3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists

The integrin VLA-4 (41) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R² _CVof 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.     

Some aspects of the polymerization of n-butyl vinyl ether by chromyl chloride

The rate of n-butyl vinyl ether polymerization by chromyl chloride is first order in [catalyst] and second order in [monomer]. Added H₂O (after a certain concentration) and HCl increase the rate, thiophene retards the rate, while pyridine inhibits the rate. DP is independent of [chromyl chloride] and increases with increasing [monomer] up to 1M, thereafter becoming independent of it. Both rate and DP increase over the range 10?32°C and decrease at higher temperatures.     

Collisional quenching of electronically excited germanium atoms, Ge[4p(S0)], by small molecules investigated by time-resolved atomic resonance absorption spectroscopy

The collisional quenching of electronically excited germanium atoms, Ge[4p²(¹S₀)], 2.029 eV above the 4p²(³P₀) ground state, has been investigated by time-resolved atomic resonance absorption spectroscopy in the ultraviolet at λ = 274.04 nm [4d(¹P₁⁰) ← 4p²(¹S₀)]. In contrast to previous investigations using the ‘single-shot mode’ at high energy, Ge(¹S₀) has been generated by the repetitive pulsed irradiation of Ge(CH₃)₄ in the presence of excess helium gas and added gases in a slow flow system, kinetically equivalent to a static system. This technique was originally developed for the study of Ge[4p²(¹D₂)] which had eluded direct quantitative kinetic study until recently. Absolute second-order rate constants obtained using signal averaging techniques from data capture of total digitised atomic decay profiles are reported for the removal of Ge(¹S₀) with the following gases (k_R in cm³ molecule⁻¹ s⁻¹, 300 K): Xe, 7.1 ± 0.4 × 10⁻¹³; N₂, 4.7 ± 0.6 × 10⁻¹²; O₂, 3.6 ± 0.9 × 10⁻¹¹; NO, 1.5 ± 0.3 × 10⁻¹¹; CO, 3.4 ± 0.5 × 10⁻¹²; N₂O, 4.5 ± 0.5 × 10⁻¹²; CO₂, 1.1 ± 0.3 × 10⁻¹¹; CH₄, 1.7 ± 0.2 × 10⁻¹¹; CF₄, 4.8 ± 0.3 × 10⁻¹²; SF₆, 9.5 ± 1.0 × 10⁻¹³; C₂H₄, 3.3 ± 0.1 × 10⁻¹⁰; C₂H₂, 2.9 ± 0.2 × 10⁻¹⁰; Ge(CH₃)₄, 5.4 ± 0.2 × 10⁻¹¹. The results are compared with previous data for Ge(¹S₀) derived in the single-shot mode where there is general agreement though with some exceptions which are discussed. The present data are also compared with analogous quenching rate data for the collisional removal of the lower lying Ge[4p²(¹D₂)] state (0.883 eV), also characterized by signal averaging methods similar to that described here.     

New insight into the substituent effects on the hydrolytic deamination of saturated and unsaturated cytosine

Ab initio calculations were carried out to understand the effect of electron donating groups (EDG) and electron withdrawing groups (EWG) at the C5 position of cytosine (Cyt) and saturated cytosine (H₂Cyt) of the deamination reaction. Geometries of the reactants, transition states, intermediates, and products were fully optimized at the B3LYP/6-31G(d,p) level in the gas phase as this level of theory has been found to agree very well with G3 theories. Activation energies, enthalpies, and Gibbs energies of activation along with the thermodynamic properties (ΔE, ΔH, and ΔG) of each reaction were calculated. A plot of the Gibbs energies of activation (ΔG^‡) for C5 substituted Cyt and H₂Cyt against the Hammett σ-constants reveal a good linear relationship. In general, both EDG and EWG substituents at the C5 position in Cyt results in higher ΔG^‡ and lower σ values compared to those of H₂Cyt deamination reactions. C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) increase ΔG^‡ values for Cyt, while the same substituents decrease ΔG^‡ values for H₂Cyt which is likely due to steric effects. However, the Hammett σ-constants were found to decrease at the C5 position of cytosine (Cyt) and saturated cytosine (H2Cyt) on the deamination reaction. Both ΔG^‡ and σ values decrease for the substituents Cl and Br in the Cyt reaction, while ΔG^‡ values increase and σ decrease in the H₂Cyt reaction. This may be due to high polarizability of bromine which results in a greater stabilization of the transition state in the case of bromine compared to chlorine. Regardless of the substituent at C5, the positive charge on C4 is greater in the TS compared to the reactant complex for both the Cyt and H₂Cyt. Moreover, as the charges on C4 in the TS increase compared to reactant, ΔG^‡ also increase for the C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) in Cyt, while ΔG^‡ decrease in H₂Cyt. In addition, analysis of the frontier MO energies for the transition state structures shows that there is a correlation between the energy of the HOMO–LUMO gap and activation energies.     

Reactions of rhenium and manganese carbonyl complexes with 1,8-bis(diphenylphosphino)naphthalene: Ligand chelation, C-H and C-P bond-cleavage reactions

Reaction of [Re₂(CO)₈(MeCN)₂] with 1,8-bis(diphenylphosphino)naphthalene (dppn) afforded three mono-rhenium complexes fac-[Re(CO)₃(κ¹:η¹-PPh₂C₁₀H₆)(PPh₂H)] (1), fac-[Re(CO)₃{κ¹:κ¹:η¹-(O)PPh₂C₁₀H₆(O)PPh(C₆H₄)}] (2) and fac-[ReCl(CO)₃(κ²-PPh₂C₁₀H₆PPh₂)] (3). Compounds 1-3 are formed by Re-Re bond cleavage and P-C and C-H bond activation of the dppn ligand. Each of these three complexes have three CO groups arranged in facial fashion. Compound 1 contains a chelating cyclometalated diphenylnaphthylphosphine ligand and a terminally coordinated PPh₂H ligand. Compound 2 consists of an orthometalated dppn-dioxide ligand coordinated in a κ¹:κ¹:η¹-fashion via both the oxygen atoms and ortho-carbon atom of one of the phenyl rings. Compound 3 consists of an unchanged chelating dppn ligand and a terminal Cl ligand. Treatment of [Mn₂(CO)₈(MeCN)₂] with a slight excess of dppn in refluxing toluene at 72 °C, gave the previously reported [Mn₂(CO)₈(μ-PPh₂)₂] (4), formed by cleavage of C-P bonds, and the new compound fac-[MnCl(CO)₃(κ²-PPh₂C₁₀H₆PPh₂)] (5), which has an unaltered chelating dppn and a terminal Cl ligand. In sharp contrast, reaction of [Mn₂(CO)₈(MeCN)₂] with slight excess of dppn at room temperature yielded the dimanganese [Mn₂(CO)₉{κ¹-PPh₂(C₁₀H₇)}] (6) in which the diphenylnaphthylphosphine ligand, formed by facile cleavage of one of the P-C bonds, is axially coordinated to one Mn atom. Compound 6 was also obtained from the reaction of [Mn₂(CO)₉(MeCN)] with dppn at room temperature. The XRD structures of complexes 1-3, 5, 6 are reported.     

Dirhenium carbonyl complexes bearing 2-vinylpyridine,morpholine and 1-methylimidazole ligands

Treatment of the labile compound [Re₂(CO)₈(MeCN)₂] with 2-vinylpyridine in refluxing benzene affords exclusively the new compound [Re₂(CO)₈(μ-η¹:η²-NC₅H₄CHCH₂)] (1) in 39% yield in which the μ-η¹:η²-vinylpyridine ligand is coordinated to one Re atom through the nitrogen and to the other Re atom via the olefinic double bond. Reaction of [Re₂(CO)₈(MeCN)₂] with morpholine in refluxing benzene furnishes two compounds, [Re₂(CO)₉(η¹-NC₄H₉O)] (2) and [Re₂(CO)₈(η¹-NC₄H₉O)₂] (3) in 5% and 29% yields, respectively. Reaction of [Re₂(CO)₈(MeCN)₂] with 1-methylimidazole gives [Re₂(CO)₈{η¹-NC₃H₃N(CH₃)}₂] (4) and the mononuclear compound fac-[ReCl(CO)₃{η¹-NC₃H₃N(CH₃)}₂] (5) in 18% and 26% yields, respectively. In the disubstituted compounds 2 and 4, the heterocyclic ligands occupy equatorial coordination sites. The mononuclear compound 5 consists of three CO groups, two N coordinated η¹-1-methylimidazole ligands and a terminal Cl ligand. The XRD structures of complexes 1, 3 and 5 are reported.     

Carbon–hydrogen and carbon–phosphorus bond cleavage in a triruthenium cluster complex containing dppm: The crystal and molecular structures of Ru3(CO)6{μ 3-OPPh2 C2H(C6H4)PPhCH2PPh}(μ 3-OPPh2)Ph and Ru3(CO)6 {μ-OPPh2C2H(C6H4)PPhO}(μ-PPh2)(μ-PPh2O)

The crystal and molecular structures of Ru₃(CO)₆{μ ₃-OPPh₂C₂H(C₆H₄)PPhCH₂PPh}-(μ ₃-OPPh₂)Ph (1) and Ru₃(CO)₆{μ-OPPh₂C₂H(C₆H₄)PPhO}(μ-PPh₂)(μ-PPh₂O) (2) have been determined by single crystal X-ray diffraction. Both complexes contain oxygen atoms oxidatively inserted into phosphorus–ruthenium bonds, and unique σ/π multidentate ligands formed from C $---{\text{H}}$ H and C $--$ P bond cleavage in bis(diphenylphosphino)acetylene and bis(diphenylphosphino)methane. Complex 1 crystallized in the triclinic space group ${\bar 1}$ , with lattice parameters a = 11.642(4) Å, b = 15.018(5) Å, c =16.587(5) Å, α = 2.48(3)°, β = 76.47(2)°, γ = 70.35(3)°, V = 2651.1(15) ų, Z = 2. Complex 2 crystallized in the centered monoclinic space group, C2/c, with lattice parameters a = 34.467(4) Å, b = 14.274(2) Å, c = 23.258(3) Å, β = 5.29(1)°, V = 11394(3) ų, Z = 8.     

Reactions of [Mn2(μ-pyS)2(CO)6] with bidentate phosphines: X-ray structure of [Mn(η2-pyS) (η2-dppp)(CO)2] [dppp = Ph2P(CH2)3PPh2, pySH = pyridine-2-thiol]

The dimeric complex [Mn₂(-pyS)₂(CO)₆] (1) reacted with 2 molar equivalents of Ph₂P(CH₂)₃PPh₂ (dppp) and Ph₂P(CH₂)₂PPh₂ (dppe) to give the respective monomeric chelate complexes [Mn(²-pyS)(²-dppp)(CO)₂] (2) and [Mn(²-pyS)(²-dppe)(CO)₂] (3). In contrast, with 2 molar equivalents of Ph₂P(CH₂)₅PPh₂ (dpppe), 1 gave the highly insoluble polymeric complex [Mn(²-pyS)(-dpppe)(CO)₂]n (4). An X-ray structure determination shows that 2 crystallizes in the monoclinic space group P2₁/n with a = 10.721(2) Å, b = 19.712(5) Å, c = 14.846(4) Å, = 109.06(2)°, V = 2965.5(14) ų, and Z = 4. The complex has a distorted octahedral geometry with the dppp ligand, one CO group and the N atom of the chelating pyS ligand occupying equatorial sites, and one CO group and the S atom of the pyS ligand lying in the axial positions.