Chains or rings? Polymorphism of an isoniazid derivative derivatized with diacetone alcohol.

Isoniazid was derivated with diacetone alcohol in a Schiff-base reaction in order to yield N'-[(2E)-4-hydroxy-4-methylpentan-2-ylidene]pyridine-4-carbohydrazide. The resulting product was determined to be polymorphic, exhibiting two crystal forms: form I and form II. From the crystal structure determination using SC-XRD it was determined that form I crystalizes in the C2/c space group while form II crystalizes in the P21/c space group. The hydrogen bonding patterns of both forms are distinctively different from each other: form I forms a chain hydrogen bond motif by forming a hydrogen bond between the hydroxyl group and the oxygen of the amide group while form II forms dimers with a ring hydrogen bond motif forming between the hydroxyl group and the pyridine group. From DSC analysis form I and form II are enantiotropically related, with form I converting to form II at 132.3 °C before melting at 142.3 °C. Based on both experimental and computational evidence, we conclude that form I is a metastable form, with form II being the most stable form. This is another case of a "disappearing polymorph."

Synthesis of 6-Membered-Ring Fused Thiazine-Dicarboxylates and Thiazole-Pyrimidines via One-Pot Three-Component Reactions.

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76-85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70-91%.

Total synthesis of ent-pavettamine.

Pavettamine, a plant toxin first isolated from Pavetta harborii in 1995, was previously identified as a polyamine with C 2 symmetry and a 1,3-syn-diol moiety on a C10 carbon backbone - one of very few substituted polyamines to be isolated from nature. Its absolute configuration was later established by our first reported total synthesis in 2010. Herein we report the first total synthesis of the enantiomer of pavettamine, ent-pavettamine. The symmetrical structure of the molecule allows for the synthesis of a common C5 fragment that can be divergently transformed into two synthons for later convergent coupling to furnish the target carbon framework. Based on the success of the protocol we employed for the synthesis of the naturally occurring pavettamine, (S)-malic acid was again the starting material of choice for the synthesis of the two individual C5 fragments, with strategic differences in terminal-group manipulation allowing for the synthesis of ent-pavettamine rather than pavettamine. Chain extension and stereoselective ketone reduction were achieved using the (R)-methyl p-tolyl sulfoxide chiral auxiliary to give the desired 1,3-syn-diol C5 unit. A protecting-group strategy was also developed for the orthogonal protection of the alcohol and amine functional groups as they were unveiled. The functionalized C5 fragments were coupled via reductive amination revealing the C10 carbon backbone. Deprotection of the alcohol and amine functional groups successfully provided ent-pavettamine as a TFA salt.

A Cytotoxic Bis(1,2,3-triazol-5-ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation.

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI -CNC pincer complex suitable for oxidation to the redox-stable [AuIII (CNC)Cl]+ cation. Although the ligand salt and the [AuIII (CNC)Cl]+ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII (CNC)Cl]+ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII (CNC)Cl]+ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.

Catalyst-free synthesis of novel 1,5-benzodiazepines and 3,4-dihydroquinoxalines using isocyanide-based one-pot, three- and four-component reactions.

Reaction of benzimidazolone derivatives, or their thio- or aza-counterparts, with an isocyanide in the presence of acetone unexpectedly gave rise to novel tricyclic benzodiazepine derivatives in good yield by means of a four-component reaction incorporating two moles of acetone. Benzimidazole starting substrates bearing an electron-withdrawing group gave rise instead to dihydroquinoxaline derivatives by means of a three-component reaction. Use of deuterated acetone instead of acetone in the reactions significantly affected yield and reactivity in the four-component reaction but not in the three-component reaction.

Synthesis and Photophysical Properties of T-Shaped Coinage-Metal Complexes.

The photophysical properties of a series of T-shaped coinage d10 metal complexes, supported by a bis(mesoionic carbene)carbazolide (CNC) pincer ligand, are explored. The series includes a rare new example of a tridentate T-shaped AgI complex. Post-complexation modification of the AuI complex provides access to a linear cationic AuI complex following ligand alkylation, or the first example of a cationic square planar AuIII -F complex from electrophilic attack on the metal centre. Emissions ranging from blue (CuI ) to orange (AgI ) are obtained, with variable contributions of thermally-dependent fluorescence and phosphorescence to the observed photoluminescence. Green emissions are observed for all three gold complexes (neutral T-shaped AuI , cationic linear AuI and square planar cationic AuIII ). The higher quantum yield and longer decay lifetime of the linear gold(I) complex are indicative of increased phosphorescence contribution.

Fischer Carbene Complexes of Iridium(I) for Application in Catalytic Transfer Hydrogenation.

New examples of the very rare class of iridium(I) Fischer carbene complexes (FCCs) are reported from the facile transmetalation from group 6 FCCs. Postcomplexation modification of either the carbene ligand or the ancillary coligands results in a tunable IrI metal center, for unprecedented application as a (pre)catalyst in a benchmark transfer hydrogenation reaction. The introduction of an aminocarbene ligand with a pendant N-donor moiety capable of hemilabile coordination yielded the best catalytic results with turnover frequencies reaching 445 h-1 and requiring 0.1 mol % catalyst and 0.5 mol % base loading, respectively.

Efficient one-pot synthesis of functionalised imidazo[1,2-a]pyridines and unexpected synthesis of novel tetracyclic derivatives by nucleophilic aromatic substitution.

Novel tetracyclic imidazo[1,2-a]pyridine derivatives have been prepared by intramolecular nucleophilic aromatic substitution of 5-fluoroimidazo[1,2-a]pyridines under basic conditions. Use of the non-nucleophilic alcoholic solvent tert-butanol, rather than methanol, increased the yield of the tetracycles by reducing the competing intermolecular reaction observed for methanol. In addition, a modified protocol for the dehydration of formamides to isocyanides has been found to be tolerant of an unprotected hydroxyl functional group and one-pot conversion to imidazo[1,2-a]pyridyl-aminocyclohexanol analogues is reported.

V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity.

Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens.

Synthesis of heterobimetallic gold(i) ferrocenyl-substituted 1,2,3-triazol-5-ylidene complexes as potential anticancer agents.

1,2,3-Triazol-5-ylidene (trz) complexes of gold(i) containing a ferrocenyl substituent on the C4-position of the trz ring were synthesized to yield the neutral heterobimetallic gold(i) trz chlorido (2), gold(i) trz phenyl (3), and the cationic gold(i) trz triphenylphospine (5) complexes. In order to compare the effect of silver(i) as central metal vs. gold(i), [Ag(trz)2]+ (4) was also prepared, while variation of the C4-1,2,3-triazol-5-ylidene substituent from a ferrocenyl to a phenyl group was done to prepare the monometallic analogue of 5, namely the cationic Au(i) trz triphenylphosphine complex 6. The complexes were characterised with spectroscopic and electrochemical methods, and the single crystal X-ray structures of 2-6 were determined. NMR stability studies of 5 as a representative example of the series of complexes were performed to confirm the stability of the complexes in the solvent dimethylsulfoxide and in aqueous solution. The anti-cancer potential of 5 was evaluated against the lung cancer cell lines A549 and H1975, and the human embryonic kidney cell line (HEK-293) was used as a non-cancer model. IC50 values of 0.89, 0.23 and 5.43 µM, respectively, were obtained for A549, H1975 and HEK-293, respectively, indicating the activity and selectivity of 5 for cancer cells. Fluorescence microscopy experiments as a preliminary mode-of-action study evidenced an apoptotic cell death mechanism rather than necrotic cell death.

Alginate microbead-encapsulated silver complexes for selective delivery of broad-spectrum silver-based microbicides.

In sub-Saharan Africa, human immunodeficiency virus (HIV) infections are predominantly acquired via heterosexual contact, and women are at greatest risk of being infected. This region also has the highest rates of sexually transmitted infections (STIs) per capita worldwide; STIs are strongly associated with increased HIV transmission. Therefore, there is an urgent requirement for microbicides that are active against HIV and STIs. Silver compounds exhibit broad antimicrobial activity, making them potentially ideal broad-spectrum microbicides. However, for silver compounds to be effective microbicides, they must be active within seminal fluid and the delivery vehicle used must protect the silver microbicide from vaginal fluid components but selectively release it during intercourse and/or following ejaculation. In this study, silver complexes were synthesised from the ligands saccharin, benzimidazole and 8-hydroxyquinoline and their microbicidal activity was assessed. We show that a silver saccharinate-benzimidazole complex (AgSB) exhibited activity against HIV-1, herpes simplex virus type 2 (HSV-2) and Neisseria gonorrhoeae at concentrations significantly below LD(50) levels for the vaginal mucosal cell line SiHa. Furthermore, we show that alginate microbeads are stable in vaginal fluid simulant but rapidly dissolve in seminal fluid simulant. Finally, we have established that microbead-encapsulated AgSB, dissolved in seminal fluid simulant, is active against the above pathogens, albeit at higher concentrations for HIV-1. This research therefore highlights, for the first time, the potential use of silver complexes encapsulated in alginate microbeads as a novel system for the delivery and selective release of broad-spectrum silver-based microbicides within the vaginal milieu during sexual intercourse/after ejaculation.

Crystal structures of 2,2'-bipyridin-1-ium 1,1,3,3-tetracyano-2-ethoxyprop-2-en-1-ide and bis(2,2'-bipyridin-1-ium) 1,1,3,3-tetracyano-2-(dicyanomethylene)propane-1,3-diide.

In 2,2'-bipyridin-1-ium 1,1,3,3-tetra-cyano-2-eth-oxy-prop-2-en-1-ide, C10H9N2 (+)·C9H5N4O(-), (I), the ethyl group in the anion is disordered over two sets of atomic sites with occupancies 0.634 (9) and 0.366 (9), and the dihedral angle between the ring planes in the cation is 2.11 (7)°. The two independent C(CN)2 groups in the anion make dihedral angles of 10.60 (6) and 12.44 (4)° with the central propenide unit, and the bond distances in the anion provide evidence for extensive electronic delocalization. In bis-(2,2'-bipyridin-1-ium) 1,1,3,3-tetra-cyano-2-(di-cyano-methyl-ene)propane-1,3-diide [alternative name bis-(2,2'-bipyridin-1-ium) tris-(di-cyano-methyl-ene)methane-diide], 2C10H9N2 (+)·C10N6 (2-) (II), the dihedral angles between the ring planes in the two independent cations are 7.7 (2) and 10.92 (17)°. The anion exhibits approximate C 3 symmetry, consistent with extensive electronic delocalization, and the three independent C(CN)2 groups make dihedral angles of 23.8 (2), 27.0 (3) and 27.4 (2)° with the central plane. The ions in (I) are linked by an N-H⋯N hydrogen bond and the resulting ion pairs are linked by two independent C-H⋯N hydrogen bonds, forming a ribbon containing alternating R 4 (4)(18) and R 4 (4)(26) rings, where both ring types are centrosymmetric. The ions in (II) are linked by two independent N-H⋯N hydrogen bonds and the resulting ion triplets are linked by a C-H⋯N hydrogen bond, forming a C 2 (1)(7) chain containing anions and only one type of cation, with the other cation linked to the chain by a further C-H⋯N hydrogen bond.

Di-chlorido-dimethyl-bis-(thio-urea-κS)tin(IV).

The title compound, [Sn(CH3)2Cl2(CH4N2S)2], crystallizes with two half-mol-ecules in the asymmetric unit. Both mol-ecules are completed by inversion symmetry with the two Sn(IV) atoms located on inversion centers. The metal atoms have distorted octa-hedral coordination environments defined by two Cl atoms, two C atoms of methyl groups and two thio-urea S atoms. In the crystal, mol-ecules are linked via N-H⋯Cl and N-H⋯S hydrogen bonds, forming a three-dimensional structure.

The synthesis of a corrole analogue of aquacobalamin (vitamin B12a) and its ligand substitution reactions.

The synthesis of a Co(III) corrole, [10-(2-[[4-(1H-imidazol-1-ylmethyl)benzoyl]amino]phenyl)-5,15-diphenylcorrolato]cobalt(III), DPTC-Co, bearing a tail motif terminating in an imidazole ligand that coordinates Co(III), is described. The corrole therefore places Co(III) in a similar environment to that in aquacobalamin (vitamin B12a, H2OCbl(+)) but with a different equatorial ligand. In coordinating solvents, DPTC-Co is a mixture of five- and six-coordinate species, with a solvent molecule occupying the axial coordination site trans to the proximal imidazole ligand. In an 80:20 MeOH/H2O solution, allowed to age for about 1 h, the predominant species is the six-coordinate aqua species [H2O-DPTC-Co]. It is monomeric at least up to concentrations of 60 µM. The coordinated H2O has a pKa = 9.76(6). Under the same conditions H2OCbl(+) has a pKa = 7.40(2). Equilibrium constants for the substitution of coordinated H2O by exogenous ligands are reported as log K values for neutral N-, P-, and S-donor ligands, and CN(-), NO2(-), N3(-), SCN(-), I(-), and Cys in 80:20 MeOH/H2O solution at low ionic strength. The log K values for [H2O-DPTC-Co] correlate reasonably well with those for H2OCbl(+); therefore, Co(III) displays a similar behavior toward these ligands irrespective of whether the equatorial ligand is a corrole or a corrin. Pyridine is an exception; it is poorly coordinated by H2OCbl(+) because of the sterically hindered coordination site of the corrin. With few exceptions, [H2O-DPTC-Co] has a higher affinity for neutral ligands than H2OCbl(+), but the converse is true for anionic ligands. Density functional theory (DFT) models (BP86/TZVP) show that the Co-ligand bonds tend to be longer in corrin than in corrole complexes, explaining the higher affinity of the latter for neutral ligands. It is argued that the residual charge at the metal center (+2 in corrin, 0 in corrole) increases the affinity of H2OCbl(+) for anionic ligands through an electrostatic attraction. The topological properties of the electron density in the DFT-modeled compounds are used to explore the nature of the bonding between the metal and the ligands.

Outer-sphere anion recognition by a cyclen-based octadentate europium(III) complex: pH dependent recognition of ortho-phthalic acid.

An octadentate cyclen-based europium complex with amidic and hydroxyalkyl pendent moieties exhibits pH dependent ligand denticity associated with anion recognition. Unusually high hydration numbers are determined for ortho-phthalate ternary outer-sphere complexes for which modulation of lanthanide-based luminescence is observed.

Formation of isostructural solid solutions in 2,6-disubstituted N-phenylformamides and N-phenylthioamides.

In order to investigate possible isostructural solid solutions of disubstituted N-phenylformamides and thioamides, we have studied the re-crystallization of pairs of compounds selected from 2,6-difluoro-N-phenylformamide (I), 2,6-dichloro-N-phenylformamide (II), 2,6-dimethyl-N-phenylformamide (III), 2,6-dichloro-N-phenylthioamide (IV), 2,6-dimethyl-N-phenylthioamide (V), 2,6-diisopropyl-N-phenylformamide (VI) and 2,6-diisopropyl-N-phenylthioamide (VII). For single-component 2,6-disubstituted-N-phenylformamides only the trans form occurs in the pure crystal, while for thioamides the cis form occurs, with only one exception. By forming solid solutions of pairs of these molecules the resulting structures all adopt similar N-H...O/S chains in the crystals. Solid solutions (1), (2) and (3), resulting from the mixing of (I) and (II), (II) and (III), and (IV) and (V), respectively, are all isostructural with each other (space group Pbca). Only co-crystal (1) is isostructural to both starting materials, while (2) is isostructural to only one of the starting pair, (II). Solid solution (3), which adopts the same Pbca structure as (1) and (2), is different to the monoclinic structures of both the reactants. Solid solution (4) is monoclinic, with similar hydrogen-bonded chains, and isostructural to the two components, resulting from the composition from the mixing of (VI) and (VII). Isostructural indices were used to quantify crystal-packing similarities and differences. Occupancy factors of the reactants in each co-crystal differ widely.

Phenylvinylcobalamin: an alkenylcobalamin featuring a ligand with a large trans influence.

Cob(I)alamin reacts with phenylacetylene to produce two diastereomers in which the organic ligand is coordinated to the upper (ß) and lower (α) face of the corrin ring, respectively. The isomers were separated chromatographically and characterised by ESI-MS and, in the case of the ß isomer, by (1)H and (13)C NMR. Only the ß isomer crystallised and its molecular structure, determined by X-ray diffraction, shows that the organic ligand coordinates Co(III) through the ß carbon of the phenylvinyl ligand. The Co-C bond length is 2.004(8) Å while the Co-N bond length to the trans 5,6-dimethylbenzimidazole (dmbzm) base is 2.217(8) Å, one of the longest Co-Ndmbzm bond lengths known in an organocobalamin. Unlike benzylcobalamin (BzCbl), phenylvinylcobalamin (PhVnCbl) is stable towards homolysis. DFT calculations (BP86/TZVP) on model compounds of BzCbl and PhVnCbl show that the Co-C bond dissociation energy for homolysis to Co(II) and an organic radical in the former is 8 kcal mol(-1) lower than in the latter. An analysis of the electron density at the Co-C bond critical point using Bader's QTAIM approach shows that the Co-C bond in PhVnCbl is shorter, stronger and somewhat more covalent than that in BzCbl, and has some multiple bond character. Together with calculations that show that the benzyl radical is more stable than the phenylvinyl radical, this rationalises the stability of PhVnCbl compared to BzCbl. The phenylvinyl ligand has a large trans influence. The pKa for deprotonation of dmbzm and its coordination by the metal in ß-PhVnCbl is 4.60 ± 0.01, one of the highest values reported to date in cobalamin chemistry. The displacement of dmbzm ligand by CN(-) in ß-PhVnCbl occurs with log K = 0.7 ± 0.1; the trans influence order of C-donor ligands is therefore CN(-) < CCH < CHCH2 = PhVn < Me < Et.

3-Methyl-1-tosyl-1H-indole-2-carbaldehyde.

The title indole derivative, C(17)H(15)NO(3)S, crystallizes with two independent mol-ecules in the asymmetric unit. The benzene ring of the tosyl group is almost perpedicular to the indole ring in both mol-ecules, with inter-planar angles of 82.60 (5)° and 81.82 (6)°. The two mol-ecules are, as a consequence, able to form an almost centrosymmetric non-bonded dimer, in which the molecules are linked by pairs of C-H⋯π inter-actions. The crystal structure displays a three-dimensional network of C-H⋯O inter-actions. A π-π inter-action occurs between inversion-related indole rings with a centroid-centroid distance of 3.6774 (16) Šand an inter-planar angle of 1.53 (15)°. This inter-action leads to a stacking of mol-ecules along the a axis.

Tungsten-183 NMR study of cis-[W(CO)4(PPh3)(4-RC5H4N)]; effect of varying the σ donor strength of the pyridine.

Tungsten-183 NMR data are reported for the complexes cis-[W(CO)4(PPh3)(4-RC5H4N)] (R = H, Me, Ph, COMe, COPh, OMe, NMe2, Cl, NO2). The (183)W chemical shift (obtained by indirect detection using (31)P) is found to correlate with the Hammett σ function for the group R, with (183)W shielding increasing approximately linearly with the donor strength of the pyridine over a range of 93 ppm. The X-ray structures of cis-[W(CO)4(PPh3)(4-MeOC5H4N)] and cis-[W(CO)4(PPh3)(4-PhCOC5H4N)] are also reported.