Manuel A. Fernandes

Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis.

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings.

Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance

The HIV protease plays a major role in the life cycle of the virus and has long been a target in antiviral therapy. Resistance of HIV protease to protease inhibitors (PIs) is problematic for the effective treatment of HIV infection. The South African HIV-1 subtype C protease (C-SA PR), which contains eight polymorphisms relative to the consensus HIV-1 subtype B protease, was expressed in Escherichia coli, purified, and crystallized. The crystal structure of the C-SA PR was resolved at 2.7 Å, which is the first crystal structure of a HIV-1 subtype C protease that predominates in Africa. Structural analyses of the C-SA PR in comparison to HIV-1 subtype B proteases indicated that polymorphisms at position 36 of the homodimeric HIV-1 protease may impact on the stability of the hinge region of the protease, and hence the dynamics of the flap region. Molecular dynamics simulations showed that the flap region of the C-SA PR displays a wider range of movements over time as compared to the subtype B proteases. Reduced stability in the hinge region resulting from the absent E35-R57 salt bridge in the C-SA PR, most likely contributes to the increased flexibility of the flaps which may be associated with reduced susceptibility to PIs. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:36

The synthesis of angularly fused polyaromatic compounds by using a light-assisted, base-mediated cyclization reaction.

The synthesis of substituted polyaromatic compounds that contain at least four benzene rings fused together in an angular fashion is described. Suzuki coupling of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde with a number of aromatic boronic acids affords products such as 1-(1,4-dimethoxy-3-methyl-2-naphthyl)-3,4-dihydronaphthalene-2-carbaldehyde. Exposure of these dihydronaphthalenes to potassium tert-butoxide and DMF at 80 degrees C yields polyaromatic compounds such as 9,14-dimethoxynaphtho[1,2-a]anthracene.

CAN-Mediated Oxidations for the Synthesis of Xanthones and Related Products

Reaction of (2,4,5-trimethoxyphenyl)(2-hydroxyphenyl)methanone with ceric ammonium nitrate furnished the xanthone, 2,3-dimethoxy-9H-xanthen-9-one. Under the same conditions the related (1,4-dimethoxynaphthalen-2-yl)(2-hydroxyphenyl)methanone resulted in the formation of 12a-methoxy-5H-benzo[c]xanthenes 5,7(12aH)-dione. Other examples of this novel transformation are also outlined.

Reactions of [Rh(Tp*)(PPh3)2] (Tp* = hydrotris(3,5-dimethylpyrazolyl)-borate) involving fragmentation or loss of Tp*. Structures of [Rh(Cl)2(H)(PPh3)2(pz*)], [(PPh3)2Rh(μ-SC6F5)2Rh (SC6F5)(H)(PPh3)(pz*)] (pz* = 3,5-dimethylpyrazole) and [{Rh(Cl)2(PPh3)2}2Hg]

Abstract The complex [Rh(Tp*)(PPh3)2] reacts with dichloromethane to give [Rh(Cl)(H)2(PPh3)2(pz*)] (1) and [Rh(Cl)2(H)(PPh3)2(pz*)] (2), with C6F5SH to give [(PPh3)2Rh(μ-SC6F5)2Rh(SC6F5)(H)(PPh3)(pz*)] (3) and with HgCl2 to give [{Rh(Cl)2(PPh3)2}2Hg] (4), all under mild conditions. The crystal structures show that 2 has a slightly distorted octahedral geometry, 3 has approximately square planar Rh(I) and octahedral Rh(III) geometries, with an angle of 160.7° between the two RhS2 planes and 4 has rhodium with a square pyramidal geometry where mercury occupies a position at the apex of the pyramid; the Rh–Hg–Rh geometry is linear and, with respect to the Rh–Hg–Rh axis, the ligands (Cl, PPh3) on one rhodium are offset by approximately 42° relative to their counterparts on the second rhodium. In 2 an intramolecular hydrogen bond exists between the pyrazole NH and one of the chloride ligands. Structure 4 is unusual in that it contains an unsupported mercury bridge.

Coordination geometries and crystal structures of cadmium(II) complexes with a new amino alcohol (NN′O) ligand

The new ligand 2-(2-(2-hydroxyethylamino)ethylamino)cyclohexanol, (HEAC), was prepared under microwave conditions through ring opening of cyclohexene oxide with 2-(2-amino-ethylamino)ethanol. Its cadmium(II) complexes [Cd2(HEAC)2(μ-Cl)2Cl2] (1) and [Cd(HEAC)2][CdI4] (2) were identified by elemental analysis, FT-IR, Raman, 1H NMR spectroscopies, and single-crystal X-ray diffraction. HEAC formed 1 : 1 M : L complexes with cadmium chloride and cadmium iodide. Complex 1 crystallized as a dimer with two asymmetrically bound bridging Cl− and a terminally coordinated Cl− on each metal. The geometry around the cadmiums in 1 with four five-membered chelate rings and four Cl− ligands is distorted octahedral for each Cd(II). The cyclohexanol OH of each ligand forms intramolecular hydrogen bonds. In 2, the coordination numbers for cadmium in [Cd(HEAC)2]2+ and [CdI4]2− moieties are six and four, respectively. In [Cd(HEAC)2]2+ each ligand coordinates through two N- and one O-donors, leading to a distorted octahedral geometry. The geometry of [CdI4]2− in 2 is slightly distorted tetrahedral. The protonation equilibrium constants of the two secondary amino groups in HEAC, determined by pH-potentiometry, were 6.26 and 9.26, respectively, at 25°C. Stability constants for this ligand with Ni(II), Cu(II), and Zn(II) (1 : 1 M : L), determined by glass-electrode potentiometry, were 7.13, 10.50, and 5.42, respectively.

Structural and melting point characterisation of six chiral ammonium naphthalene carboxylate salts

The hydrogen bonded networks of ammonium carboxylate salts formed between naphthalene-2-carboxylate or naphthalene-2,6-dicarboxylate with both optically active and racemic forms of 1-phenylethylammonium are reported. In their solid state form, the ammonium carboxylate salts feature three charge-separated N–H⋯O hydrogen bonds to form two types of 1-D hydrogen bonded columns between naphthalene-2-carboxylate: (naphthalene-2-carboxylate)·((R)-1-phenylethylammonium) (1) and ((naphthalene-2-carboxylate)·((S)-1-phenylethylammonium) (2) form non-centrosymmetric hydrogen bonded columns having a two-fold screw axis, while ((naphthalene-2-carboxylate)·((RS)-1-phenylethylammonium) (3) forms centrosymmetric hydrogen bonded columns having an inversion centre. The melting points of these three salts depend on the type of hydrogen bonded network that is formed. By linking the hydrogen bonded columns through the naphthalene-2,6-dicarboxylate anion, (naphthalene-2,6-dicarboxylate)·((R)-1-phenylethylammonium)2 (4), naphthalene-2,6-dicarboxylate)·((S)-1-phenylethylammonium)2 (5) and ((naphthalene-2,6-dicarboxylate)·((RS)-1-phenylethylammonium)2 (6) form closely related 2-D hydrogen bonded sheets that decompose rather than melt.

Disruption of a robust supramolecular heterosynthon in achiral benzylammonium and (pyridylmethyl)ammonium m-iodobenzoate salts

The X-ray crystal structures of five achiral ammonium carboxylate salts are presented: (benzylammonium)·(m-iodobenzoate) (1), ((2-pyridylmethyl)ammonium)·(m-iodobenzoate) (2), ((3-pyridylmethyl)ammonium)·(m-iodobenzoate) (3), (4-pyridylmethyl)ammonium)·(m-iodobenzoate) (4) and (4-pyridylmethyl)ammonium)·(m-iodobenzoate)·(m-iodobenzoic acid) (5). The absence of a chiral ammonium group on the cation disrupts the formation of the well-established type II robust supramolecular heterosynthon in compunds 1 and 3. All five salts have I⋯I halogen bonds and salts 1, 3 and 4 have additional C–H⋯π hydrogen bonds.

Probing the nature of the Co(III) ion in corrins: the structural and electronic properties of dicyano- and aquacyanocobyrinic acid heptamethyl ester and a stable yellow dicyano- and aquacyanocobyrinic acid heptamethyl ester.

A stable yellow derivative of cobyrinic acid heptamethyl ester, (5R,6R)-Coα,Coβ-dicyano-5,6-dihydro-5-hydroxy-heptamethylcob(III)yrinate-c,6-lactone (DCSYCbs), was prepared from dicyanocobyrinic acid heptamethyl ester (DCCbs). The C5 carbon is oxidized and the c side chain cyclized to form a lactone at C6; the 13 atom, 14 π-e(-) delocalized system of corrins is interrupted, giving a triazamethine system with four conjugated double bonds between N22 and N24 and an isolated double bond between N21 and C4. Stable yellow aquacyanocobyrinic acid heptamethyl ester (ACSYCbs) was prepared by driving off HCN with N(2) in a methanol/acetic acid solution. The electronic spectra of DCCbs and DCSYCbs appear similar except that the bands in DCSYCbs are shifted to shorter wavelengths and the γ-band is much less intense. The experimental spectra were adequately modeled using TD-DFT at the PBE1PBE/6-311G(d,p) level of theory. DCSYCbs crystallizes in the space group P2(1)2(1)2(1) (R(1) = 6.08%) with Z = 4, including one methanol solvent molecule and one water molecule per cobester. The addition of a hydroxyl group at C5 causes loss of the double bond between C5 and C6 and elongation of the C5-C6 bond. From a combination of two-dimensional (1)H TOCSY and ROESY NMR spectra and (1)H/(13)C HSQC and HMBC data, the complete (1)H and (13)C NMR assignments of DCSYCbs were possible, except for two of the ester methyl groups and the (13)C resonances of the two axial cyanide ligands. The latter were assigned using relative chemical shifts calculated by GIAO-DFT methods. The (59)Co resonance of DCCbs was observed at 4074 ppm while that of DCSYCbs is shifted downfield to 4298 ppm. Comparison with available (59)Co data of analogous systems suggests that the more π-conjugated corrin of DCCbs interacts more strongly with the metal than the less extensively conjugated macrocycle of DCSYCbs. As the strength of the interaction between Co(III) and an equatorial macrocycle increases, ν(CN) of axially coordinated CN(-) shifts to lower frequency; in DCSYCbs and DCCbs ν(CN) occurs at 2138 and 2123 cm(-1), respectively. Hence the corrin ligand in DCCbs interacts more strongly with the metal than the stable yellow corrin ligand, with its diminished conjugation. The UV-vis spectral data and DFT-calculated MOs are consistent with greater overlap between the corrin and the metal orbitals in DCCbs relative to DCSYCbs, which gives the metal in the former a softer, more covalent character.

Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1.

Cytosolic glutathione transferases (GSTs) are major detoxification enzymes in aerobes. Each subunit has two distinct domains and an active site consisting of a G-site for binding GSH and an H-site for an electrophilic substrate. While the active site is located at the domain interface, the role of the stability of this interface in the catalytic function of GSTs is poorly understood. Domain 1 of class alpha GSTs has a conserved tryptophan (Trp21) in helix 1 that forms a major interdomain contact with helices 6 and 8 in domain 2. Replacing Trp21 with an alanine is structurally non-disruptive but creates a cavity between helices 1, 6 and 8 thus reducing the packing density and van der Waals contacts at the domain interface. This results in destabilization of the protein and a marked reduction in catalytic activity. While functionality at the G-site is not adversely affected by the W21A mutation, the H-site becomes more accessible to solvent and less favorable for the electrophilic substrate 1-chloro-2,4-dinitrobenzene (CDNB). Not only does the mutation result in a reduction in the energy for stabilizing the transition state formed in the S(N)Ar reaction between the substrates GSH and CDNB, it also compromises the ability of the enzyme to form and stabilize a transition state analogue (Meisenheimer complex) formed between GSH and 1,3,5-trinitrobenzene (TNB). The study demonstrates that the stability of the domain-domain interface plays a role in mediating the catalytic functionality of the active site, particularly the H-site, of class alpha GSTs.