Gamall Makhloufi

Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure-Activity Relationship Study.

A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 μM, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.

Proton Conduction and Long-Range Ferrimagnetic Ordering in Two Isostructural Copper(II) Mesoxalate Metal–Organic Frameworks

Two compounds of formula {(H3O)[Cu7(Hmesox)5(H2O)7]·9H2O}n (1a) and {(NH4)0.6(H3O)0.4[Cu7(Hmesox)5(H2O)7]·11H2O}n (1b) were prepared and structurally characterized by single-crystal X-ray diffraction (H4mesox = mesoxalic acid, 2-dihydroxymalonic acid). The compounds are crystalline functional metal-organic frameworks exhibiting proton conduction and magnetic ordering. Variable-temperature magnetic susceptibility measurements reveal that the copper(II) ions are strongly ferro- and antiferromagnetically coupled by the alkoxide and carboxylate bridges of the mesoxalate linker to yield long-range magnetic ordering with a Tc of 17.6 K, which is reached by a rare mechanism known as topologic ferrimagnetism. Electric conductivity, measured by impedance methods, shows values as high as 6.5 × 10(-5) S cm(-1) and occurs by proton exchange among the hydronium/ammonium and water molecules of crystallization, which fill the voids left by the three-dimensional copper(II) mesoxalate anionic network.

Cytotoxic 14-Membered Macrolides from a Mangrove-Derived Endophytic Fungus, Pestalotiopsis microspora

Seven new 14-membered macrolides, pestalotioprolides C (2), D-H (4-8), and 7-O-methylnigrosporolide (3), together with four known analogues, pestalotioprolide B (1), seiricuprolide (9), nigrosporolide (10), and 4,7-dihydroxy-13-tetradeca-2,5,8-trienolide (11), were isolated from the mangrove-derived endophytic fungus Pestalotiopsis microspora. Their structures were elucidated by analysis of NMR and MS data and by comparison with literature data. Single-crystal X-ray diffraction analysis was used to confirm the absolute configurations of 1, 2, and 10, while Moshers method and the TDDFT-ECD approach were applied to determine the absolute configurations of 5 and 6. Compounds 3-6 showed significant cytotoxicity against the murine lymphoma cell line L5178Y with IC50 values of 0.7, 5.6, 3.4, and 3.9 μM, respectively, while compound 5 showed potent activity against the human ovarian cancer cell line A2780 with an IC50 value of 1.2 μM. Structure-activity relationships are discussed. Coculture of P. microspora with Streptomyces lividans caused a roughly 10-fold enhanced accumulation of compounds 5 and 6 compared to axenic fungal control.

Solvation-Induced Helicity Inversion of Pseudotetrahedral Chiral Copper(II) Complexes

The helicity of four-coordinated nonplanar complexes is strongly correlated to the chirality of the ligand. However, the stereochemical induction of either the Δ- or the Λ-configuration at the metal ion is also modulated by environmental factors that change the conformational distribution of ligand rotamers. Calculation of the potential energy surface of bis{(R)-N-(1-(4-X-phenyl)ethyl)salicylaldiminato-κ(2)N,O}copper(II) with X = Cl at the density functional theory level showed a clear dependence of the helicity-determining angle θ between the two coordination planes on the relative population of different ligand conformers. The influence of different substituents (X = H, Cl, Br, and OCH3) on complex helicity was studied by determination of the absolute configuration at the metal ion in complexes with either (R)- or (S)-configured ligands. X-ray single-crystal analysis showed that (R)-configured ligands with H, Cl, Br induce Δ, while OCH3-substituted (R)-configured ligands induce Λ in the solid state. According to vibrational circular dichroism and electronic circular dichroism studies in solution, however, all tested complexes with (R)-ligands exhibited a propensity for Δ, with high diastereomeric ratio for X = Cl and X = Br and moderate diastereomeric ratio for X = H and X = OCH3 substituted ligands. Therefore, solvation of copper complexes with X = OCH3 goes along with helicity inversion. This solid-state versus solution study demonstrates that it is not sufficient to determine the chiral-at-metal configuration of a compound by X-ray crystallography alone, because the solution structure can be different. This is particularly important for the use of chiral-at-metal complexes as catalysts in stereoselective synthesis.

A fluorite isoreticular series of porous framework complexes with tetrahedral ligands: new opportunities for azolate PCPs

Three porous coordination polymers with a simplified formula of [M4(μ4-Cl)L2]·nGuest (M = Cu, Cd) based on two adamantane-derived tetrahedral tetrazolate ligands were synthesized. Along with one known representative, the row of compounds establishes a new isoreticular series with fluorite as the underlying net.

Syntheses, structures and properties of group 12 element (Zn, Cd, Hg) coordination polymers with a mixed-functional phosphonate-biphenyl-carboxylate linker

The new phosphonate-carboxylate ligand from 4-phosphono-biphenyl-4′-carboxylic acid (H2O3P–(C6H4)2–CO2H, H3BPPA) is based on the rigid biphenyl system and is studied toward the coordination behavior of group 12 elements zinc, cadmium and mercury. The crystalline products from hydrothermal syntheses highlight the versatile and different coordination modes with the (partially) deprotonated H3BPPA ligand to give coordination polymeric 3D-[Zn5(μ3-OH)4(μ4-O3P–(C6H4)2–CO2-μ2)2]n (5), 2D-[Zn(μ6-O3P–(C6H4)2–CO2H)]n (6), 3D-[Cd3(μ5-O3P–(C6H4)2–CO2-μ2)(μ6-O3P–(C6H4)2–CO2-μ3)]n (7) and 2D-[Hg(μ3-HO3P–(C6H4)2–CO2H)]n (8). The cobalt complex, 2D-[Co(μ4-O3P–(C6H4)2–CO2H)]n (9) is isostructural to 6. Through additional classic strong carbonyl O–H⋯O hydrogen bonding the dimensionality of the 2D coordination networks increases to 3D supramolecular frameworks. The carboxy-phosphonate ligand shows five different coordination modes which can be described as μ4-O3P–CO2-μ2 (5), μ6-O3P– (6), μ5-O3P–CO2-μ2, μ5-O3P–CO2-μ3 (7), and μ3-O3P– (8), that is, the ligand bridges altogether between 3 to 8 metal atoms with the phosphonate group alone connecting already 3 to 6 metal atoms. Layers of metal–oxygen polyhedra are interconnected via the biphenyl linker, which either coordinates metal atoms with both donor groups or the –COOH end forms tail-to-tail hydrogen bonds to create 3D or 2D coordination networks, respectively. In the flat {MOx} layers in 6 and 7 the Zn and Cd metal nodes represent a honeycomb and an mcm net, respectively. The coordination polyhedra of the Cd atoms in compound 7 were analyzed towards a trigonal-prismatic coordination environment. The complexes are hydrolytically very stable due to their hydrothermal preparation from aqueous solution at 180–200 °C. The compounds could be stored in water or air for months without apparent decomposition. Compounds 5 and 7, where the ligand is fully deprotonated, start to decompose at ∼400 °C. The fluorescence emission spectrum of the ligand, 4, shows an intense peak at 365 nm (λex = 316 nm). The fluorescence emission of the metal complexes 5, 7 and 9 is shifted towards larger wavelengths with values of 417 nm, 415 nm and 410 nm, respectively (λex = 354 nm for 5, λex = 350 nm for 7, λex = 400 nm for 8, λex = 360 nm for 9). In addition, the crystal structures of the H3BPPA ligand precursors 4-iodo-4′-biphenylcarboxylic acid methyl ester, and 4-diethylphosphono-4′-biphenylcarboxylic acid methyl ester are described here for the first time.

Induction of new metabolites from the endophytic fungus Bionectria sp. through bacterial co-culture

A new alkaloid, 1,2-dihydrophenopyrrozin (1), along with five known compounds (2-6) was isolated from an axenic culture of the endophytic fungus, Bionectria sp., obtained from seeds of the tropical plant Raphia taedigera. Co-cultivation of this fungus either with Bacillus subtilis or with Streptomyces lividans resulted in the production of two new o-aminobenzoic acid derivatives, bionectriamines A and B (7 and 8) as well as of two additional known compounds (9 and 10). None of the latter compounds (7-10) were detected in axenic cultures of the fungus or of the bacteria indicating activation of silent biogenetic gene clusters through co-cultivation with bacteria. The structures of the new compounds were unambiguously determined based on detailed NMR and MS spectroscopic analysis and by comparison with the literature. The crystal structure of agathic acid (6) is reported here for the first time. Penicolinate A (4) exhibited potent cytotoxic activity against the human ovarian cancer cell line A2780 with an IC50 value of 4.1μM.

The Ugi four-component reaction as a concise modular synthetic tool for photo-induced electron transfer donor-anthraquinone dyads.

Summary Phenothiazinyl and carbazolyl-donor moieties can be covalently coupled to an anthraquinone acceptor unit through an Ugi four-component reaction in a rapid, highly convergent fashion and with moderate to good yields. These novel donor–acceptor dyads are electronically decoupled in the electronic ground state according to UV–vis spectroscopy and cyclic voltammetry. However, in the excited state the inherent donor luminescence is efficiently quenched. Previously performed femtosecond spectroscopic measurements account for a rapid exergonic depopulation of the excited singlet states into a charge-separated state. Calculations of the Gibbs energy of photo-induced electron transfer from readily available UV–vis spectroscopic and cyclovoltammetric data applying the Weller approximation enables a quick evaluation of these novel donor–acceptor dyads. In addition, the X-ray structure of a phenothiazinyl–anthraquinone dyad supports short donor–acceptor distances by an intramolecular π-stacking conformation, an important assumption also implied in the calculations of the Gibbs energies according to the Weller approximation.

De Novo Ring-Forming Consecutive Four-Component Syntheses of 4-Pyrazolyl-1,2,3-triazoles from (Triisopropylsilyl)butadiyne as a C4 Building Block

4-Pyrazolyl-1,2,3-triazoles can be readily synthesized in a one-pot fashion and moderate yield by employing a consecutive four-component process consisting of a sequentially Pd-Cu-catalyzed alkynylation-cyclocondensation-desilylation-CuAAC process. Most distinctly, (triisopropylsilyl)butadiyne is employed as a four-carbon building block in this one-pot de novo formation of both heterocyclic moieties.

Bioactive chemical constituents of Duboscia macrocarpa Bocq., and X-ray diffraction study of 11β, 12β-epoxyfriedours-14-en-3α-ol

A new γ-lactone triterpenoid, Evodoulolide (1) and a new triterpenoid Duboscic acid B (2), along with five known compounds, maslinic acid (3), arboreic acid (4), (E)-3-(4-hydroxyphenyl)-N-[2-(4-hydroxyphenyl) ethyl] prop-2-enamide (5), (E)-heptacos-19-enoic acid (6) and 11β,12β-epoxyfriedours-14-en-3α-ol (7) were isolated from the trunk wood of Duboscia macrocarpa. Their structures were elucidated from extensive 1D- and 2D-NMR and MS and by comparison of their spectra with published data. Compounds 1, 3, 5 and 6 exhibited significant α-glucosidase inhibitory activity. Compound 5 was found to be a potent inhibitor (IC50=5.1±0.1μM) of α-glucosidase as compared to acarbose (IC50=625.0±1μM) used as standard drug. These compounds did not show anti-glycation activity using the BSA-MG glycation model or inhibition against the α-chymotrypsin enzyme. The chemotaxonomic connotation of the isolated secondary metabolites is also herein described. The single-crystal X-ray and absolute configuration diffraction analysis of 11α, 12α-epoxyfriedours-14-en-3-ol (7) is also described here for the first time.