Synthesis and Medicinal Applications of N-Heterocyclic Carbene Complexes based on Caffeine and other Xanthines.

Xanthines are purine derivatives predominantly found in plants. These include compounds such as caffeine, theophylline, and theobromine and exhibit a variety of pharmacological properties, demonstrating efficacy in treating neurodegenerative disorders, respiratory dysfunctions, and also in cancer. The versatile attributes of these materials render them privileged scaffolds for the development of compounds for various biological applications. Xanthines are N-heterocyclic carbene precursors that combine a pyrimidine and an imidazole ring. Owing to their biological relevance, xanthines have been employed as N-heterocyclic carbenes in the development of metallodrugs for anticancer and antimicrobial purposes. In this conceptual review, we examine key examples of N-heterocyclic carbene complexes derived from caffeine and other xanthines, elucidating their synthetic methods and describing their pertinent medicinal applications.

Synthesis, Base Pairing Properties, and Biological Activity Studies of Platinum(II) Complexes Based on Uracil Nucleosides.

The synthesis and base pairing properties of platinum complexes based on uridine and deoxyuridine nucleosides and preliminary studies of their antiproliferative activity are described. Platinum(II) uridine and deoxyuridine complexes were synthesized by C-I oxidative addition to Pt(0)(PPh3)4. First, the synthesis was performed with protected nucleosides to generate complexes 1 and 2, which were deprotected under basic conditions, affording complexes 3 and 4 in good yields. The synthesis with the unprotected nucleosides was also performed and provided complexes 3 and 4 effectively. Base pairing interactions were measured for complex 1, either for self-base pairing or for the Watson-Crick base pair. Complex 1 undergoes self-base pairing in CDCl3, and this aggregation was found not to be dependent on metalation. Contrastingly, for the Watson-Crick base pair with adenine, base pairing was also observed, but metalation was found to affect hydrogen bonding considerably. Complexes 3 and 4 and the corresponding ligand precursors were evaluated for their antiproliferative activity against human glioblastoma cell line U-251. The compounds showed IC50 values of 3.30 (3) and 1.84 (4) µM but are also toxic for nontumorous cell lines.

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine.

Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.

Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis.

The synergistic combinations of drugs are promising strategies to boost the effectiveness of current antifungals and thus prevent the emergence of resistance. In this work, we show that copper and the antifungal fluconazole act synergistically against Candida glabrata, an opportunistic pathogenic yeast intrinsically tolerant to fluconazole. Analyses of the transcriptomic profile of C. glabrata after the combination of copper and fluconazole showed that the expression of the multidrug transporter gene CDR1 was decreased, suggesting that fluconazole efflux could be affected. In agreement, we observed that copper inhibits the transactivation of Pdr1, the transcription regulator of multidrug transporters and leads to the intracellular accumulation of fluconazole. Copper also decreases the transcriptional induction of ergosterol biosynthesis (ERG) genes by fluconazole, which culminates in the accumulation of toxic sterols. Co-treatment of cells with copper and fluconazole should affect the function of proteins located in the plasma membrane, as several ultrastructural alterations, including irregular cell wall and plasma membrane and loss of cell wall integrity, were observed. Finally, we show that the combination of copper and fluconazole downregulates the expression of the gene encoding the zinc-responsive transcription regulator Zap1, which possibly, together with the membrane transporters malfunction, generates zinc depletion. Supplementation with zinc reverts the toxic effect of combining copper with fluconazole, underscoring the importance of this metal in the observed synergistic effect. Overall, this work, while unveiling the molecular basis that supports the use of copper to enhance the effectiveness of fluconazole, paves the way for the development of new metal-based antifungal strategies.

Development of Triazoles and Triazolium Salts Based on AZT and Their Anti-Viral Activity against HIV-1.

We report herein a set of 3'-azido-3'-deoxythymidine (AZT) derivatives based on triazoles and triazolium salts for HIV-1 infection. The compounds were synthesized via click chemistry with Cu(I) and Ru(II) catalysts. Triazolium salts were synthesized by reaction with methyl iodide or methyl triflate in good yields. The antiviral activity of the compounds was tested using two methodologies: In method one the activity was measured on infected cells; in method two a pre-exposure prophylaxis experimental model was employed. For method one the activity of the compounds was moderate, and in general the triazolium salts showed a decreased activity in relation to their triazole precursors. With method two the antiviral activity was higher. All compounds were able to decrease the infection, with two compounds able to clear almost all the infection, while a lower antiviral activity was noted for the triazolium salts. These results suggest that these drugs could play an important role in the development of pre-exposure prophylaxis therapies.

Synthesis of Platinum(II) N-Heterocyclic Carbenes Based on Adenosine.

Organometallic derivatization of nucleosides is a highly promising strategy for the improvement of the therapeutic profile of nucleosides. Herein, a methodology for the synthesis of metalated adenosine with a deprotected ribose moiety is described. Platinum(II) N-heterocyclic carbene complexes based on adenosine were synthesized, namely N-heterocyclic carbenes bearing a protected and unprotected ribose ring. Reaction of the 8-bromo-2',3',5'-tri-O-acetyladenosine with Pt(PPh3)4 by C8-Br oxidative addition yielded complex 1, with a PtII centre bonded to C-8 and an unprotonated N7. Complex 1 reacted at N7 with HBF4 or methyl iodide, yielding protic carbene 2 or methyl carbene 3, respectively. Deprotection of 1 to yield 4 was achieved with NH4OH. Deprotected compound 4 reacted at N7 with HCl solutions to yield protic NHC 5 or with methyl iodide yielding methyl carbene 6. Protic N-heterocyclic carbene 5 is not stable in DMSO solutions leading to the formation of compound 7, in which a bromide was replaced by chloride. The cis-influence of complexes 1-7 was examined by 31P{1H} and 195Pt NMR. Complexes 2, 3, 5, 6 and 7 induce a decrease of 1JPt,P of more than 300 Hz, as result of the higher cis-influence of the N-heterocyclic carbene when compared to the azolato ligand in 1 and 4.

On the reactivity of mRNA Cap0: C-H oxidative addition of 7-methylguanosine to Pt0 and base pairing studies.

7-Methylguanosine, whose lability to form an ylide/NHC has been known for decades, reacts with [Pt(PPh3)4] via C-H oxidative addition to yield a hydrido-PtII carbene complex. 1H NMR studies on Watson-Crick base-pairs showed no significant effect of metallation.

N-Heterocyclic Carbenes Derived from Guanosine: Synthesis and Evidences of Their Antiproliferative Activity.

Palladium(II) and platinum(II) complexes bearing N-heterocyclic carbenes derived from guanosine are synthesized via oxidative addition, followed by protonation in the presence of acid. Cytotoxicity of the compounds is evaluated in several cell lines. Compounds 2a, 2b, and 3a are selective for glioblastoma U251 cells and are nontoxic toward healthy human embryonic kidney (HEK293) cells.

Unveiling the role of ancillary ligands in acceptorless benzyl alcohol dehydrogenation and etherification mediated by mesoionic carbene iridium complexes.

We synthesized a set of triazolylidene iridium(iii) complexes [IrCp*(C^N)L]n+ (Cp* = pentamethylcyclopentadienyl, C^N = C,N-bidentate coordinating pyridyl-triazolylidene) containing different neutral or anionic ancillary ligands L and evaluated their impact on the catalytic activity in alcohol conversion. We demonstrate that these ancillary ligands have a strong influence on the catalytic selectivity and direct whether the iridium center preferentially catalyzes either the dehydrogenation or the dehydration of benzyl alcohol. Ligand exchange experiments provide a direct correlation of ligand lability with catalytic activity and selectivity. These results underline the relevance of ancillary ligands and provide a rational approach to tailor the catalytic activity of the iridium center towards aldehyde formation (loss of H2) or etherification (elimination of H2O).

Ligand exchange and redox processes in iridium triazolylidene complexes relevant to catalytic water oxidation.

Iridium(III) complexes containing a bidentate spectator ligand have emerged as powerful catalyst precursors for water oxidation. Here we investigate the initial steps of the transformation at the iridium center when using complex [IrCp*(pyr-trz)Cl] 1 (Cp* = pentamethylcyclopentadienyl, pyr-trz = 4-(2-pyridyl)-1,2,3-triazol-5-ylidene), a potent water oxidation catalyst precursor. Ligand exchange with water is facile and is reversed in the presence of chloride ions, while MeCN substitution is effective only from the corresponding aqua complex. A pKa of 8.3 for the aqua complex was determined, which is in agreement with strong electron donation from the triazolylidene ligand that is comparable to aryl anions. Evaluation of the pH-dependent oxidation process in aqueous media reveals two regimes (pH 4-8.5 and above pH 10.5) where proton-coupled electron transfer processes occur. These investigations will help to further optimize water oxidation catalysts and indicate that MeCN as a cosolvent has adverse effects for initiating water coordination in the oxidation process.

Iridium complexes containing mesoionic C donors: selective C(sp3)-H versus C(sp2)-H bond activation, reactivity towards acids and bases, and catalytic oxidation of silanes and water.

Metalation of a C2-methylated pyridylimidazolium salt with [IrCp*Cl2]2 affords either an ylidic complex, resulting from C(sp(3))-H bond activation of the C2-bound CH3 group if the metalation is performed in the presence of a base, such as AgO2 or Na2CO3, or a mesoionic complex via cyclometalation and thermally induced heterocyclic C(sp(2))-H bond activation, if the reaction is performed in the absence of a base. Similar cyclometalation and complex formation via C(sp(2))-H bond activation is observed when the heterocyclic ligand precursor consists of the analogous pyridyltriazolium salt, that is, when the metal bonding at the C2 position is blocked by a nitrogen rather than a methyl substituent. Despite the strongly mesoionic character of both the imidazolylidene and the triazolylidene, the former reacts rapidly with D(+) and undergoes isotope exchange at the heterocyclic C5 position, whereas the triazolylidene ligand is stable and only undergoes H/D exchange under basic conditions, where the imidazolylidene is essentially unreactive. The high stability of the Ir-C bond in aqueous solution over a broad pH range was exploited in catalytic water oxidation and silane oxidation. The catalytic hydrosilylation of ketones proceeds with turnover frequencies as high as 6,000 h(-1) with both the imidazolylidene and the triazolylidene system, whereas water oxidation is enhanced by the stronger donor properties of the imidazol-4-ylidene ligands and is more than three times faster than with the triazolylidene analogue.

Carbene transfer from triazolylidene gold complexes as a potent strategy for inducing high catalytic activity.

A series of gold(I) complexes [AuCl(trz)] were synthesized that contain 1,2,3-triazolylidene (trz) ligands with variable wingtip groups. In the presence of AgBF4, these complexes undergo ligand redistribution to yield cationic complexes [Au(trz)2]BF4 in high yields as a result of efficient carbene transfer. Identical reactivity patterns were detected for carbene gold complexes comprised of Arduengo-type IMes ligands (IMes = N,N'-dimesityl-imidazol-2-ylidene). Reaction of cationic complexes [Au(trz)2](+) with [AuCl(trz')] afforded the heteroleptic complex [Au(trz)(trz')](+) and [AuCl(trz)] (trz, trz' = triazolylidene ligands with different wingtip groups). Carbene transfer occurs spontaneously, yet is markeldy rate-enhanced in the presence of Ag(+). The facile carbene transfer was exploited as a catalyst activation process to form active gold species for the aldol condensation of isocyanides and aldehydes to form oxazolines. The catalytic activity is strongly dependent on the presence of Ag(+) ions to initiate catalyst activation. High turnovers (10(5)) and turnover frequencies (10(4) h(-1)) were accomplished. Structural analysis at early stages of the reaction support the critical role of triazolylidene dissociation to activate the precatalyst and dynamic light scattering revealed the presence of nanoparticles (±100 nm diameter) as potential catalytically active species. Furthermore, the triazolylidene scaffold had no impact on the diastereoselectivity of the oxazoline formation, and chiral triazolylidenes did not induce any asymmetry in the product. The facile dissociation of carbenes from [AuCl(carbene)] in the presence of Ag(+) ions suggests a less stable Au-Ccarbene interaction than often assumed, with potential implications for gold-catalyzed reactions that employ a silver salt as (putative) halide scavenger.

Reactivity studies of iridium pyridylidenes [Tp(Me2)Ir(C(6)H(5))(2)(C(CH)(3)C(R)NH] (R=H, Me, Ph).

The reactivity of a series of iridiumpyridylidene complexes with the formula [Tp(Me2) Ir(C6 H5 )2 (C(CH)3 C(R)NH] (1 a-1 c) towards a variety of substrates, from small molecules, such as H2 , O2 , carbon oxides, and formaldehyde, to alkenes and alkynes, is described. Most of the observed reactivity is best explained by invoking 16 e(-) unsaturated [Tp(Me2) Ir(phenyl)(pyridyl)] intermediates, which behave as internal frustrated Lewis pairs (FLPs). H2 is heterolytically split to give hydridepyridylidene complexes, whilst CO, CO2 , and H2 CO provide carbonyl, carbonate, and alkoxide species, respectively. Ethylene and propene form five-membered metallacycles with an IrCH2 CH(R)N (R=H, Me) motif, whereas, in contrast, acetylene affords four-membered iridacycles with the IrC(CH2 )N moiety. C6 H5 (CO)H and C6 H5 CCH react with formation of IrC6 H5 and IrCCPh bonds and the concomitant elimination of a molecule of pyridine and benzene, respectively. Finally the reactivity of compounds 1 a-1 c against O2 is described. Density functional theory calculations that provide theoretical support for these experimental observations are also reported.

Application of 1,2,3-triazolylidenes as versatile NHC-type ligands: synthesis, properties, and application in catalysis and beyond.

Triazolylidenes have rapidly emerged as a powerful subclass of N-heterocyclic carbene ligands for transition metals. They are readily available through regioselective [2 + 3] cycloaddition of alkynes and azides and subsequent metallation according to procedures established for related carbenes. Due to their mesoionic character, triazolylidenes are stronger donors than Arduengo-type imidazol-2-ylidenes. Spurred by these attractive attributes and despite their only recent emergence, triazolylidenes have shown major implications in catalysis. This feature article summarises the synthetic accessibility of triazolylidene metal complexes and their electronic and structural characteristics, and it compiles their applications, in particular, as catalyst precursors for various bond forming and redox reactions, as well as first approaches into photophysical and biochemical domains.

Iridium(III) complexes with polypyridine ligands coordinated as N-heterocyclic carbenes. Synthesis, structure and photophysical properties.

Unsaturated [Tp(Me2)Ir(III)] fragments, readily generated from compounds [Tp(Me2)Ir(C(6)H(5))(2)(N(2))], (1a) and [Tp(Me2)Ir(η(4)-CH(2)=C(Me)C(Me)=CH(2)] (1b) (Tp(Me2) = hydrotris(3,5-dimethylpyrazolyl)borate), induce the isomerisation of the polypyridines, 2,2'-bipyridine, 1,10-phenanthroline and 2,2':6'2''-terpyridine, to form complexes that contain the carbene tautomer of these ligands. For terpy, a binuclear compound has also been isolated, in which this molecule bridges two Ir(III) centres, thanks to its coordination as a bidentate N-heterocyclic carbene. The new compounds have been structurally authenticated by X-ray crystallography and their photophysical properties have been investigated.

Photolytic water oxidation catalyzed by a molecular carbene iridium complex.

The complex IrCl(2)(Cp*)(trz) (trz = triazolylidene), 2, was prepared from readily available 1,3-dimethyl-4-phenyl-1,2,3-triazolium salt. Under basic conditions, the C-bound phenyl group readily cyclometalates, while under acidic conditions, cyclometalation is reversed. The sensitivity of the C(aryl)-Ir bond but not the C(trz)-Ir bond towards acidolysis provided a basis for using 2 as a catalyst in Ce(IV)-mediated water oxidation. The catalytic activity is characterized by a robust catalytic cycle, affording excellent turnover numbers (TON > 20,000). Under cerium-free conditions and in the presence of hematite as a photoelectrode, light-induced activity was observed. The photoelectrochemical reaction is strongly pH-dependent, which requires pH adjustments when running multiple cycle experiments to regenerate the catalytic activity. Analogous chelating complexes display better stability and higher catalytic activity than the monodentate complex 2.

Mesoionic oxides: facile access from triazolium salts or triazolylidene copper precursors, and catalytic relevance.

Reaction of CsOH with triazolium salts affords mesoionic compounds containing an exocyclic oxygen; the same product is obtained by reaction of the corresponding Cu(I) triazolylidenes with CsOH and represents an unusual reactivity pattern of N-heterocyclic carbene precursors that has implications for carbene copper-catalyzed reactions.

Tautomerisation of 2-substituted pyridines to N-heterocyclic carbene ligands induced by the 16†e- unsaturated [Tp(Me2)Ir(III)(C6H5)2] moiety.

The complex [Tp(Me2)Ir(C(6)H(5))(2)(N(2))] reacts with several 2-substituted pyridines to generate N-heterocyclic carbenes resulting from a formal 1,2-hydrogen shift from C(6) to N. In this paper we provide a detailed report of the scope and the mechanistic aspects (both experimental and theoretical) of the tautomerisation of 2-substituted pyridines.