π-acceptor. The bonding analysis indicates that the carbon atom in the organometallic allene acts as a better π-acceptor than σ-donor, while the heavier tetrel atoms in the inorganometallic allenes are better σ-donors than π-acceptors. The npz-orbital is found to be a better σ-donor than the valence ns-orbital. However, when the bonding representation is changed to a traditional electron-sharing model, the contribution from the ns-orbital was found to be the largest in comparison to the interaction from the remaining three valence np-orbitals. It can be suggested that the ns-orbitals contribute more towards chemical bonding when participating via an electron-sharing interaction than a donor-acceptor interaction.

An organometallic analogue of combretastatin A-4 and its apoptosis-inducing effects on lymphoma, leukemia and other tumor cells in vitro.

Hexacarbonyl[1,3-dimethoxy-5-((4'-methoxyphenyl)ethynyl)benzene]dicobalt (NAHO27), an organometallic analogue of combretastatin A-4, has been synthesized and its activity against lymphoma, leukemia, breast cancer and melanoma cells has been investigated. It was shown that NAHO27 specifically induces apoptosis in BJAB lymphoma and Nalm-6 leukemia cells at low micromolar concentration and does not affect normal leukocytes in vitro. It also proved to be active against vincristine and daunorubicin resistant leukemia cell lines with p-glycoprotein-caused multidrug resistance and showed a pronounced (550%) synergistic effect when co-applied with vincristine at very low concentrations. Mechanistic investigations revealed NAHO27 to induce apoptosis via the mitochondrial (intrinsic) pathway as reflected by the processing of caspases 3 and 9, the involvement of Bcl-2 and smac/DIABLO, and the reduction of mitochondrial membrane potential. Gene expression analysis and protein expression analysis via western blot showed an upregulation of the proapoptotic protein harakiri by 9%.

1-Titanacyclobuta-2,3-diene - an elusive four-membered cyclic allene.

The synthesis of an unusual 1-metalla-2,3-cyclobutadiene complex [rac-(ebthi)Ti(Me3SiC3SiMe3)] (rac-ebthi = rac-1,2-ethylene-1,1'-bis(η5-tetrahydroindenyl)), a formal metallacyclic analogue of a non-existent four-membered 1,2-cyclobutadiene, is described. By variation of the cyclopentadienyl ligand of the titanocene precursor it was possible to stabilise this highly exotic compound which selectively reacts with ketones and aldehydes to yield enynes by oxygen transfer to titanium. Analysis of the bonding and electronic structure of the metallacycle shows that the complex is best described as an unusual antiferromagnetically coupled biradicaloid system, possessing a formal Ti(iii) centre coordinated with a monoanionic radical ligand.

Completely Unexpected Coordination Selectivity of Copper Iodide for Thioether Over Ethynyl

The reactivity of the tetradentate ligand bis(p-thiomethylphenylacetylene) (MeSC6H4C≡C–C≡CC6H4SMe; L2) towards the CuI salt is compared to that for the known organometallic analogue trans-bis(p-thiomethylethynylbenzene)bis(trimethyl-phosphine)platinum(II) (trans-Pt(PMe3)2(C≡CC6H4SMe)2; L1). While L1 with CuI form a highly luminescent porous 2D coordination polymer (CP) of general formula ([Cu4I4]L1 · EtCN)n (CP1; Juvenal et al. in Inorg Chem 55:11096–11109, 2016) exhibiting both Cu(η2–C≡C) and Cu–S bonds, L2 reacts with CuI to produce a luminescent non-porous 2D CP exhibiting the general formula ([Cu4I4]{L2}3)n, CP2, which does not use the highly expected Cu(η2–C≡C) linkage, relying strictly upon Cu–S coordination. An examination of the X-ray structures for both L2 and CP2 indicates that CP2 network is built upon an expansion of the L2 lattice (plane sliding and slight L2–L2 distance separation) resembling to a sort of template effect. CP2 has been characterized by TGA, UV–Vis, emission spectroscopy, and photophysics, which are accompanied by DFT and TDDFT computations.

Presenting a ferrocene Ferris wheel

By fusing ferrocene molecules together, a research team has prepared new iron-based macrocycles that resemble a Ferris wheel. Ferrocene linear chains and macrocycles have been made before, but they contained spacer groups separating the metallocene units, which don’t allow much interaction between the iron atoms. Michael S. Inkpen, Nicholas J. Long, and Tim Albrecht of Imperial College London and their colleagues have now made examples in which five to nine ferrocene units are fused by direct cyclopentadienyl C–C linkages. These redox-active ferrous/ferric nanorings have substantial charge delocalization and are more stable than previous ferrocene-based macromolecules, with the six-membered version representing an organometallic analog of benzene (Nat. Chem. 2016, DOI: 10.1038/nchem.2553). The researchers made the ferrocene rings via copper-mediated Ullmann coupling reactions of dilute solutions of iodinated ferrocene or linear ferrocene oligomers. The internal cavity of the molecules provides opportuniti...

Synthesis and Characterization of Dirhenadehydro[12]annulenes.

The 12-membered-ring metallacycles [mer-Re{≡CCH=C(R)C≡C-}Cl(PMe2 Ph)3 )]2 (R=CMe3 , 1-adamantyl), which are organometallic analogues of antiaromatic octadehydro[12]annulene, are prepared by heating the methyl carbyne complexes mer-Re{≡CCH=C(R)C≡CH}(CH3 )Cl(PMe2 Ph)3 . An intermolecular σ-bond metathesis between the Re-CH3 bond and the acetylenic C-H bond is proposed for their formation.

ChemInform Abstract: Advanced 1,1‐Carboboration Reactions with Pentafluorophenylboranes

AbstractReview: 56 refs.

4-Ethylphenyl-Cobalamin Impairs Tissue Uptake of Vitamin B12 and Causes Vitamin B12 Deficiency in Mice

Coβ-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean±SEM) was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L) compared to controls (0.30±0.02 µmol/L) and CNCbl (0.29±0.01 µmol/L) treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L) than in CNCbl treated animals (87.64±0.93 nmol/L). However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively). Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.

Cisplatin-related drugs for nongenomic targets: Forcing the reactivity with nucleobases

The products obtained by forcing the reaction with nucleosides (guanosine, Guo, and adenosine, Ado) of potential anticancer drugs for nongenomic targets [PtCl(O,O'-acac)(L)] (L = dimethyl sulfoxide, DMSO; dimethyl sulfide, DMS), closely related to their very powerful organometallic analogues [Pt(O,O'-acac)(γ-acac)(L)], have been studied. [PtCl(O,O'-acac)(L)] and [Pt(O,O'-acac)(γ-acac)(L)] complexes were reported unreactive toward nucleobases. Aquo species [Pt(O,O'-acac)H2O(L)]+, obtained from [PtCl(O,O'-acac)(L)] by Ag+ driven coordinated Cl– removal, gave access to [Pt(O,O'-acac)(L)(nucleoside)]+ ([Pt(O,O'-acac)(DMSO)(Guo)]+, [Pt(O,O'-acac)(DMS)(Guo)]+, [Pt(O,O'-acac)(DMSO)(Ado)]+). The effect of the chelate oxygen donor acac (with respect to a chelate diammine), the role of the sulfur ligand (DMSO, DMS), and the influence of the purinic nucleoside itself on the coordinated Guo or Ado dynamic motions in [Pt(O,O'-acac)(L)(nucleoside)]+ complexes have been investigated by NMR spectroscopy. Interestingly, a slow rotation of nucleobase around the Pt–N(7) bond with formation of two rotamers was observed already at room temperature only in the case of [Pt(O,O'-acac)(DMSO)(Guo)]+. On the other hand, no hindered rotation at room temperature was detected in the analogous [Pt(O,O'-acac)(DMS)(Guo)]+ and [Pt(O,O'-acac)(DMSO)(Ado)]+ complexes. Data suggest that rotation of the nucleoside in [Pt(O,O'-acac)(L)(nucleoside)]+ is very different with respect to the analogous [Pt(diammine)(L)(nucleoside)]2+ systems, due to specific interactions between the acac chelate ligand, the DMSO, and the nucleobase.

ChemInform Abstract: Bioorganometallic Compounds with Antimalarial Targets: Inhibiting Hemozoin Formation

AbstractReview: 121 refs.

New Insights into Cinchonine-Aluminium Complexes and Their Application as Chiral Building Blocks: Unprecedented Ligand-Exchange Processes in the Presence of ZnR2Compounds

Previous studies have demonstrated that [(CN)(2)AlCl] and [R(2)Al(μ-CN)](2) (CN=deprotonated cinchonine) complexes can effectively act as chiral, semirigid, N,N-ditopic metalloligands for Zn-containing nodes, and provide viable means for constructing new, homochiral, heterometallic, coordination polymers of zigzag and helical topologies. These findings have prompted further investigations on the organometallic analogues of the formula [(CN)(2)AlR], anticipating their utility as N,N-metalloligands for ZnR(2) units. Surprisingly, reactions of [(CN)(2)AlMe]-type metalloligands with ZnR(2) compounds (R=Me or Et) revealed unprecedented ligand-exchange processes, including zinc-to-aluminium and aluminium-to-zinc transmetalations of alkyl groups. The molecular and crystal structure of the resulting compounds was determined by X-ray diffraction analysis. From the reaction of [(CN)(2)AlMe] with ZnMe(2) a new pseudopolymorphic form of a noncovalent porous material based on [Me(2)Al(μ-CN)](2) molecules was isolated. Strikingly, the analogous reaction involving ZnEt(2) led to the generation of a new chiral 4N-tetratopic heterometalloligand [(CN)EtAl(μ-CN)(2)ZnEt]. The latter unit was successfully connected by alkyl-exchanged ZnMe(2) nodes to give an original homochiral heterometallic {[(CN)EtAl(μ-CN)(2)ZnEt]ZnMe(2)}(n) coordination polymer adopting a snake 1D motif. The outcome of the revealed reactions indicates the complicated multistep reaction route that involves redistribution of cinchonine and alkyl ligands among the Al and Zn centers, and a general reaction scheme is proposed. The results are in strong contrast with the previously studied inorganic-organic [(CN)(2)AlCl/ZnCl(2)] system, which exclusively affords a helical coordination polymer based on ZnCl(2) nodes and (CN)(2)AlCl metalloligands and lacks the exchange of CN ligands.

ChemInform Abstract: Recent Advances in the Synthesis of Raloxifene: A Selective Estrogen Receptor Modulator

AbstractReview: 60 refs.

Bioorganometallic Compounds with Antimalarial Targets: Inhibiting Hemozoin Formation

About half of the world’s population is at risk of malaria, and in tropical countries it remains a major cause of morbidity and death in children. Drug resistance to current established antimalarial drugs such as chloroquine is driving the rise in malaria-attributed deaths. In the mid-1990s, two groups—in France and in Venezuela—probed the potential contribution of organometallic analogues as a means of discovering new antimalarial drugs. In the present review, key topics of organometallic antimalarials are outlined using examples from the literature. The interdisciplinary research environment of bioorganometallics allows researchers to investigate the whole spectrum of the drugs’ mechanisms of action. Targeting the digestive vacuole and inhibiting hemozoin formation is believed to be the main mechanism by which these drugs induce parasite death.

Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator

Estrogens are a group of steroids that exert important effects on reproductive and many non-reproductive tissues. Selective estrogen receptor modulators (SERM) are a class of therapeutic agents widely prescribed for the treatment and prevention of breast cancer, osteoporosis, and postmenopausal symptoms. Raloxifene, an example of oral SERM is prescribed primarily for the treatment and prevention of postmenopausal disorders in woman. The current review provides an outline of practical methodologies used to access benzothiophenyl scaffolds of raloxifene and relevant structural analogs. The contents are discussed in five sections: (a) synthesis of raloxifene, (b) organometallic analogs, (c) radiolabelled analogs, (d) constrained raloxifene analogs, and (e) other oxygen, sulfur, and nitrogen based raloxifene analogs. In addition to the synthesis, biological activity of a few synthetic analogs has been discussed.

Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis

Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)(3)) and cyrhetrene (CpRe(CO)(3)) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7-chloroquinolin-4-yl)-N'-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)(3) moiety in any of the biological assays.

Planar chiral (η6-arene)Cr(CO)3containing carboxylic acid derivatives: Synthesis and use in the preparation of organometallic analogues of the antibiotic platensimycin

With more and more organometallic compounds receiving attention for applications in medicinal organometallic chemistry, the need arises for stereoselective syntheses of more complicated structures containing organometallic moieties, for example as isosteric substitutes for organic drug candidates. Herein, the synthesis and characterization of both diastereomers of a planar chiral (η(6)-arene)Cr(CO)(3) containing carboxylic acid derivative, namely, 3-{η(6)-(1, 2, 3, 4-tetrahydro-1-endo/exo-methyl-2-oxonaphthalen-1-yl)-tricarbonylchromium(0)}propanoic acid (7 and 8) is reported. The molecular structures of both were confirmed by single crystal X-ray diffraction. The degree of diastereoselectivity in Cr(CO)(3) complexation with methyl/tert-butyl-3-(1,2,3,4-tetrahydro-1-methyl-2-oxonaphthalen-1-yl)propanoate (4a/4b) vs. the Michael addition of methyl/tert-butyl acrylate to (η(6)-1-methyl-2-tetralone)Cr(CO)(3) (9) was also examined. In the latter case the alkylation was found to be completely diastereoselective and gave methyl/tert-butyl-3-{η(6)-(1, 2, 3, 4-tetrahydro-1-endo-methyl-2-oxonaphthalen-1-yl)-tricarbonylchromium (0)}propanoate (5a and 5b) in excellent yield. Both the carboxylic acids 7 and 8 were coupled with the aminoresorcyclic acid core to achieve diastereomeric bioorganometallics 15a and 15b based on the naturally occurring antibiotic platensimycin lead structure (1a, see Fig. 1). The newly synthesized bioorganometallics were tested against various Gram-positive and Gram-negative bacterial strains but show no promising antibacterial activity.