para metallation of 3-acetyl-chromen-2-one Schiff bases in tetranuclear palladacycles: focus on their biomolecular interaction and in vitro cytotoxicity.

Three tetranuclear (1-3) complexes and a mononuclear (4) palladium(ii) complex were synthesized from 3-acetyl-chromen-2-one Schiff base ligands [H2-3MAC-Rtsc] (where R = H [H2-3MAC-tsc]; CH3[H2-3MAC-mtsc]; C2H5[H2-3MAC-etsc] or C6H5[H2-3MAC-ptsc]) and potassium tetrachloropalladate. Their formation was confirmed by spectroscopic techniques and X-ray crystallographic analysis. Their ability to bind with DNA and albumin was analysed by using absorption and emission titrations. The MTT assay was carried out to analyze the anticancer potential of the ligands and synthesized complexes against HepG2 (human liver cancer) and HT-29 (human colon cancer) cells. In addition, the compounds were less toxic when tested against the human normal keratinocyte cells (HaCaT). Ligands and complexes displayed better cytotoxicity with lower IC50 values than the standard drug cisplatin. Further AO-EB and DAPI staining assays were carried out to detect the mode of cell death induced by the complexes i.e. apoptosis or necrosis. The complex 3 showed better cytotoxicity and was further subjected to flow cytometric analysis. The results suggested that the complex 3 induced apoptotic cell death.

Synthesis and electronic investigation of mono- and di-substituted 4-nitro- and 4-amino-pyrazol-1-yl bis(pyrazol-1-yl)pyridine-type ligands and luminescent Eu(iii) derivatives.

Four new disubstituted and monosubstituted nitro- and amino- bis(pyrazol-1-yl)pyridine (bppy) ligands, substituted at the pyrazole 4-position (1, 2, 5, 6) have been synthesized, along with two luminescent Eu(iii) tris-ß-diketonate derivatives of the amino substituted ligands (7, 8). The compounds have been studied using UV-Vis absorbance spectroscopy and cyclic voltammetry which has allowed for characterization of the electronic environments of these ligands. The calculated HOMO-LUMO gap values (1: 3.54 eV; 2: 3.53 eV; 5: 3.01 eV; 6: 3.66 eV) differ from that of bppy (3.86 eV) and the range is indicative that tuning of the ligand electronic environment is possible. Additionally, fluorescence spectroscopy studies were employed to determine ligand T1 energy levels of the amine-bearing ligands 2 and 6, yielding values of T1 of 25 381 cm-1 and 26 201 cm-1, respectively. These ligands were employed in the synthesis of Eu(iii) complexes 7 and 8, for which the absolute and intrinsic quantum yields, lifetimes and ligand sensitization efficiencies were determined.

Targeting Antioxidant Pathways with Ferrocenylated N-Heterocyclic Carbene Supported Gold(I) Complexes in A549 Lung Cancer Cells.

Ferrocene containing N-heterocyclic carbene (NHC) ligated gold(I) complexes of the type [Au(NHC)2]+ were prepared and found to be capable of regulating the formation of reactive oxygen species (ROS) via multiple mechanisms. Single crystal X-ray analysis of bis(1-(ferrocenylmethyl)-3-mesitylimidazol-2-ylidene)-gold(I) chloride (5) and bis(1,3-di(ferrocenylmethyl)imidazol-2-ylidene)-gold(I) chloride (6) revealed a quasi-liner geometry around the gold(I) centers, (i.e., the C-Au-C bond angle were measured to be ~177° and all the Au-Ccarbene bonds distances were in the range of 2.00 (7) - 2.03 (1) Å). A series of cell studies indicated that cell proliferation inhibition and ROS generation were directly proportional to amount of ferrocene contained within the [Au(NHC)2]+ complexes (IC50 of 6 < 5 < bis(1-benzyl-3-mesitylimidazol-2-ylidene)-gold(I) chloride (4)). Complexes 4-6 were also confirmed to inhibit thioredoxin reductase as inferred from lipoate reduction assays and increase chelatable intracellular zinc concentrations. RNA microarray gene expression assays revealed that 6 induces endoplasmic reticulum stress response pathways as a result of ROS increase.

Room-temperature monoclinic and low-temperature triclinic phase-transition structures of meso-octamethylcalix[4]pyrrole-dimethyl sulfoxide (1/1).

Crystals of the title complex, C28H36N4*C2H6OS, undergo a phase transition between room temperature and 198 K, as determined by X-ray diffraction techniques. A monoclinic form is observed at room temperature, while a triclinic modification is found at 198 K, with Z' changing from 1 to 2. Differential scanning calorimetry (DSC) of the calixpyrrole-dimethyl sulfoxide complex revealed a series of phase changes between 273 and 243 K. The transition from the room-temperature monoclinic form to the low-temperature triclinic form is reversible, as determined by changes in the cell dimensions from remeasuring selected reflections at room temperature and at temperatures below 223 K. The uncomplexed calix[4]pyrrole molecule shows no phase changes occurring between room temperature and 233 K, the low-temperature limit of the DSC.

Synthesis of a metal-free texaphyrin.

The synthesis of a metal-free form of texaphyrin, an aromatic porphyrin-like macrocycle, is described. Previously, texaphyrins could only be obtained reproducibly in the form of metal complexes. Using ferrocenium cation as the oxidizing agent and starting with a reduced porphyrinogen-like nonaromatic form of texaphyrin, we isolated, in good yield, the metal-free oxidized texaphyrin as its HPF(6) salt. This product was characterized by X-ray diffraction analysis, UV-vis spectroscopy, and cyclic voltammetry. [structure: see text]

N-(4-Biphenylyl)urea.

In the crystal structure of the title compound, C13H12N2O, N-H(anti)...O hydrogen bonds produce the so-called urea alpha-network and the N-H(syn) donor forms an unconventional N-H...pi hydrogen bond.

Self-assembled helices from 2,2'-biimidazoles.

2,2'-Biimidazoles were synthesized by palladium(0)-catalyzed coupling of 2-iodoimidazoles bearing an alkyl and an ester group at the 4- and 5-positions, respectively. The products were found to be fluorescent and moderately soluble in organic solvents. Three biimidazoles were subjected to single crystal X-ray diffraction analysis. In all three instances, adjacent molecules were found to be bound together in the solid state by pairs of N-H...N hydrogen bonds, forming twisted ribbon-like columns which resemble double helices. The amount of helical twist observed between neighboring biimidazole subunits in these helices varies with the identity of the alkyl and ester groups; in two cases it is approximately 60 degrees, whereas in the third it is about 90 degrees. Mass spectra of six different biimidazoles display ions with masses corresponding to dimers; this indicates that these compounds retain some affinity for each other in the gas phase. The three most soluble biimidazoles also show mass spectrometric peaks ascribable to trimers and tetramers. The solution-phase aggregation tendencies of these latter three compounds were studied by vapor pressure osmometry. In each case, the apparent molecular weight in 1,2-dichloroethane solution is higher than would be expected for free monomers.

A cascade of reactions involving anchimeric assistance leads to a highly 'crowded' hexa(alkylcarboxy)benzene.

The substitution of hexabromomethylbenzene with 1-adamantyl carboxylate quantitatively leads to the corresponding hexacyl derivative via anchimeric assistance by the alkylcarboxy substituents.

Lithiation of meso-octamethylcalix[4]pyrrole: a general route to C-Rim monosubstituted calix[4]pyrroles.

Lithiation and subsequent addition of an electrophile to meso-octamethylcalix[4]pyrrole provides a straightforward synthetic route to new, C-rim monosubstituted calix[4]pyrroles. A variety of electrophiles were used, resulting in calix[4]pyrroles with appended functional groups including carboxyl, ester, iodo, and formyl. This method was optimized to give maximum yields of the monosubstituted derivatives with lowest possible contamination by di- and trisubstituted congeners. Solid-state studies, performed for a number of these derivatives, showed unexpected supramolecular interactions involving both solvents and the monosubstituted calix[4]pyrrole derivatives themselves.

Spiro[1-azabicyclo[5.3.0]decane-6,2'(5'H)-furan]-5',10-dione: an example of kryptoracemic crystallization.

A racemic mixture of the title compound, C12H15NO3, crystallizes in the chiral, monoclinic space group P2(1), with one enantiomerically related pair of molecules per asymmetric unit. This mode of crystallization is extremely rare. The molecules pack to form several close C-H...O interactions. Interestingly, while the conformations of the individual rings in the two molecules are very similar, the overall molecular conformation is different.

Novel 2- and 5-azido-N-(diphenylcarbamoyl)proline methyl esters. Examples of a novel proline oxidation.

The crystal structures of two azido-substituted proline derivatives are reported. Racemic 2-azido-1-(diphenyl-carbamoyl)proline methyl ester, (I), C19H19N5O3, is resolved upon crystallization from methylene chloride-diethyl ether. The azido moieties are nonlinear with N--N--N angles of 173 (1) and 170.3 (2) degrees for (I) and (II) [cis-5-azido-N-(diphenylcarbamoyl)proline methyl ester, C19H19N5O3], respectively. Close intramolecular contacts between the carbonyl O atom of the amide and the central N atom of the azido group are found. The contact distances between N7 and O14 are 2.780 (14) and 2.815 (2) A for (I) and (II), respectively.

4,7-Dimethoxybenzo[c]furan.

The title compound, C10H10O3, is nearly planar with a maximum deviation from planarity of 0.140 (2) A for methoxy atom C11. The geometry of the benzo[c]furan moiety is indicative of a non-aromatic ring system. The bond lengths more closely resemble those of two non-interacting diene systems than those of an aromatic one. There are alternating long and short bond lengths around the ring skeleton with the long and short C-C bonds averaging 1.437 (2) and 1.354 (2) A, respectively. There are close C-H ... O intermolecular contacts which may help stabilize the molecule in the solid state.

Two [7.3.1]azabicyclo-z-3-ene-1,5-diyne analogues of dynemicin A.

The crystal structures of methyl 6-methoxy-17-oxo-2-azatricyclo[7.7.1.0(3,8)]heptadeca-3(8),4 ,6,13-tetraene- 11,15-diyne-2-carboxylate ethyl acetate solvate, (1), 2C19H15NO4.0.5C4H8O2, and tricyclo[3.3.1.1(3,7)]decyl 6-methoxy-17-oxo-2-azatricyclo[7.7.1.0(3,8)]heptadeca-3(8),4 ,6,13-tetraene- 11,15-diyne-2-carboxylate ethyl acetate solvate, (2), C28H27NO4.0.5C4H8O2, are reported. For compound (1), two crystallographically independent molecules are observed. Interestingly, for both compounds (1) and (2), a molecule of ethyl acetate is found in the crystal lattice disordered about an inversion center. The azabicyclo[7.3.1]enediyne core appears to be fairly rigid. Only minor differences are observed in the ring conformation between the two independent molecules in (1) and between compounds (1) and (2) themselves. The conformation is also similar to that found in deoxydynemicin A [Shiomi, Iinuma, Naganawa, Hamada, Hattori, Nakamura, Takeuchi & Iitaka (1990). J. Antibiot. 43, 1000-1005] and triacetyldynemicin A [Konishi, Ohkuma, Tsuno, Oki, Van Duyne & Clardy (1990). J. Am. Chem. Soc. 112, 3715-3716]. The transannular diyne distance (C3...C8) averages 3.428 (2) A for compound (1) and is 3.403 (3) A for compound (2).

A novel dioxabicyclo[3.3.1]nonane, a key intermediate in the synthesis of erythronolide B seco-acid.

In the title compound, (1R,4S,5R,6R,8R)-1-ethyl-4,6,8-trimethyl-2,9-dioxabicyclo[3.3.1]++ +nonan-6-yl 1-imidazolecarboxylate, C16H24N2O4, the 2,9-dioxabicyclo[3.3.1]nonane ring system assumes a double-chair conformation. Bond angles around the ring are enlarged compared to normal tetrahedral values to alleviate some of the overcrowding which results from close intramolecular H...H and C...C contacts. The N-imidazolylcarbonyloxy group is nearly planar with dihedral angles of 5.2 (2) and 6.0 (2) degrees between the imidazole and carbonyl groups for molecules 1 and 2, respectively.

Structure of a chiral intermediate in the synthesis of (+)-19-epiajmalicine.

[2S*-(2 beta,3 alpha,6 alpha,12b beta)]-Methyl 3-acetyl-1,2,3,4,6,7,12,12b-octahydro-6-methoxycarbonyl-indolo+ ++[2,3-a] quinolizine-3-ethanoate, C22H26N2O5, M(r) = 398.46, orthorhombic, P2(1)2(1)2(1), a = 9.463 (2), b = 11.251 (3), c = 18.871 (6) A, V = 2009.2 (9) A3, Z = 4, Dx = 1.32 g cm-3 (178 K), lambda(Mo K alpha) = 0.7107 A, mu = 0.8762 cm-1, F(000) = 848, T = 178 K, R = 0.0536 for 1673 reflections [Fo > or = 6 sigma (Fo)]. Molecules are hydrogen bonded along the 2(1)-screw axis parallel to a. The hydrogen-bond geometric parameters for N12-H12...O19 (related by 0.5 + x, 1.5 - y, 1 - z) are N...O 2.986 (6), H...O 2.30 (5) A, N-H...O 161 (5) degrees. The C and D rings are trans fused with ring-junction torsion angles of -39.6 (5) and 63.8 (5) degrees for C12a-C12b-N5-C6 and C1-C12b-N5-C4, respectively. The conformation of the C ring is half chair with N5 and C6 -0.168 (4) and 0.552 (5) A, respectively, out of the plane defined by the remaining four atoms of the ring. The D ring is in the chair conformation.

Structure of a tricyclic subunit of manzamine A.

(4a alpha,7a beta,10a beta)-2-Benzyl-1,2,3,4,4a,7,7a,8,9,10-decahydro-8,8- dimethylpyrrolo[2,3-i]isoquinolinium iodide, C20H29N2+.I-, M(r) = 424.37, monoclinic, P2(1)/n, a = 9.441 (4), b = 10.378 (4), c = 20.023 (9) A, beta = 91.56 (3) degrees, V = 1961 (1) A3, Z = 4, Dx = 1.44 g cm-3 (188 K), lambda(Mo K alpha) = 0.7107 A, mu = 16.16 cm-1, F(000) = 864, T = 188 K, R = 0.0288 for 3070 reflections [Fo greater than or equal to 4 sigma(Fo)]. The crystal structure determination was undertaken in order to establish the configuration around C10a. The rings of the isoquinoline group are trans, with the pyrrole moiety cis fused. The A ring is in the chair conformation, while the cyclohexene ring, B, is in the boat conformation owing to the cis fusion of the five-membered pyrrole ring. The pyrrole ring, C, assumes the half-chair conformation. The C-N bonds of the quaternary N atom, N8, are longer than those of the tertiary N atom, N2 [1.517 (2) for N8 and 1.463 (2) A for N2].

Structure of a protected C3-C10 subunit of erythromycin and its C8 epimer.

(1) (2S,3R,4R,6R)-3,4-O-Carbonyl-7,7-dimethylenedithio-2,4,6-trimet hylnonane-1,3,4-triol, C15H26O4S2, M(r) = 334.49, triclinic, P1, a = 6.460 (2), b = 8.917 (3), c = 15.616 (5) A, alpha = 83.60 (3), beta = 83.41 (2), gamma = 89.52 (2) degrees, V = 888.0 (5) A3, Z = 2, Dx = 1.25 g cm-3, mu = 2.980 cm-1, lambda (Mo K alpha) = 0.7107 A, F(000) = 360, T = 298 K, R = 0.0465 for 1832 reflections [Fo greater than or equal to 4 sigma (Fo)]. (2) (2S,3R,4R,6S)-3,4-O-Carbonyl-7,7-dimethylenedithio-2,4,6-trimet hylnonane-1,3,4-triol, C15H26O4S2, M(r) = 334.49, monoclinic, P21, a = 8.1849 (8), b = 8.9456 (14), c = 12.0258 (14) A, beta = 100.878 (8) degrees, V = 864.7 (2) A3, Z = 2, Dx = 1.28 g cm-3, mu = 3.060 cm-1, lambda (Mo K alpha) = 0.7107 A, F(000) = 360, T = 298 K, R = 0.0569 for 2001 reflections [Fo greater than or equal to 4 sigma (Fo)]. The two diastereomers differ in configuration at C6. For (1) there are two unique molecules in the unit cell. These two molecules differ in conformation by a rotation about the bond C7-C8. The molecules are hydrogen bonded into infinite chains along b. The hydroxyl O atom of molecule (2), O10', acts as both a donor and an acceptor in hydrogen-bonding interactions with the carbonyl O atom, O14, and the hydroxyl H atom, H10, of molecule (1).(ABSTRACT TRUNCATED AT 250 WORDS)

Structure of 18'-epivinblastine.

Methyl (3aR-[3a alpha,4 beta,5 beta,5a beta,9(3R*,5S*,7R*,9R*), 10bR,13a alpha])-4-(acetyloxy)-3a-ethyl-9-[5-ethyl-1,4,5,6,7,8,9, 10-octahydro-5-hydroxy-9-(methoxycarbonyl)-2H-3,7- methanoazacycloundecino[5,4-b]indol-9-yl]-3a,4,5,5a,6,11,12, 13a-octahydro-5-hydroxy-8-methoxy-6-methyl-1H-indolizino-[8,1-c,d] carbazole- 5-carboxylate methanol solvate, C46H58N4O9. 2CH3OH (1), Mr = 875.07, monoclinic, P2(1), a = 10.2759 (12), b = 22.353 (3), c = 10.4051 (12) A, beta = 106.502 (9) degrees, V = 2291.6 (5) A3, Z = 2, Dx = 1.27 g cm-3, Mo K alpha radiation, lambda = 0.7107 A, mu = 0.8397 cm-1, F(000) = 940, T = 198 K, R = 0.0470 for 2751 reflections, Fo greater than or equal to 4 sigma(Fo). The C ring of the vindoline moiety is in the boat conformation with the hydroxy group and the tertiary N in the bowsprit positions resulting in a fairly short intramolecular hydrogen-bonding interaction. The relevant parameters for O3--H3...N9 are O...N 2.651 (6), H...N 1.94 (5) A and O--H...N 147 (5) degrees. The D and E rings are in the sofa and envelope conformations, respectively. The piperidine ring of the catharanthine portion of the molecule assumes the chair conformation while the conformation of the azacyclononene ring is a boat-chair. An intramolecular hydrogen bond between the indolino NH of the catharanthine moiety and methoxy O (O25) of the vindoline moiety is also observed. The relevant parameters for N16'--H16'...O25 are N...O 2.827 (6), H...N2.14 (6) A and O--H...N 136 (5) degrees.

The structure at 198 K of (1R,5R,15R,16R)-5-isopropenyl-2-methyl- 1-[N-(trans-2-phenylcyclohexyloxycarbonyl)amino]-2-cyclohexene.

trans-2-Phenylcyclohexyl N-(5-isopropenyl-2-methyl-2-cyclohexan-1-yl) carbamate, C23H31NO2, Mr = 353.50, orthorhombic, P2(1)2(1)2(1), a = 8.813 (2), b = 9.043 (2), c = 25.643 (5) A, V = 2043.6 (8) A3, Z = 4, Dx = 1.15 g cm-3 (198 K), Mo K alpha radiation, lambda = 0.7107 A, mu = 0.6734 cm-1, F(000) = 768, T = 198 K, R = 0.0547 for 1772 reflections [Fo greater than or equal to 4 sigma(Fo)]. Molecules are H-bonded into infinite columns parallel to a. The H bond involves the NH group and the carbonyl O atom of the carbamate moiety with relevant parameters: N11-H11...O13 (related by 1/2 + x, 1/2 - y, - z); N...O 2.910 (5), H...O 2.11 (5) A, N-H...O 159 (4) degrees.