Graphs to chemical structures 5. Combinatorial enumeration of centroidal and bicentroidal three-dimensional trees as stereochemical models of alkanes

Three-dimensional trees (3D-trees), which are defined as a 3D version of trees, are enumerated by Fujita’s proligand method formulated in Part 1 to Part 3 of this series (Fujita in Theor Chem Acc 113:73–79, 113:80–86, 2005; 115:37–53, 2006). Such 3D-trees are classified into centroidal and bicentroidal 3D-trees, which correspond to respective promolecules having proligands as substituents. In order to enumerate such centroidal and bicentroidal 3D-trees, cycle indices with chirality fittingness (CI-CFs) are formulated as being composed of three kinds of sphericity indices, i.e., a _d for homospheric cycles, c _d for enantiospheric cycles, and b _d for hemispheric cycles. The CI–CFs are capable of giving itemized results with respect to chiral and achiral 3D-trees so that they are applied to derive functional equations (a(x), c(x ²), and b(x)). The generating functions of planted 3D-trees, which are formulated and calculated elsewhere, are introduced into such functional equations. Thereby, the numbers of 3D-trees or equivalently those of alkanes as stereoisomers are calculated and collected up to a carbon content of 20 in a tabular form. Now, the enumeration problem initiated by a mathematician Cayley (Philos Mag 47(4):444–446, 1874) has been solved in such a systematic and integrated manner as satisfying both mathematical and chemical requirements.     

Graphs to chemical structures. 4: Combinatorial enumeration of planted three-dimensional trees as stereochemical models of monosubstituted alkanes

Planted three-dimensional (3D) trees, which are defined as a 3D version of planted trees, are enumerated by means of Fujita’s proligand method formulated in Parts 1–3 of this series [Fujita in Theor Chem Acc 113:73–79, 80–86, 2005; Fujita in Theor Chem Acc 115:37–53, 2006]. By starting from the concepts of proligand and promolecule introduced previously [Fujita in Tetrahedron 47:31–46, 1991], a planted promolecule is defined as a 3D object in which the substitution positions of a given 3D skeleton are occupied by a root and proligands. Then, such planted promolecules are introduced as models of planted 3D-trees. Because each of the proligands in a given planted promolecule is regarded as another intermediate planted promolecule in a nested fashion, the given planted promolecule is recursively constructed by a set of such intermediates planted promolecules. The recursive nature of such intermediate planted promolecules is used to derive generating functions for enumerating planted promolecules or planted 3D-trees. The generating functions are based on cycle indices with chirality fittingness (CI-CFs), which are composed of three kinds of sphericity indices (SIs), i.e., a _d for homospheric cycles, c _d for enantiospheric cycles, and b _d for hemispheric cycles. For the purpose of evaluating c _d recursively, the concept of diploid is proposed, where the nested nature of c _d is demonstrated clearly. The SIs are applied to derive functional equations for recursive calculations, i.e., a(x), c(x ²), and b(x). Thereby, planted 3D-trees or equivalently monosubstituted alkanes as stereoisomers are enumerated recursively by counting planted promolecules. The resulting values are collected up to 20 carbon content in a tabular form. Now, the enumeration problem initiated by mathematician Cayley [Philos Mag 47(4):444–446, 1874] has been solved in such a systematic and integrated manner as satisfying both mathematical and chemical requirements.     

A three-dimensional chemical phase pharmacophore mapping,QSAR modelling and electronic feature analysis of benzofuran salicylic acid derivatives as LYP inhibitors

Lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has a critical negative regulatory role in T-cell antigen receptor (TCR) and emerged as a promising drug target for human autoimmune diseases. A five-point pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic ring features was generated for a series of benzofuran salicylic acid derivatives as LYP inhibitors in order to elucidate their anti-autoimmune activity. The generated pharmacophore yielded a significant 3D-QSAR model with r² of 0.9146 for a training set of 27 compounds. The model also showed excellent predictive power with Q² of 0.7068 for a test set of eight compounds. The investigation of the 3D-QSAR model has revealed the structural insights which could lead to more potent analogues. The most active and inactive compounds were further subjected to electronic structure analysis using density functional theory (DFT) at B3LYP/3?21^?G level to support the 3D-QSAR predictions. The results obtained from this study are expected to be useful in the proficient design and development of benzofuran salicylic acid derivatives as inhibitors of LYP.     

Derivation of class II force fields: V. Quantum force field for amides,peptides, and related compounds

As the field of biomolecular structure advances, there is an ever-growing need for accurate modeling of molecular energy surfaces to simulate and predict the properties of these important systems. To address this need, a second generation amide force field for use in simulations of small organics as well as proteins and peptides has been derived. The critical question of what accuracy can be expected from calculations in general, and with this class II force field in particular, is addressed for structural, dynamic, and energetic properties. The force field is derived from a recent methodology we have developed that involves the systematic use of quantum mechanical observables. Systematic ab initio calculations were carried out for numerous configurations of 17 amide and related compounds. Relative energies and first and second derivatives of the energy of 638 structures of these compounds resulted in 140,970 ab initio quantum mechanical observables. The class II peptide quantum mechanical force field (QMFF), containing 732 force constants and reference values, was parameterized against these observables. A major objective of this work is to help establish the role of anharmonicity and coupling in improving the accuracy of molecular force fields, as these terms have not yet become an agreed upon standard in the ever more extensive simulations being used to probe biomolecular properties. This has been addressed by deriving a class I harmonic diagonal force field (HDFF), which was fit to the same energy surface as the QMFF, thus providing an opportunity to quantify the effects of these coupling and anharmonic contributions. Both force field representations are assessed in terms of their ability to fit the observables. They have also been tested by calculating the properties of 11 stationary states of these amide molecules. Optimized structures, vibrational frequencies, and conformational energies obtained from the quantum calculations and from both the QMFF and the HDFF are compared. Several strained and derivatized compounds including urea, formylformamide, and butyrolactam are included in these tests to assess the range of applicability (transferability) of the force fields. It was found that the class II coupled anharmonic force field reproduced the structures, energies, and vibrational frequencies significantly more faithfully than the class I harmonic diagonal force field. An important measure, rms energy deviation, was found to be 1.06 kcal/mol with the class II force field, and 2.30 kcal/mol with the harmonic diagonal force field. These deviations represent the error in relative configurational energy differences for strained and distorted structures calculated with the force fields compared with quantum mechanics. This provides a measure of the accuracy that might be expected in applications where strain may be important such as calculating the energy of a system as it approaches a (rotational) barrier, in ligand binding to a protein, or effects of introducing substituents into a molecule that may induce strain. Similar results were found for structural properties. Protein dynamics is becoming of ever-increasing interest, and, to simulate dynamic properties accurately, the dynamic behavior of model compounds needs to be well accounted for. To this end, the ability of the class I and class II force fields to reproduce the vibrational frequencies obtained from the quantum energy surface was assessed. An rms deviation of 43 cm⁻¹ was achieved with the coupled anharmonic force field, as compared to 105 cm⁻¹ with the harmonic diagonal force field. Thus, the analysis presented here of the class II force field for the amide functional group demonstrates that the incorporation of anharmonicity and coupling terms in the force field significantly improves the accuracy and transferability with regard to the simulation of structural, energetic, and dynamic properties of amides. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 430–458, 1998     

Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication,amplification of chirality and implication for the origin of biological enantioenriched chirality

We discovered asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product 5-pyrimidyl alkanol acts as a highly efficient asymmetric autocatalyst to afford more of itself (Soai reaction). Asymmetric autocatalysis proceeded quantitatively (>99% yield), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three rounds of consecutive asymmetric autocatalysis to >99.5% ee by asymmetric amplification. Circularly polarized light, and inorganic and organic crystals, act as the origin of chirality to trigger asymmetric autocatalysis. Asymmetric autocatalysis has enormous power to recognize and amplify the chirality of hydrogen, carbon, oxygen, and nitrogen isotopomers. Moreover, absolute asymmetric synthesis, i.e., the formation of enantioenriched compounds without the intervention of any chiral factor, is realized by asymmetric autocatalysis. By using designed molecules based on 5-pyrimidyl alkanol, the intramolecular asymmetric control, self-replication, and improvement of chiral multifunctionalized large molecules has been developed by applying asymmetric autocatalysis.     

Nano-Fe3O4@silica sulfuric acid as a reusable and magnetically separable potent solid acid catalyst in Biginelli-type reaction for the one-pot multicomponent synthesis of fused dihydropyrimidine derivatives: A greener NOSE and SFRC approach

An efficient, highly product selective, eco-friendly, one-pot multicomponent synthesis of dihydropyrimidine derivatives via Biginelli reaction has been described. The reaction was developed by greener nanoparticle-catalyzed organic synthesis enhancement (NOSE) chemistry and solvent free reaction condition (SFRC) approaches, which helped us in making the procedure greener. The reaction went smoothly with a diverse range of aromatic, aliphatic, hetero-aromatic aldehydes, different amine sources, as well as various β-dicarbonyl compounds, showing the flexibility of this methodology. Magnetically separable nano-Fe₃O₄@SiO₂@SO₃H, which acts as a potent solid acid catalyst, was characterized by FT-IR, SEM, EDX and TEM, VSM, and TGA analyses. The catalyst was recycled from the reaction mixture easily by an external magnet and reused in five more consecutive runs without much decrease in catalytic activity. Its catalytic efficiency was compared to other nano and bulk solid acid catalyst in order to ascertain the best combination for the conversion.     

A Metal–Organic Supramolecular Box as a Universal Reservoir of UV,WL, and NIR Light for Long‐Persistent Luminescence

Long persistent luminescence (LPL) materials have a unique photophysical mechanism to store light radiation energy for subsequent release. However, in comparison to the common UV source, white‐light (WL) and near‐infrared (NIR) excited LPL is scarce. Herein we report a metal–organic supramolecular box based on a D–π–A‐type ligand. Owing to the integrated one‐photon absorption (OPA) and two‐photon absorption (TPA) attributes of the ligand, the heavy‐atom effect of the metal center, as well as π‐stacking and J‐aggregation states in the supramolecular assembly, LPL can be triggered by all wavebands from the UV to the NIR region. This novel designed supramolecular kit to afford LPL by both OPA and TPA pathways provides potential applications in anti‐counterfeiting, camouflaging, decorating, and displaying, among others.     

Reactions of enaminones and related compounds with N,N-dimethylacetamide dimethyl acetal. A simple one-pot metal-free synthesis of polysubstituted benzene derivatives

Herein a simple one-pot metal-free synthesis of alkyl-, aryl-, heteroaryl- and alkoxycarbonyl substituted 1,3-bis(dimethylamino)benzene derivatives is described. The products were prepared from the corresponding methyl ketones or compounds with an α-methylene group in regard to the carbonyl group, using N,N-dimethylacetamide dimethyl acetal (DMADMA) as the reagent.     

A simple and sensitive liquid chromatographic method for the analysis of free docosanoic, tetracosanoic and hexacosanoic acids in human plasma as fluorescent derivatives

Docosanoic (C22), tetracosanoic (C24) and hexacosanoic (C26) acids are saturated very-long-chain fatty acids (VLCFA) present at trace levels in biosamples. VLCFA can be used as potential biomarkers for the diagnosis of hereditary diseases such as X-linked adrenoleukodystrophy. Because the analytes to be detected are at trace levels, a sensitive fluorimetric liquid chromatographic method was developed to analyze VLCFA in plasma. The method is simple based on extracting VLCFA from plasma with toluene, and the obtained toluene extract was subject to the derivatization of VLCFA with a fluorescent reagent 2-(2-naphthoxy)ethyl-2-(piperidino)ethanesulfonate (NOEPES) without solvent evaporation/replacement. The resulting fluorescent derivatives were monitored by fluorimetric detection (excitation at 225 nm and emission at 360 nm), giving a high sensitivity with the limit of detection about 5.0 nM (S/N = 3, 10 μL injected) of the analytes. Application of the method to the analysis of VLCFA in the plasma of patients with adrenoleukodystrophy proved practical and effective.