L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase

Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.     

De novo prediction of ground state multiplicity and structural isomerism for transition metal complexes

Prediction of the ground state geometries and multiplicities for 33 transition metal tetrachlorides has been carried out using two different levels of quantum mechanics: semiempirical and density functional theory. All data regarding geometry and spin state provided by both computational methods were compared with experimental data when available. The calculations were performed for all possible spin multiplicities. The most important geometries for coordination number four (tetrahedral, square-planar, dodecahedral, and disphenoidal), as well as less symmetric structural isomers, were evaluated. A match between both computational methods in terms of predicted ground state multiplicity and geometry was found for 26 species, which translated into almost 80% agreement. Even though the PM3(tm) geometry prediction protocol involved more steps for isolating a feasible global minimum, the aggregate of these calculations was still orders of magnitude faster than DFT calculations using extended basis sets. The calculations indicate that caution is needed in the application of the PM3(tm) method to very high-spin transition metal complexes, but point to the suitability of very rapid semiempirical methods for reliable prediction of structural and ‘spin’ isomers, and hence their use in an efficient de novo design protocol for transition metal complexes.     

Extensions of the Marcus equation for the prediction of approximate transition state geometries in hydrogen transfer and methyl transfer reactions

The objective of this work is to propose a way to calculate approximate transition state geometries that can then be used as initial guesses in ab initio calculations. Transition state geometries are calculated for 26 hydrogen transfer reactions and 6 methyl transfer reactions at the MP2/6-31G* and MP2/6-311++G(d,p) levels. Selected cases are also done at other levels including CCSD(T)/6-311++G(d,p). The transition state geometry obeys an equation which arises from an extension of the Marcus equation proposed by Blowers and Masel [8]: In this equation, r B _,equ is the equilibrium bond length for the bond that breaks during the reaction, r F _,equ is the equilibrium bond length for the new bond which forms. r ^t _B and r ^t _F are the bond lengths at the saddle point in the potential energy surface. r ^t _B and r ^t _F are found to obey with an average error of 0.04 ?. In the last two equations above, ΔU is the heat of reaction, E ⁰ _A is the intrinsic barrier, and C _A is a constant that comes from the model of Blowers and Masel [8]. It is proposed that the above three equations are useful in generating initial guesses for transition state geometries in ab initio calculations. In the cases that were tried, rapid convergence was found when these guesses were used. Received: 23 February 2000 / Accepted: 13 May 2000 / Published online: 27 September 2000     

PathOpt—A global transition state search approach: Outline of algorithm

We propose a new algorithm to determine reaction paths and test its capability for Ar₁₂ and Ar₁₃ clusters. Its main ingredient is a search for the local minima on a (n?1) dimensional hyperplane (n = dimension of the complete system in Cartesian coordinates) lying perpendicular to the straight line connection between initial and final states. These minima are part of possible reaction paths and are, hence, used as starting points for an uphill search to the next transition state. First, path fragments are obtained from subsequent relaxations starting from these transition states. They can be combined with information from the straight line connection procedure to obtain complete paths. Our test computations for Ar₁₂ and Ar₁₃ clusters prove that PathOpt delivers several reaction paths in one round. © 2013 Wiley Periodicals, Inc.     

Rhodium‐ and ruthenium‐complex‐catalyzed condensation of ferrocene‐containing dithiols and diols with diarylsilanes to give silaferrocenophanes and ferrocene polymers

1,1′‐Ferrocenedithiol reacts with di(4‐methoxyphenyl)silane, diphenylsilane, and di(4‐fluorophenyl)silane in the presence of RhCl(PPh₃)₃ catalyst to give mixtures of 2,2‐diaryl‐1,3‐dithia‐2‐sila[3]ferrocenophanes (1a–3a) and ? (Fc? S? SiAr₂? S) _n? (Fc = 1,1′‐ferrocenylene; 1b: Ar = C₆H₄OMe‐4; 2b: Ar = Ph; 3b: Ar = C₆H₄F‐4). The products are isolated and characterized by NMR spectroscopy and elemental analyses. The polymers 1b–3b, obtained from a toluene‐soluble fraction of the products, show GPC elution patterns corresponding to M_n values of 2700–4600 (polystyrene standards). The UV–vis spectra of the ferrocenophanes and polymers exhibit a d–d transition peak at about 440 nm, while the polymers show a π–π* transition peak at 320–330 nm. The cyclic voltammograms of 3a (Ar = C₆H₄F ? 4) and 3b show a reversible redox of the iron center at 0.27 V and 0.35 V (Ag⁺/Ag) respectively. Reaction of 1,1′‐ferrocenedimethanol with diphenylsilane in the presence of RuCl₂(PPh₃)₃ catalyst results in selective formation of 3,3‐diphenyl‐2,4‐dioxa‐3‐sila[5]ferrocenophane ( 4 ), whose structure was determined by X‐ray crystallography. Copyright © 2001 John Wiley & Sons, Ltd.     

A stereoselective approach to 6-alkylated piperidinone & 2-piperidine via three-component vinylogous Mannich reactions (VMR) and a concise synthesis of (S)-anabasine

A three-component diastereoselective vinylogous Mannich-type reaction (VMR) with the silyl ketene acetal (1) was developed. Adducts from the reactions provided valuable intermediates for construction of a variety of chiral 6-alkylated piperidinone and 2-piperidine compounds. The strategy was applied in a concise synthesis (S)-anabasine.     

Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study

Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis. The 3D structures of PPO1 and PPO2 were built through homology modeling, while the 3D crystal structures of PPO3 and PPO4 were retrieved from PDB. Pharmacophore modeling was performed using LigandScout 3.1 software and top five models were selected to screen the libraries (2601 of Aurora and 727, 842 of ZINC). Top 10 hit compounds (C1-10) were short-listed having strong binding affinities for PPO1-4. Drug and synthetic accessibility (SA) scores along with absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment were employed to scrutinize the best lead hit. C4 (name) hit showed the best predicted SA score (5.75), ADMET properties and drug-likeness behavior among the short-listed compounds. Furthermore, docking simulations were performed to check the binding affinity of C1-C10 compounds against target proteins (PPOs). The binding affinity values of complex between C4 and PPOs were higher than those of other complexes (−11.70, −12.1, −9.90 and −11.20 kcal/mol with PPO1, PPO2, PPO3, or PPO4, respectively). From comparative docking energy and binding analyses, PPO2 may be considered as better target for melanogenesis than others. The potential binding modes of C4, C8 and C10 against PPO2 were explored using molecular dynamics simulations. The root mean square deviation and fluctuation (RMSD/RMSF) graphs results depict the significance of C4 over the other compounds. Overall, bioactivity and ligand efficiency profiles suggested that the proposed hit may be more effective inhibitors for melanogenesis.     

A Theoretical Studies on the Thermolysis Mechanism of α-Aminonitrile

Introduction α-Aminonitrile(or aminoacetonitrile) is a kind of reactive bioorganic molecules, and it may exist in insterstellar clouds. its importance lies in that a-aminonitrile may play a role in the generation of large carbon-nitrogen chain molecules. By means of flash vacuum thermolysis and gas-solid reaction (FVT-GSR) tech-nique, Guillemin, et al., studied the thermolysis of a-aminonitrile, they considered that the elimination of HCN (shown as following) is a key step in many reactions of α-     

A new chemical access for 3′-acetyl-4′-hydroxychalcones using borontrifluoride-etherate via a regioselective Claisen-Schmidt condensation and its application in the synthesis of chalcone hybrids

A new chemical access has been developed for the synthesis of 3′-acetyl-4′-hydroxychalcones from 1-(5-acetyl-2-hydroxy-phenyl)-ethanone and various substituted benzaldehydes via a regioselective Claisen-Schmidt condensation using borontrifluoride-etherate (BF₃·OEt₂) at room temperature, in good to excellent yields within 12-24 h. Application of this methodology has also been demonstrated in the synthesis of chalcone hybrids.     

糖苷键水解过渡态的模拟-2-(对甲氧苯基)-亚氨基哌啶的合成和晶体结构

由戊内酰胺和三氯氧磷, 对甲氧苯胺一步反应合成了2-(对甲氧苯基)-亚胺基哌啶, 并对所得化合物进行IR, UV, ^1H NMR, ^1^3C NMR和X-ray表征。X-ray结果显示含N的六元环是一个半椅式构型, N1, C8, C9, N2, C12基本上在同一平面, N2, C8, N1, C5存在共振结构, 在弱酸体系中其半椅式构型和电荷分布与不稳定的过渡态相类似。     

A rigorous approach to the formulation of extended Born‐Oppenheimer equation for a three‐state system

If a coupled three‐state electronic manifold forms a sub‐Hilbert space, it is possible to express the non‐adiabatic coupling (NAC) elements in terms of adiabatic–diabatic transformation (ADT) angles. Consequently, we demonstrate: (a) Those explicit forms of the NAC terms satisfy the Curl conditions with non‐zero Divergences; (b) The formulation of extended Born‐Oppenheimer (EBO) equation for any three‐state BO system is possible only when there exists coordinate independent ratio of the gradients for each pair of ADT angles leading to zero Curls at and around the conical intersection(s). With these analytic advancements, we formulate a rigorous EBO equation and explore its validity as well as necessity with respect to the approximate one (Sarkar and Adhikari, J Chem Phys 2006, 124, 074101) by performing numerical calculations on two different models constructed with different chosen forms of the NAC elements. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

A Multiconformational Transition State Theory Approach to OH Tropospheric Degradation of Fluorotelomer Aldehydes

Experimental work on the OH-initiated oxidation reactions of fluorotelomer aldehydes (FTALs) strongly suggests that the respective rate coefficients do not depend on the size of the C_xF_2x+1 fluoroalkyl chain. FTALs hence represent a challenging test to our multiconformer transition state theory (MC-TST) protocol based on constrained transition state randomization (CTSR), since the calculated rate coefficients should not show significant variations with increasing values of . In this work we apply the MC-TST/CTSR protocol to the cases and calculate both rate coefficients at 298.15 K with a value of cm³ molecule⁻¹ s⁻¹, practically coincident with the recommended experimental value of k_exp= cm³ molecule⁻¹ s⁻¹. We also show that the use of tunneling corrections based on improved semiclassical TST is critical in obtaining Arrhenius-Kooij curves with a correct behavior at lower temperatures.     

A double Mannich approach to the synthesis of substituted piperidones—application to the synthesis of substituted E-ring analogues of methyllycaconitine

The double Mannich reaction of acyclic α,γ-substituted β-keto esters and bis(aminol) ethers gives substituted 3,5-substituted-4-piperidones with high levels of diastereoselectivity. These piperdiones can be easily transformed into substituted E-ring analogues of the delphinium alkaloid methyllycacotine.     

A transition metal-free approach to a regioselective total synthesis of the natural product derivative 6-methylellipticine,a potent anticancer agent

A transition metal-free and regioselective total synthesis of 6-methylellipticine, a potent anticancer agent, was developed. This synthetic approach mainly involved two key reactions: a direct amination of multi-functional phenol via an alkylation-Smiles rearrangement protocol, and an intramolecular C–H bond arylation reaction promoted by potassium tert-butoxide. These reactions resulted in the formation of two key intermediates, diarylamine and carbazole derivative, under transition metal-free conditions. The last cyclization afforded the target product 6-methylellipticine.     

A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors

As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC₅₀ value of 10 ± 5 μM in HIV infected human T-cells. Additional docking of “in-house” compound libraries unearthed a methyl ester based nitrile derivative displaying an IC₅₀ value of 0.5 μM in a combined 3′-processing and strand-transfer assay.     

Chain‐growth condensation polymerization approach to synthesis of well‐defined polybenzoxazole: Importance of higher reactivity of 3‐amino‐4‐hydroxybenzoic acid ester compared to 4‐amino‐3‐hydroxybenzoic acid ester

Application of chain‐growth condensation polymerization (CGCP) to obtain well‐defined polybenzoxazole (PBO) was examined. CGCP of both phenyl 3‐{(2‐methoxyethoxy)methoxy (MEM‐oxy)}‐4‐(octylamino)benzoate ( 1b ) (para‐substituted monomer) and phenyl 4‐MEM‐oxy‐3‐(octylamino)benzoate ( 3b ) (meta‐substituted monomer) was examined in the presence of metal disilazide base and phenyl 4‐nitro‐ or methylbenzoate 2 as an initiator. Polymerization of the latter monomer, but not the former, afforded polymer with controlled molecular weight based on the feed ratio of monomer to initiator and with a narrow molecular weight distribution. Accordingly, monomer 3c , in which the octyl group on the amino nitrogen of 3b was replaced with a 4‐(octyloxy)benzyl (OOB) group, was polymerized in the presence of lithium 1,1,1,3,3,3‐hexamethyldisilazide (LiHMDS), phenyl 4‐methylbenzoate ( 2b ), and LiCl in THF at 0 °C to yield poly 3c with well‐defined molecular weight (M_n = 4520–9080) and low polydispersity (M_w/M_n ≤ 1.11). Treatment of poly 3c with trifluoroacetic acid simultaneously removed the MEM and OOB groups, affording poly(o‐hydroxyamide) (poly 4 ) without scission of the amide linkages. Cyclodehydration of poly 4 proceeded at 350 °C to yield PBO (poly 5 ), which was insoluble in organic solvents and acids. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1730–1736     

Transition state structure invariance to model system size and calculation levels: a QM/MM study of the carboxylation step catalyzed by Rubisco

The present study elucidates structural features related to the molecular mechanism in the carboxylation step of the reaction catalyzed by Rubisco. Starting from the initial X-ray Protein Data Bank structure of a Rubisco monomer, the reactive subsystem in vacuo is subjected to quantum chemical semiempirical and ab initio studies, while the effects of the protein environments are included by means of a hybrid quantum mechanical/molecular mechanical (QM/MM) approach. The QM/MM is used to characterize the transition structure for carboxylation inside the protein. The calculations were made with the AM1/CHARMM/GRACE scheme. Comparisons between the in vacuo and in situ transition structures show remarkable invariance with respect to geometric parameters, index and transition vector amplitudes. The transition state couples the carbon dioxide attack to the C2 center of the substrate in its dienol form with a simultaneous intramolecular hydrogen transfer from the C2 atom to the hydroxyl group linked to the C3 center. This study suggests that carboxylation may be simultaneously coupled to the activation of the C3 center in the enzyme. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 10 December 1998     

Excess polarizabilities upon excitation from the ground state to the first dipole‐allowed excited state of diphenylpolyenes

This paper discusses the excess polarizabilities upon excitation from the ground state to the first dipole‐allowed excited state (S₁) of diphenylpolyenes by using the time‐dependent density functional theory. Two hybrid exchange‐correlation (xc) potentials Becke‐3 Lee‐Yang‐Parr (B3LYP) and Perdew‐Burke‐Ernzerhof (PBE1PBE) were employed. Our calculations indicate that the magnitude of the excess polarizability will decrease while the molecule evolves from the unrelaxed S₁ state to the relaxed S₁ state. This decreasing trend is found to be independent of substituents, though substituents can change the value of the excess polarizability. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Access to [6.4.0]carbocyclic systems by tandem metathesis of dienynes. A step toward the synthesis of a PreD3-D3 transition state analogue

[reaction: see text] A new approach to the synthesis of linearly fused 6-8-6 tricarbocyclic systems, tandem ring-closing metathesis of dienynes, allows access to compounds with a carbon framework analogous to the proposed transition state of the isomerization of previtamin D(3) to vitamin D(3).