Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.

Ag(I) and Cu(I) complexes of tetramethyldiphosphinedisulfide: synthesis and structure

Reaction of [M(NCCH3)(4)][PF6] (M = Ag, Cu) with the S2P2Me4 ligand in dichloromethane solution led to substitution of all the nitrile ligands by two molecules of the sulfur ligand, affording the new species [Ag(S2P2Me4)(2)][PF6] (1) and [Cu(S2P2Me4)(2)][PF6] (2). The structures of these complexes were determined by single crystal X-ray diffraction. showing the expected tetrahedral coordination around each metal. Density functional theory (DFT) calculations confirmed the different geometries and energies of the free and coordinated ligand, and provided a very good reproduction of the experimental structures, both for Ag and Cu. The lengths of the S=P bonds are barely affected by coordination, indicating that the pi bond is not important in binding to the metal. (C) 2002 Elsevier Science B.V. All rights reserved.

Gas-phase rate coefficients for reactions of NO3, OH, O-3 and O(P-3) with unsaturated alcohols and ethers: correlations and structure-activity relations (SARs)

Experimental difficulties sometimes force modellers to use predicted rate coefficients for reactions of oxygenated volatile organic compounds (oVOCs). We examine here methods for making the predictions for reactions of atmospheric initiators of oxidation, NO3, OH, O-3 and O(P-3), with unsaturated alcohols and ethers. Logarithmic correlations are found between measured rate coefficients and calculated orbital energies, and these correlations may be used directly to estimate rate coefficients for compounds where measurements have not been performed. To provide a shortcut that obviates the need to calculate orbital energies, structure-activity relations (SARs) are developed. Our SARs are tested for predictive power against compounds for which experimental rate coefficients exist, and their accuracy is discussed. Estimated atmospheric lifetimes for oVOCs are presented. The SARs for alkenols successfully predict key rate coefficients, and thus can be used to enhance the scope of atmospheric models incorporating detailed chemistry. SARs for the ethers have more limited applicability, but can still be useful in improving tropospheric models. (C) 2008 Elsevier Ltd. All rights reserved.

Gas-phase rate coefficients for the reactions of O(3P), S(3P), Se(3P), and Te(3P) with alkenes: application of perturbation frontier molecular orbital theory, correlations, and structure-activity relations (SARs)

The kinetics of the reactions of the atoms O(P-3), S(P-3), Se(P-3), and Te((3)p) with a series of alkenes are examined for correlations relating the logarithms of the rate coefficients to the energies of the highest occupied molecular orbitals (HOMOs) of the alkenes. These correlations may be employed to predict rate coefficients from the calculated HOMO energy of any other alkene of interest. The rate coefficients obtained from the correlations were used to formulate structure-activity relations (SARs) for reactions of O((3)p), S(P-3), Se (P-3), and Te((3)p) with alkenes. A comparison of the values predicted by both the correlations and the SARs with experimental data where they exist allowed us to assess the reliability of our method. We demonstrate the applicability of perturbation frontier molecular orbital theory to gas-phase reactions of these atoms with alkenes. The correlations are apparently not applicable to reactions of C(P-3), Si(P-3), N(S-4), and Al(P-2) atoms with alkenes, a conclusion that could be explained in terms of a different mechanism for reaction of these atoms.

The relation between content and structure in language production: an analysis of speech errors in semantic dementia

In order to explore the impact of a degraded semantic system on the structure of language production, we analysed transcripts from autobiographical memory interviews to identify naturally-occurring speech errors by eight patients with semantic dementia (SD) and eight age-matched normal speakers. Relative to controls, patients were significantly more likely to (a) substitute and omit open class words, (b) substitute (but not omit) closed class words, (c) substitute incorrect complex morphological forms and (d) produce semantically and/or syntactically anomalous sentences. Phonological errors were scarce in both groups. The study confirms previous evidence of SD patients’ problems with open class content words which are replaced by higher frequency, less specific terms. It presents the first evidence that SD patients have problems with closed class items and make syntactic as well as semantic speech errors, although these grammatical abnormalities are mostly subtle rather than gross. The results can be explained by the semantic deficit which disrupts the representation of a pre-verbal message, lexical retrieval and the early stages of grammatical encoding.

Cobalt(III) complexes of some aromatic thiohydrazides – Synthesis, characterization and structure

Co(NH3)(5)Cl]Cl-2 forms neutral 1:3 complex by reaction with aromatic thiohydrazides, i.e. thiobenzhydrazide, o-hydroxythiobenzhydrazide, thiophen-2-thiohydrazide and furan-2-thiohydrazide. All these complexes are diamagnetic and have been characterized by elemental analysis and combination of spectroscopic methods. Cyclic voltammometry of the complexes shows irreversible metal centered and ligand centered electron transfer reactions. One complex, tris-o-hydroxythiobenzhydrazidocobalt(III),has been crystallized from DMSO solution to produce solvated crystals and its structure has been established by X-ray crystallography. Cobalt(III) ion is linked through three hydrazinic nitrogen and three sulfur atoms of three identical deprotonated ligand molecules in a distorted octahedral environment. Involvement of -OH group in intramolecular and intermolecular hydrogen bonding is crucial for crystal formation.

The synthesis of dicobalt and dinickel complexes of trimethylsilylethynyl-1, 2-dihydrofullerene; characterisation by n.m.r. and structure of the first acyclic metal fullerene derivative: molecular structure of [η2-{2-H-1-(Me3SiC ≡ C)-C60}Ni2(η-C5H5)2]

The synthesis and characterisation of the complexes [η2-{2-H-1-(Me3SiC ≡ C)-C60}Co2(CO)6] (2)} and [η-2-{2-H-1-(Me3SiC ≡ C)-C60}Ni2η-C5H5)2] (3)} is reported, together with a single-crystal molecular structure for (3). This provides the first structural data for an acyclic metal derivative of [60]-fullerene.

Synthesis and structure of oligomeric dimesitylgermyl-substituted carbodiimides; characterization of higher oligomers

New cyclic oligomers of dimesitylgermylene carbodiimides (Mes2GeNCN)n (n = 3 (1) and 4 (2)) were synthesized by reactions of dimesityldichlorogermane with either cyanamide in the presence of triethylamine or lithium cyanamide. The reactions always gave 1, the trimer of the hypothetical (Mes2GeN−CN), as the major compound. Higher oligomers 3 (n up to 20−30) also can be isolated, depending on the reaction conditions. In THF solution at room temperature, 2 and 3 slowly isomerize to 1, which seems to be the most stable compound. X-ray analysis of trimer 1 and tetramer 2 shows unstrained tetrahedral germanium atoms and linear diimine linkers.

Synthesis and structure of the Mn II,II complex salt [Mn2(η1η1μ2-oda)(phen)4(H2O)2][Mn2][Mn2(η1η1μ2-oda)(phen)4(η1-oda)2].4H2O (odah2 = octanedioic acid): a catalyst for H2O2 disproportionation

The synthesis and X-ray crystal structure of the MnII,11 complex double salt [Mn2(η1η1µ2-oda)(phen)4(H2O)2][Mn2(η1η1µ2-oda(phen)4(η1-oda)2]·4H2O is reported, together with its catalytic activity towards the disproportionation of H2O2.

Influence of hydrogen bonding in the structure of mixed-ligand copper(II) chelates. Spectra and structure of [aquo((2,2'-dipyridylamine)-(3-chloro-2,4-pentanedionato)copper(II)] nitrate

The IR, the ligand field spectra and the crystal structure of the mixed-ligand compound [(aquo)2,2P1 , a = 8.718(5), b = 9.407(5), c = 13.484 (7) Å, = 94.17(4)°, = 105.12(5)°, = 119.75(5)°, Z = 2, R = 0.0332, R W = 0.0869).

Synthesis and structure of Ir4Sn3(CO)6{CH(SiMe3)2}5O3; a heterometallic ‘raft’ with sail hoisted!

Heterometallic raft clusters have been obtained previously for a variety of metals but none for tin and iridium, and more significantly none to date have had metal groups bonded above the raft plane. We report a hexametallic Ir4Sn2 raft to which a third tin group is attached by a single short IrSn bond and three IrOSn bridges.