Pyrimidine-based Ligands Research Articles

Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.

Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics, and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here, we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists. Focused structure-activity relationship elucidation and rigidization resulted in a substantially optimized partial RXR agonist with low nanomolar potency, no cytotoxic activity, and very favorable physicochemical properties highlighting this promising scaffold for the development of next-generation RXR targeting drugs.

N^N^C-Cyclometalated rhodium(III) complexes with isomeric pyrimidine-based ligands: unveiling the impact of isomerism on structural motifs, luminescence and cytotoxicity.

The impact of isomerism of pyrimidine-based ligands and their rhodium(III) complexes with regard to their structures and properties was investigated. Two isomeric ligands, 4-(3,5-dimethyl-1H-pyrazol-1-yl)-2,5-diphenylpyrimidine (HL2,5) and 4-(3,5-dimethyl-1H-pyrazol-1-yl)-2,6-diphenylpyrimidine (HL2,6), were synthesized. The ligands differ by the degree of steric bulk: the molecular structure of HL2,5 is more distorted due to presence of pyrazolyl and phenyl groups in the neighbouring positions 4 and 5 of the pyrimidine ring. The complexation of HL2,5 and HL2,6 with RhCl3 leads to the sp2 C-H bond activation, resulting in the isolation of two complexes, [RhL2,5(Solv)Cl2]·nEtOH and [RhL2,6(Solv)Cl2]·nEtOH (Solv = H2O, EtOH), with the deprotonated forms of the pyrazolylpyrimidine molecules which coordinate the Rh3+ ion as N^N^C-tridentate ligands. According to DFT modelling, the mechanism of the deprotonation involves (i) the C-H bond breaking in the 2-phenyl group followed by the coordination of the C atom to the Rh atom, (ii) the protonation of coordinated chlorido ligand, (iii) the ejection of the HCl molecule and (iv) the coordination of the H2O molecule. The ligand isomerism has an impact on emission properties and cytotoxicity of the complexes. Although the excited states of the complexes effectively deactivate through S0/T1 and S0/S1 crossings associated with the cleavage of the weak H2O ligands upon excitation, the [RhL2,5(Solv)Cl2]·nEtOH complex appeared to be emissive in the solid state, while [RhL2,6(Solv)Cl2]·nEtOH is non-emissive at all. The complexes show significant cytotoxic activity against cancerous HepG2 and Hep2 cell lines, with the [RhL2,6(Solv)Cl2]·nEtOH complex being more active than its isomer [RhL2,5(Solv)Cl2]·nEtOH. On the other hand, noticeable cytotoxicity of the latter against HepG2 is supplemented by its non-toxicity against non-cancerous MRC-5 cells.

Exploring structural and optical properties of a new series of soft salts based on cyclometalated platinum complexes.

A series of nine new soft salts based on two platinum(II) complexes, namely ([Pt(C^N)(CN)2]-[Pt(C^N)(en)]+) (en = ethane-1,2-diamine), has been developed and synthesized. Their photophysical properties in both solution and the solid state were described. All soft salt complexes exhibit phosphorescence emission with PLQY in the solid state up to 0.36. Most of these materials displayed aggregation-induced emission (AIE) or aggregation-induced emission enhancement (AIEE) in water/DMSO solutions as the water ratio increased. Structure-property relationships were analyzed in relation to emission properties. The presence of the free nitrogen atoms in soft salt complexes with a C^N pyrimidine-based ligand allowed for reversible sensitivity to acidic vapors, resulting in the quenching of phosphorescence emission. Additionally, for selected soft salts, we described reversible vapochromism behaviour, making these new materials interesting for multi-detection purposes in anti-counterfeiting applications.

A binuclear Cd(II) complex containing bridging pyrimidine-based ligands

AbstractIn this work, a pyrimidine-based ligand,N′-(amino(pyrimidin-2-yl)methylene)pyrimidine-2-carbohydrazonamide hydrate (APPH · H2O), and its binuclear complex of cadmium, [Cd(μ-APPH)Br]2,1, were prepared and identified by elemental analysis, FT-IR,1H NMR spectroscopy as well as single-crystal X-ray diffraction. X-ray structure analysis of1revealed octahedrally coordinated cadmium centers with a CdN4Br2environment containing two bridging APPH ligands; each APPH ligand acts as an N4-donor (N2-donor toward each cadmium atom) and forms two five-membered chelate rings that are approximately perpendicular to each other. In the network of1, the N–H · · · Br hydrogen bonds form motifs such asR22(12, 14), R66(24, 26, …, 46).${\rm{R}}_{\rm{2}}^{\rm{2}}(12,{\rm{ }}14),{\rm{ R}}_{\rm{6}}^{\rm{6}}(24,{\rm{ }}26,{\rm{ }} \ldots ,{\rm{ }}46).$The crystal network is further stabilized by π-π stacking interactions between pyrimidine rings. The optimized structures of the ligand and complex were investigated along with their charge distribution patterns by density functional theory and natural bond orbital analysis, respectively.

A near-infra-red emitting manganese(II) complex with a pyrimidine-based ligand

A polymeric manganese(II) complex, [MnL2Cl2]n (L = 2-amino-4-methylpyrimidine) has been synthesized by the reaction between MnCl2·4H2O and L in the 1:1 and 1:2 metal-to-ligand molar ratios. The Mn2+ ions adopt distorted octahedral environment formed by four Cl− ligands and two N1 atoms of the pyrimidine rings of two L molecules. The chlorido-ligands adopt a μ2-bridging coordination mode linking manganese atoms into the polymeric chain. The free ligand L shows excitation-wavelength-dependent emission originating from the π-π* and n-π* excited states with nanosecond lifetimes in the blue region of the spectrum. The complex [MnL2Cl2]n demonstrates photoluminescence with the maximum in the near-infrared region (λmax = 740 nm, φ = 1.7%) with microsecond lifetimes (τ = 124 μs).

Half Sandwich Rhodium(III) and Iridium(III) Complexes as Cytotoxic and Metallonuclease Agents.

Half sandwich complexes of the type [(η5-C5Me5)M(L1-3)Cl]Cl.2H2O were synthesized using [{(η5-C5Me5)M(μ-Cl)Cl}2], where M = Rh(III)/Ir(III) and L1-3 = pyrimidine-based ligands. The complexes were characterized by spectral analysis. DNA interaction studies by absorption titration and hydrodynamic measurement and suggest intercalative mode of binding of complexes with CT-DNA. The molecular docking study also supports intercalation of the complexes between the stacks of nucleotide base pairs. The gel electrophoresis assay demonstrated the ability of the complexes to interact and cleave plasmid DNA. Minimum inhibitory concentrations (MIC) of the complexes were investigated by the microdilution broth method. The cytotoxic properties of the metal complexes were evaluated using brine shrimp lethality bioassay.

Synthesis, characterization, antimicrobial activity and DFT studies of 2-(pyrimidin-2-ylamino)naphthalene-1,4-dione and its Mn(II), Co(II), Ni(II) and Zn(II) complexes

A pyrimidine-based ligand, 2-(pyrimidin-2-ylamino)naphthalene-1,4-dione (L), has been synthesized by the reaction of 2-aminopyrimidine with 2-hydroxy-1,4-napthoquinone. Reaction of the ligand with Ni(II), Co(II), Mn(II) and Zn(II) acetate gave the corresponding metal complexes which were characterized by spectroscopic techniques, (infrared, electronic), elemental analysis, room-temperature magnetometry, conductance measurements and thermogravimetry-differential scanning calorimetry (TG-DSC) analyses. The room-temperature magnetic data and electronic spectral measurements of the complexes gave evidence of 4-coordinate square planar/tetrahedral geometry. The thermal analyses values obtained indicated the monohydrate complexes. The antimicrobial screening of the compounds showed mild to very good results. The Mn(II) complex showed the best result within in the range of 11.5–29 mm. The electronic, structural and spectroscopic properties of the complexes were further discussed using density functional theory. Molecular docking studies showed significant binding affinity with the drug targets and the metal complexes have potentials to be used as drugs.

Effects of methyl groups in a pyrimidine-based flexible ligand on the formation of silver(i) coordination networks

A methyl substituted pyrimidine-based ligand affords coordination polymers with almost linearly coordinated Ag(i) ions regardless of the silver(i) salt used.

Hysteretic spin crossover in isomeric iron(ii) complexes.

Two mononuclear iron(ii) complexes with isomeric N,N,N-tridentate pyrimidine-based ligands were synthesized. Both complexes show reproducible hysteretic spin crossover. Low spin state to high spin state switching is cooperative due to autocatalysis.

Double Variational Binding--(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands.

Variational quantitative binding–conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process.

Two distinct tetranuclear motifs, rectangular vs. extended, are observed for complexes of a bis-tetradentate pyrimidine-based ligand

The 1 : 2 reactions of 4,6-bis[N,N-bis(2′-pyridylmethyl)aminomethyl]-2-phenylpyrimidine (LMe) and MnII, CoII, NiII and CuII chloride salts in MeOH gave the tetranuclear complexes [MnII4(LMe)2Cl8]·2H2O (1), CoII4(LMe)2Cl8·10H2O (2), [Ni4II(LMe)2Cl4]Cl4·8H2O (3) and [CuII4(LMe)2Cl6]Cl2·8H2O (4), respectively. X-ray crystal structure determinations carried out on three of the complexes revealed that in the case of NiII (3′) the LMe ligand is bound in the expected bis-tetradentate fashion, bridging the encapsulated pair of NiII centers via the pyrimidine ring, and that two pairs of chloride anions bridge a pair of such dimetallic units, affording a closed rectangular tetranuclear core overall. In contrast, in the case of MnII (1′) and CuII (4′) only one binding pocket of the LMe ligand strand binds in the expected tetradentate manner, whilst the other binds in a terdentate manner as one pyrimidine nitrogen atom does not bind, so in these cases the pyrimidine moiety does not bridge the metal centres, resulting instead in ‘extended’, linear tetranuclear assemblies.

Three new pyridine-2,6-dicarboxylate copper(II) compounds with coordinated pyrimidine-based ligands: Synthesis, characterization and crystal structures

Three new Cu(II) compounds of pyridine-2,6-dicarboxylic acid (H2pdc) with substituted pyrimidines as additional ligands have been synthesized and structurally characterized using X-ray diffraction, i.e. [Cu(pdc)(4HOpym)(H2O)2](H2O)2 (1) (4HOpym=4-hydroxypyrimidine), [Cu(pdc)(anpym)(H2O)] (2) (anpym=2-amino-5-nitropyrimidine) and [Cu(pdc)(clnpym)(H2O)](H2O) (3) (clnpym=2-chloro-4-nitropyrimidine). The three compounds are further characterized by IR, EPR and ligand field spectroscopy. The geometry around the Cu(II) ions is distorted octahedral for (1) and distorted square pyramidal for (2) and (3). Inter- and intramolecular hydrogen bondings play an important role in the structure and packing of the compounds.

Modulation of self-assembly and magnetism of Cu(ii) grids in solution

Depending on the Cu(II)/ligand molar ratio, a pyrimidine-based ligand generates a tetranuclear grid (1/1) or a dinuclear stick (2/1). EPR, MS and visible spectroscopy studies suggest that dilution produces partial dissociation of the grid in solution. Replacement of 2-H-pyrimidine by a 2-phenyl-triazine unit prevents the dissociation of the grid. All these factors influence the magnetic properties of the architectures herein involved.

Synthesis, molecular and electronic structures of half-sandwich ruthenium(II) complexes with pyrimidine-based ligands

The complexes [(C6H6)RuCl2(Hmtp)] and [(C6H6)RuCl2(C4H4N2)] have been prepared and studied by IR, 1H NMR, UV–VIS spectroscopy and X-ray crystallography. The complexes were prepared by reactions of [(C6H6)RuCl2]2 with 7-hydroxy-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine (Hmtp) and pyrimidine, respectively, in methanol. The electronic structures and UV–Vis spectra of the complexes have been calculated using the TD–DFT method.

Synthesis and characterization of cyclometalated iridium(III) complexes containing pyrimidine-based ligands

New pyrimidine derivatives ( pyr) have been synthesized using palladium-catalyzed Suzuki coupling reaction. These compounds can undergo cyclometalation with iridium trichloride to form bis-cyclometalated iridium complexes, ( pyr ) 2Ir(acac) (acac = acetylacetonate; pyr = cyclometalated pyr). The substituents at the both cyclometalated phenyl ring and pyrimidine ring were found to affect both electrochemical and photophysical properties of the complexes. Computation results on these complexes are consistent with the electrochemical and photophysical data. The complexes are green-emitting with good solution quantum yields at ∼0.30. Light-emitting devices using these complexes as dopants were fabricated, and the device performance at 100 mA/cm 2 are moderate: 9 (17 481 cd/m 2, 4.8%, 18 cd/A, 5.1 lm/W); 10 (18 704 cd/m 2, 4.9%, 18.9 cd/A, 4.7 lm/W); 13 (20 942 cd/m 2, 5.4%, 21.0 cd/A, 6.1 lm/W).

Supramolecular Co(II)-[2 × 2] Grids: Metamagnetic Behavior in a Single Molecule

The magnetic anisotropy of the supramolecular [2 x 2] grid [Co(II)4L4]8+, with a bis(bipyridyl)-pyrimidine-based ligand L, was investigated by single-crystal magnetization measurements at low temperatures. The magnetization curves exhibit metamagnetic-like behavior and are explained by the weak-exchange limit of a minimal spin Hamiltonian including Heisenberg exchange, easy-axis ligand fields, and the Zeeman term. It is also shown that the magnetic coupling strength can be varied by the substituent R1 in the two-position on the central pyrimidine group of the ligand L.