OptiDock: virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space

Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library. These compounds are docked individually using the FlexX program (Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. J. Mol. Biol. 1995, 251, 470-489) to define distinct docking modes in terms of reference placements for combinatorial core atoms. Thereafter, substituents in R-cores (consisting of the core structure substituted at a single variation site) are docked, keeping the core atoms fixed at the coordinates dictated by each reference placement. Interaction energies are calculated for each docked R-core with respect to the target protein, and energies for whole compounds are calculated by finding the reference core placement for which the sum of corresponding R-core energies is most negative. The use of diverse whole compounds to define binding modes is a key advantage of the protocol over other combinatorial docking programs. As a result, OptiDock returns better-scoring conformers than does serially applied FlexX. OptiDock is also better able to find a viable docked pose for each library member than are other combinatorial approaches.     

Structural characterization of isomeric triazolocoumarins by high- and low-energy collision spectrometry of M+˙, [M + H]+ and [M − H]− species

Two monometayl- and four dimethyl-triazolocoumarin isomers were characterized by their electron impact mass spectra and by low-energy collision experiments performed on molecular ions M⁺˙ and other fragment ions with an ion-trap mass spectrometer. High-energy collision-activated dissociation measurements were performed on the protonated [M + H]⁺ and deprotonated [M ? H]^? molecular ion obtained by fast atom bombardment and M⁺˙ species produced by electron impact ionization on a double-focusing, reverse-geometry instrument. The data obtained allowed unequivocal structural identification of all the compounds investigated.     

A new method for computing surface tension using a drop of liquid

In the simulation of a liquid drop it is expensive to calculate the excess pressure and obtain the surface tension by the Laplace formula. We use the Kelvin formula which only requires the vapour density, or at most the virial pressure. Some results are given for a Lennard-Jones 12-6 fluid.     

Regioselective and enantiospecific rhodium-catalyzed allylic amination with N-(arylsulfonyl)anilines

[reaction: see text]. The regioselective and enantiospecific rhodium-catalyzed allylic amination of secondary allylic carbonates 1 with N-(arylsulfonyl)anilines provides a convenient process for the construction of arylamines 2. This method, in conjunction with ring-closing metathesis and radical cyclization reactions, allows the direct construction of biologically relevant pharmacophores as exemplified by the construction of dihydroquinoline and dihydrobenzo[b]indoline derivatives.     

Pillared, 3D metal-organic frameworks with rectangular channels. Synthesis and characterization of coordination polymers based on tricadmium carboxylates

Hydro(solvo)thermal reactions between cadmium(II) perchlorate and 4-pyridinecarboxaldehyde in the presence of various guest molecules have resulted in a series of 3-D coordination polymers based on tricadmium carboxylates [Cd6(isonicotinate)10(H2O)2](ClO4)2(EtOH)4(H2O)4, 1, [Cd3(isonicotinate)5 (EtOH)](ClO4)(EtOH)(4-nitroaniline)0.5, 2, and [Cd6(isonicotinate)11](ClO4)(EtOH)2(H2O)2(4-cyanopyridine)0.5, 3. X-ray single crystal structure determinations show that they exhibit similar pillared, 3D framework structures based on tricadmium carboxylate building blocks. Rectangular channels are clearly present in these polymeric networks and are occupied by perchlorate anions and disordered guest molecules. Quantitative NMR and X-ray powder diffraction studies and thermogravimetric analyses (TGA) reveal that these coordination networks are capable of accommodating different guest molecules. More significantly, the guest molecules can be readily removed via evacuation to result in nanoporous polymeric coordination networks retaining the framework structures of the pristine solids. Crystal data for 1: monoclinic space group P2(1)/n, a = 19.041(1) A, b = 23.654(1) A, c = 21.568(1) A, beta = 95.440(1) degrees, and Z = 4. Crystal data for 2: triclinic space group P1, a = 12.050(1) A, b = 12.277(1) A, c = 19.103(1) A, alpha = 91.669(1) degrees, beta = 96.850(1) degrees, gamma = 117.945(1) degrees, and Z = 2. Crystal data for 3: monoclinic space group P2(1)/n, a = 19.038(1) A, b = 23.834(1) A, c = 21.756(1) A, beta = 97.580(1) degrees, and Z = 4.     

Synthesis and characterization of diametrically substituted tetra-O-n-butylcalix[4]arene ligands and their chelated complexes of titanium,molybdenum, and palladium

The ligation properties of three new upper-rim-substituted calix[4]arene ligands, 5,17-bis(hydroxymethyl)-tetra-n-butoxycalix[4]arene ((HOCH2)2-nBu4Clx, 7), 5,17-bis((diphenylphosphinito)methoxy)-tetra-n-butoxycalix[4]arene ((PPh2OCH2)2-nBu4Clx, 8), and 5,17-bis((diphenylphosphino)methyl)-tetra-n-butoxycalix[4]arene ((PPh2CH2)2-nBu4Clx, 10) are reported herein. The newly prepared compounds differ from previously reported diametrically substituted calix[4]arene derivatives in that the lower-rim substituent was n-butyl. The presence of this lower-rim substituent did not reduce the inherent crystallinity of these complexes as purification of all materials occurred via simple crystallizations. The key precursor for the syntheses of 8 and 10 was 7, acquisition of which occurred in six steps starting from tetra-tert-butylcalix[4]arene, 1. Calix[4]arene derivatives include, tetra-n-butoxycalix[4]arene (nBu4Clx, 3), 5,11,17,23-tetrabromo-tetra-n-butoxycalix[4]arene (Br4-nBu4Clx, 4), 5,17-dibromo-tetra-n-butoxycalix[4]arene (Br2-nBu4Clx, 5), 5,17-bis(formyl)-tetra-n-butoxycalix[4]arene ((CHO)2-nBu4Clx, 6), and 5,17-bis(chloromethyl)-tetra-n-butoxycalix[4]arene ((ClCH2)2-nBu4Clx, 9), all of which were synthesized using modifications of existing procedures. Characterization of all compounds occurred, when possible, using 1H, 13C, and 31P NMR, elemental analyses, FAB-MS, ESI-MS, FT-IR, and X-ray crystallography. The solid-state structures of all calix[4]arene intermediates and ligands showed that the annulus adopted the pinched-cone conformation in which the average C(5)...C(17) intraannular separation was 4.5 +/- 0.4 A. Reaction of 7 with CpTiMe3 yielded the cis-chelate, CpTi(Me)[(OCH2)2-nBu4Clx] (11), quantitatively. Data obtained using ESI-MS (positive-ion mode) confirmed the monomer formulation showed above, and 1H NMR spectra provided sufficient information to deduce the nature of the Ti coordination sphere. Reaction of 8 with cis-Cl2Pd(NCPh)2 in refluxing benzene afforded cis-Cl2Pd[(PPh2OCH2)2-nBu4Clx] (12) in good yields. The monomeric identity of this compound was verified by both X-ray crystallography and positive-ion ESI-MS. The cis-bidentate calix[4]arene ligand did not undergo any noticeable contortion upon chelation of the PdCl2 fragment. Acid-promoted decomposition of 12 occurred in the presence of adventitious HCl and gaseous HCl, and the products of this decomposition were 9 and [mu2-ClPd(PPh2OH)(PPh2O)]2. In addition, chelates of 8 that contained Mo(CO)3L (L = NCMe (14a), NCEt (14b), and CO (14c)) showed that the mode of coordination was relatively insensitive to the identity of the metal. X-ray crystallography afforded views of the solid-state structures of 14b,c and, like 12, showed that the Mo(CO)3L fragment resided above the pinched-cone of the calix[4]arene. 1H NMR revealed that C-H/pi interactions existed between L (14a,b) and a phenyl ring of the coordinated phosphinite. Finally, the bis(diphenylphosphine)calix[4]arene ligand (10) readily coordinated the Mo(CO)3L species, but the reaction did not go to completion, as evidenced by 1H NMR, even after a 5 day reaction time. Data suggest that the product is similar to that observed for 12 and 14, but the incomplete reaction complicated attempts to obtain pure material and prohibited definitive assignment of the coordination array.     

Coupling of an aldehyde or ketone to pyridine mediated by a tungsten imido complex

The reactivity of W(NPh)(o-(Me3SiN)2C6H4)(py)2 and W(NPh)(o-(Me3SiN)2C6H4)(pic)2 (py=pyridine; pic=4-picoline) with unsaturated substrates has been investigated. Treatment of W(NPh)(o-(Me3SiN)2C6H4)(py)2 with diphenylacetylene or 2,3-dimethyl-1,3-butadiene generates W(NPh)(o-(Me3SiN)2C6H4)(eta2-PhCCPh) and W(NPh)(o-(Me3SiN)2C6H4)(eta4-CH2=C(Me)C(Me)=CH2), respectively, while the addition of ethylene to W(NPh)(o-(Me3SiN)2C6H4)(py)2 generates the known metallacycle W(NPh)(o-(Me3SiN)2C6H4)(CH2CH2CH2CH2). The addition of 2 equiv of acetone to W(NPh)(o-(Me3SiN)2C6H4)(pic)2 provides the azaoxymetallacycle W(NPh)(o-(Me3SiN)2C6H4)(OCH(Me)2)(OC(Me)2-o-C5H3N-p-Me), the result of acetone insertion into the ortho C-H bond of picoline. Similarily, the addition of 2 equiv of RC(O)H [R=Ph, tBu] to W(NPh)(o-(Me3SiN)2C6H4)(py)2 generates W(NPh)(o-(Me3SiN)2C6H4)(OCH2R)(OCHR-o-C5H4N) [R=Ph, tBu,]. In contrast, reaction between W(NPh)(o-(Me3SiN)2C6H4)(py)2 and 2-pyridine carboxaldehyde yields the diolate W(NPh)(o-(Me3SiN)2C6H4)(OCH(C5H4N)CH(C5H4N)O). The synthesis of W(NPh)(o-(Me3SiN)2C6H4)(PMe3)(py)(eta2-OC(H)C6H4-p-Me), formed by the addition of p-tolualdehyde to a mixture of W(NPh)(o-(Me3SiN)2C6H4)(py)2 and PMe3, suggests that an eta2-aldehyde intermediate is involved in the formation of the azaoxymetallacycle, while the isolation of W(NPh)(o-(Me3SiN)2C6H4)(Cl)(OC(Me)(CMe3)-o-C5H4N), formed by the reaction of pinacolone with W(NPh)(o-(Me3SiN)2C6H4)(py)2, in the presence of adventitious CH2Cl2, suggests that the reaction proceeds via the hydride W(NPh)(o-(Me3SiN)2C6H4)(H)(OC(Me)(CMe3)-o-C5H4N).     

Controlling the outcome of an N-alkylation reaction by using N-oxide functional groups

Covalent modifiers of proteins are of importance in chemical proteomics, an emerging chemical technology used to assign protein function. In this study, high-field (1)H NMR techniques were used to analyze the reaction of the bioactive compound, 2,3-bis(bromomethyl)quinoxaline 1,4-dioxide, with amines (a model system for proteins containing nitrogen-based nucleophiles). Unexpectedly, the results show that a double nucleophilic substitution reaction involving 2 equiv of the amine is preferred to an intramolecular cyclization pathway. A direct comparison with the reaction carried out on a substrate lacking the N-oxide functional groups is also provided. X-ray crystal structures and computational studies are used to rationalize the observed differences in reactivity between the two systems.     

New details concerning the reactions of nitric oxide with vanadium tetrachloride

The slow addition of NO to a CCl(4) solution of VCl(4) reproducibly forms the known polymer [V(NO)(3)Cl(2)](n)() as a dark brown powder. Treatment of a CH(2)Cl(2) suspension of [V(NO)(3)Cl(2)](n)() with excess THF generates mer-(THF)(3)V(NO)Cl(2) (1) which can be isolated as an orange crystalline material in 55% yield. The reaction of 1 with excess MeCN or 1 equiv of trimpsi (trimpsi = (t)BuSi(CH(2)PMe(2))(3)) provides yellow-orange (MeCN)(3)V(NO)Cl(2)xMeCN (2xMeCN) and yellow (trimpsi)V(NO)Cl(2) (3), respectively. A black, crystalline complex formulated as [NO][VCl(5)] (4) is formed by the slow addition of NO to neat VCl(4) or by the reaction of excess ClNO with neat VCl(4). Complex 4 is extremely air- and moisture-sensitive, and IR spectroscopy suggests that in solutions and in the gas phase it dissociates back into VCl(4) and ClNO. Reaction of 4 with excess [NEt(3)(CH(2)Ph)]Cl generates [NEt(3)(CH(2)Ph)](2)[VCl(6)]x2CH(2)Cl(2) (5x2CH(2)Cl(2)), which can be isolated as deep-red crystals in 51% yield. All new complexes have been characterized by conventional spectroscopic methods, and the solid-state molecular structures of 1, 2xMeCN, and 5x2CH(2)Cl(2) have been established by single-crystal X-ray diffraction analyses.