Ferrocene-triazole conjugates: do we know why they are biologically active?

The bioorganometallic chemistry of ferrocene has been gaining significance in recent years. This review presents ferrocene-triazole conjugates displaying significant biological properties. The conjugates have been synthesized via azide-alkyne cycloaddition reactions. The data are summarized according to the type of activity (anticancer, antibacterial and/or antifungal, antiprotozoal, and other effects). The results of studies concerning the understanding of the role of the ferrocene core in their biological activity are highlighted. While generally the mode of action of these organometallic species remains unclear, the importance of redox properties of ferrocene has been postulated in several cases.

Formylation of a metathesis-derived ansa[4]-ferrocene: a simple route to anticancer organometallics.

Formylation of ansa[4]-ferrocene, obtained through the ruthenium-catalysed olefin metathesis, yields two separable, planar chiral 1,3- and 1,2-ansa-ferrocene aldehydes. Single-crystal X-ray structure analysis reveals that both regioisomers crystallize with spontaneous resolution of the racemate in the chiral P212121 space group with one molecule in the asymmetric unit. The major 1,3-isomer was further transformed into a conjugate with 1,2,3-triazole and uracil using "click" chemistry as the key synthetic step. This inorganic-organic hybrid displays anticancer activity (MCF-7, A549, MDA-MB-231 cell lines) with EC50 values comparable to those for cisplatin.

Supramolecular Interactions between ß-Cyclodextrin and the Nucleobase Derivatives of Ferrocene.

Novel conjugates of ferrocene with uracil, 5-fluorouracil, tegafur, or acyclovir are reported. Their synthesis involved (i) the azide-alkyne 1,3-dipolar cycloaddition or (ii) the formation of the ester linkage. For the first time, we present an in-depth insight into the supramolecular interactions between ß-cyclodextrin and ferrocene-nucleobase derivatives. Spectroscopic and voltammetric analyses performed within this work suggested that the ferrocene or adamantane unit of the conjugates interacted with the ß-cyclodextrin's inner cavity. The methods applied for the supramolecular studies included 1H-1H ROESY NMR, 1H NMR titration, Fourier-transform infrared spectroscopy, cyclic voltammetry, fluorescence spectra titration, and 1H DOSY NMR. 1H DOSY NMR was also employed to evaluate the apparent binding constants for all the complexes. The ferrocene-acyclovir conjugate Fc-5 featured the highest apparent binding constant value among all the complexes tested.

Photo- and Thermoswitchable Half-Sandwich Nickel(II) Complex: [Ni(η5-C5H5)(IMes)(η1-NO2)].

A new photoswitchable half-sandwich nitro NiII complex with the N-heterocyclic carbene ligand was synthesized and successfully crystallized. The compound constitutes an analogue of a known nitrate nickel(II) compound, [Ni(η5-Cp)(IMes)(NO3)] (Cp = cyclopentadienyl, C5H5; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), and crystallizes with two symmetry-independent molecules in the asymmetric unit. When irradiated with 470 nm light-emitting diode light, the complex molecules undergo a photoisomerization reaction in the solid state. Formation of the respective NO2 group linkage isomers was studied photocrystallographically at different temperatures. After irradiation of the single-crystal sample for ca. 3 h at 100 K approximately 20% conversion of the η1-nitro (Ni-NO2) ligand to its exo-nitrito (Ni-ONO) form was observed. At ∼130 K the exo-nitrito binding mode transforms further to the more stable endo-nitrito conformation, whereas at temperatures higher than 175 K the crystal converts back to the ground state. It appears that the photoisomerization reaction can be to some extent triggered, or additionally stimulated, thermally. Consequently, the highest conversion level (ca. 90%) was achieved after sample irradiation at 145 K. Despite similar molecular energies and intermolecular interactions, the two symmetry-independent molecules behave somewhat differently upon irradiation and temperature changes. The photocrystallographic findings and molecular aspects were supplemented by theoretical computations, including the quantum-mechanics/molecular-mechanics approach.

Potential bioisosteres of ß-uracilalanines derived from 1H-1,2,3-triazole-C-carboxylic acids.

The 1H-1,2,3-triazole-originated derivatives of willardiine were obtained by: (i) construction of the 1H-1,2,3-triazole ring in 1,3-dipolar cycloaddition of the uracil-derived azides and the carboxylate-bearing alkynes or α-acylphosphorus ylide, or (ii) N-alkylation of the uracil derivative with the 1H-1,2,3-triazole-4-carboxylate-derived mesylate. The latter method offered: (i) reproducible results, (ii) a significant reduction of amounts of auxiliary materials, (iii) reduction in wastes and (iv) reduction in a number of manual operations required for obtaining the reaction product. Compound 6a exhibited significant binding affinity to hHS1S2I ligand-binding domain of GluR2 receptor (EC50 = 2.90 µM) and decreased viability of human astrocytoma MOG-G-CCM cells in higher extent than known AMPA antagonist GYKI 52466.

Axially chiral racemic half-sandwich nickel(ii) complexes by ring-closing metathesis.

A remarkable nickelacycle has been synthesised via olefin metathesis of the α,ω-diene complex [Ni(η5-C5H4R)(Br)(NHC)] (R = C(CH3)2CH2CH[double bond, length as m-dash]CH2, NHC = 1-(6-hexenyl)-3-(2,4,6-trimethylphenyl)-imidazol-2-ylidene). Single-crystal X-ray analysis reveals a helical shape of the molecule and stretching of some interatomic distances in the Ni(ii) coordination sphere. The Cp-NHC tethered complex shows catalytic activity resembling that of the parent complexes.

Novel imidazolium and imidazolinium salts containing the 9-nickelafluorenyl anion--synthesis, structures and reactivity.

Investigation of the properties of carbene complexes is one of the most important fields of modern coordination chemistry. In this paper, we propose the convenient synthesis of NHC-nickel compounds. The 9-nickelafluorenyllithium complex reacts with imidazolium or imidazolinium salts to afford 9-nickelafluorenyl-NHC salts via ionic metathesis with very good yields (66-92%). These compounds can be isomerised at elevated temperatures to give Ni-NHC complexes with excellent yields (88-91%), probably via nickel mediated hydrogen transfer to the biphenyl moiety. In this reaction, the nickelacyclic ring itself serves as a base in the deprotonation of the carbene precursor. DFT calculations show the thermodynamic instability of the synthesized salts, with Gibbs free energy differences for 1 of -84 kJ mol(-1) at 298 K and -167 kJ mol(-1) at 374 K. The obtained salts and carbene complexes are relatively air and moisture stable in the solid state.

Multicomponent reactions in nucleoside chemistry.

This review covers sixty original publications dealing with the application of multicomponent reactions (MCRs) in the synthesis of novel nucleoside analogs. The reported approaches were employed for modifications of the parent nucleoside core or for de novo construction of a nucleoside scaffold from non-nucleoside substrates. The cited references are grouped according to the usually recognized types of the MCRs. Biochemical properties of the novel nucleoside analogs are also presented (if provided by the authors).

Anion exchange in [Ni(η(5)-C(5)H(4)R)(Cl)(NHC)]. Counterion effect on the structure and catalytic activity.

A series of novel complexes [Ni(η(5)-C5H4R)(L)(NHC)](+)A(-)2a-2j and [Ni(η(5)-C5H5)(A)(NHC)] 3a-3c has been obtained by anion metathesis from the corresponding chlorides 1a-1d, depending on the anion binding properties and reaction conditions. Solid-state structures of two cationic complexes (2c, 2j) and two complexes with a coordinated anion (3a, 3c) have been determined by X-ray diffraction revealing a trigonal planar geometry in all cases. Unexpectedly, 3c displayed unprecedented for this type of compounds temperature-dependent NMR spectra that were interpreted in terms of spin equilibrium. The cationic complexes 2 were less efficient in styrene polymerization than the parent chlorides 1. However, the activity of 2 and 3 in Suzuki cross-coupling did not depend considerably on the counterion.

Triple C-H bond activation of a nickel-bound methyl group: synthesis and X-ray structure of a carbide cluster (NiCp)6(µ6-C).

A new hexanuclear cyclopentadienylnickel carbide cluster (NiCp)(6)(µ(6)-C) (1) was obtained through the thermolysis of the alkene complex [NiCp(CH(3))(η(2)-CH(2)═CHC(4)H(9))] (4). The X-ray molecular structure of 1 (monoclinic; P2(1)/c; Ni-C(carbide) = 1.767(4)-2.109(4) Å) reveals a highly deformed octahedral arrangement of nickel atoms with two octahedron edges opened (Ni-Ni bonding distances = 2.410(1)-2.623(1) Å, Ni···Ni nonbonding distances = 3.107(2) and 3.108(2) Å). Cluster 1 is the first example of a homoleptic, cyclopentadienylnickel carbide cluster. Moreover, (13)C-labeling studies proved that the carbido ligand in cluster 1 originated from the Ni-bound methyl group. This transformation requires a triple C-H bond activation in the methyl group, which has not been observed so far for late transition metal compounds.