Unsupervised 3D ring template searching as an ideas generator for scaffold hopping: use of the LAMDA, RigFit, and field-based similarity search (FBSS) methods

Crystal structures taken from the Cambridge Structural Database were used to build a ring scaffold database containing 19 050 3D structures, with each such scaffold then being used to generate a centroid connecting path (CCP) representation. The CCP is a novel object that connects ring centroids, ring linker atoms, and other important points on the connection path between ring centroids. Unsupervised searching in the scaffold and CCP data sets was carried out using the atom-based LAMDA and RigFit search methods and the field-based similarity search method. The performance of these methods was tested with three different ring scaffold queries. These searches demonstrated that unsupervised 3D scaffold searching methods can find not only the types of ring systems that might be retrieved in carefully defined pharmacophore searches (supervised approach) but also additional, structurally diverse ring systems that could form the starting point for lead discovery programs or other scaffold-hopping applications. Not only are the methods effective but some are sufficiently rapid to permit scaffold searching in large chemical databases on a routine basis.     

Predicting the Outcome of Photocyclisation Reactions: A Joint Experimental and Computational Investigation

Photochemical oxidative cyclodehydrogenation reactions are a versatile class of aromatic ring‐forming reactions. They are tolerant to functional group substitution and heteroatom inclusion, so can be used to form a diverse range of extended polyaromatic systems by fusing existing ring substituents. However, despite their undoubted synthetic utility, there are no existing models—computational or heuristic—that predict the outcome of photocyclisation reactions across all possible classes of reactants. This can be traced back to the fact that “negative” results are rarely published in the synthetic literature and the lack of a general conceptual framework for understanding how photoexcitation affects reactivity. In this work, we address both of these issues. We present experimental data for a series of aromatically substituted pyrroles and indoles, and show that quantifying induced atomic forces upon photoexcitation provides a powerful predictive model for determining whether a given reactant will photoplanarise and hence proceed to photocyclised product under appropriate reaction conditions. The propensity of a molecule to photoplanarise is related to localised changes in charge distribution around the putative forming ring upon photoexcitation. This is promoted by asymmetry in molecular structures and/or charge distributions, inclusion of heteroatoms and ethylene bridging and well‐separated or isolated photocyclisation sites.     

How much does the SI,namely the proposed “New SI”, conform to principles of the Metre Treaty?

The International System of Units (SI) was first adopted in 1960, as the more recent implementation of the Metre Treaty signed in 1875. Basic features of the original SI are that (a) seven units are chosen as “base units”, all the others being “derived units”, and (b) the definitions of the base units should not create interdependence. This way, the SI conforms to the basic principle of the Metre Treaty that each signatory country can realise its choice of primary national standards of the very definitions of the units without needing to resort to calibrations obtained from another country, and without obligation to have them realised for all the units. A mismatch already occurs to some extent with respect to the above features in the present definitions of SI base units. This contribution, strictly based on metrological considerations, illustrates how the present proposal concerning new definitions for the base units, called “New SI”, would extend the mismatch. In this frame, also the meaning is discussed of the concepts of hierarchy and traceability in metrology. By outlining some of the consequences, a discussion is stimulated related to the status of base unit, to the meaning of calibration at the level of the standards of the unit definitions, and to the interdependence of countries’ standards.     

Programming Organic Molecules: Design and Management of Organic Syntheses through Free‐Radical Cascade Processes

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such “purposeful” molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free‐radical cascades. A convenient system for classifying free‐radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring‐cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three‐stage unimolecular free‐radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C‐atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of “programming” organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.     

Concept system on ‘quantity’: formation and terminology

The third edition of the International Vocabulary of Metrology occasions continued useful discussion. A Commentator, in four recent papers, presents viewpoints on the generic division of ‘property’, ‘quantity’, and ‘ordinal quantity’, as well as a perceived problem of inheritance. Alternative terms for ‘kind-of-quantity’, ‘kind-of-quantity with chosen sort of component’, and ‘dedicated kind-of-quantity’ are suggested to be formed by prefacing “quantity” with the respective adjectival modifiers “generic”, “subgeneric”, and “specific”. Furthermore, a neoterm for ‘quantity expressed by a measurement unit’ and a redefinition of ‘property’ are offered. The Commentator’s proposals and arguments are discussed with emphasis on ways of constructing concept systems to ensure proper inheritance. Some formal and semantic problems of the proposed alternative terms and definitions are advanced. Terminological concepts are defined in an Appendix.     

Modern concepts on catalysis of hydroprocessing and synthesis of alcohols from syngas by transition metal sulfides

A concept on the dynamic nature of active centers (AC) of the catalysts based on transition metal sulfides is described. The concept formed the basis of a “dynamic” model, according to which AC formed and functioning under the reaction conditions can oscillate between layers of promoted molybdenum sulfide. The model assumes the existence of “rapid” and “slow” AC and the possibility of their intertransformation due to the reversible migration of sulfur and promoter between the crystallite layers in a hydrogen atmosphere. The frequency of these migrations (oscillations) determines the catalyst activity. An assumption is substantiated that the hydrogenation sites are localized at the rims of Co(Ni)MoS₂ crystallites and desulfurization (hydrodesulfurization) sites are localized on the edges. The proposed model makes it possible to develop criteria for the evaluation of the efficiency of catalytic performance for hydrodesulfurization of hydrocarbon raw materials of various types and for synthesis of higher alcohols from syngas.     

Static atomistic modelling of the structure and ring dynamics of bulk amorphous polystyrene

A detailed static atomistic model of dense, glassy polystyrene is simulated using a well established technique that previously proved successful for simple vinyl polymers. Initial chain conformations that are generated using a Monte Carlo technique including periodic continuation conditions are “relaxed” by potential energy minimization. In total 24 microstructures at densities of 1,07 g/cm³ were obtained with a cube-edge length of 18,65 Å. Detailed analysis of the minimized structures indicates that intermolecular packing influences create a large variety of chain conformations different from the purely intramolecular ground states. The systems are amorphous, exhibiting random coil behavior. The described structures have been used for a quasistatic simulation of localized motions. These motions include stepwise rotation and oscillation of the phenyl groups. The frequency distribution for the simulated ring motions covers many orders of magnitude. It is very rare that an energy barrier with a reorientation angle indicating a ring “flip” is overcome. Motions with small reorientation of the phenyl rings, and therefore not leading to a ring “flip”, dominate with an average reorientation angle of 16° (±12°). The intermolecular effects of the analyzed processes were found very important and far-reaching, widely influencing the cooperative motions of molecular groups.     

Gezielte Konformationsänderungen an cyclischen Systemen, 1. Mitt.: Das Isokonformationskonzept

By means of the “isoconformational concept” it is shown that a correlation of conformations of ring compounds with the corresponding patern of signs for their torsional angles and an equal number of torsional degrees of freedom is feasible, as far as geometrically required conformational changes are concerned (i.e. disregarding secondary, system inherent effects). The applicability of the concept is studied by means of 1- and 1,10-substituted [2.2]metacyclophanes, the conformations of which can be deduced from the “geometric behaviour” of cyclohexane.     

[Fe(H2O)5(NO)]2+, the “Brown‐Ring” Chromophore

Although the “brown‐ring” ion, [Fe(H₂O)₅(NO)]²⁺ ( 1 ), has been a research target for more than a century, this poorly stable species had never been isolated. We now report on the synthesis of crystals of a salt of 1 which allowed us to tackle the unique bonding situation on an experimental basis. As a result of the bonding analysis, two stretched, spin‐polarised π‐interactions provide the Fe–NO binding—and challenge the concept of “oxidation state”.     

Dosimetric concepts in photobiology

Abstract —The effectiveness of an irradiation at non-ionizing wavelengths for producing photochemical changes in a transparent sample can be characterized by any one of four different quantities. The utility of each depends on the information available about the sample and the kind of analysis intended. Nomenclature for these quantities is troubled. All four have been called “dose” in the literature, with or without modifying adjectives. In addition, incompatibility between the terminology for ionizing and non-ionizing radiations leaves the concept of “dose” ambiguous in the vacuum ultraviolet. Rather than abandon the term altogether, nomenclature restricting its use is suggested here, together with measurement units and symbols for the quantities. The use of dosimetric quantities implies certain assumptions about the system being irradiated which are not always fulfilled.     

Lattice-dynamical calculations for tetracene and pentacene

Lattice-dynamical, calculations for evidently non-rigid molecules of aromatic hydrocarbons have been carried out on tetracene and pentacene. In these substances, “out-of plane” vibrations mix extensively with lattice vibrations, and significant differences can be noted between results from a “rigid-body” and a “non-rigid” treatment. For tetracene crystals, whose Raman spectral data are given in the literature, the agreement with experiment is satisfactory. This confirms the validity of such procedures for interpreting and/or predicting spectroscopic behaviour, starting from empirical atom—atom potentials and valence force fields.     

Formal Cycloadditions Driven by the Homolytic Opening of Strained,Saturated Ring Systems

The field of strain-driven, radical formal cycloadditions is experiencing a surge in activity motivated by a renaissance in free radical chemistry and growing demand for sp³-rich ring systems. The former has been driven in large part by the rise of photoredox catalysis, and the latter by adoption of the “Escape from Flatland” concept in medicinal chemistry. In the years since these broader trends emerged, dozens of formal cycloadditions, including catalytic, asymmetric variants, have been developed that operate via radical mechanisms. While cyclopropanes have been studied most extensively, a variety of strained ring systems are amenable to the design of analogous reactions. Many of these processes generate lucrative, functionally decorated sp³-rich ring systems that are difficult to access by other means. Herein, we summarize recent efforts in this area and analyze the state of the field.     

The structural theory and physical organic chemistry

Woolley's revolutionary proposal that quantum mechanics does not sanction the concept of “molecular structure”—which is but only a “metaphor”—has fundamental implications for physical organic chemistry. On the one hand, the Uncertainty Principle limits the precision with which transition state structures may be defined; on the other, extension of the structure concept to the transition state may be unviable. Attempts to define transition states have indeed caused controversy. Consequences for molecular recognition, and a mechanistic classification, are also discussed.     

Beiträge zur Chemie der Pyrrolpigmente, 49. Mitt.

From kinetic and equilibrium measurements the activation and thermodynamic parameters of diastereomeric 2,3-dihydrobilatrienes-abc in positions “4” and “15” are deduced. Compared to bilatrienes-abc a pronounced thermal lability of these diastereomers is observed—the exocyclic double bond of the saturated lactam ring being the more labile one. This feature may be of relevance to the thermal cascades and dark reactions observed for phytochrome.     

An informatic pipeline for managing high-throughput screening experiments and analyzing data from stereochemically diverse libraries

Integration of flexible data-analysis tools with cheminformatics methods is a prerequisite for successful identification and validation of “hits” in high-throughput screening (HTS) campaigns. We have designed, developed, and implemented a suite of robust yet flexible cheminformatics tools to support HTS activities at the Broad Institute, three of which are described herein. The “hit-calling” tool allows a researcher to set a hit threshold that can be varied during downstream analysis. The results from the hit-calling exercise are reported to a database for record keeping and further data analysis. The “cherry-picking” tool enables creation of an optimized list of hits for confirmatory and follow-up assays from an HTS hit list. This tool allows filtering by computed chemical property and by substructure. In addition, similarity searches can be performed on hits of interest and sets of related compounds can be selected. The third tool, an “S/SAR viewer,” has been designed specifically for the Broad Institute’s diversity-oriented synthesis (DOS) collection. The compounds in this collection are rich in chiral centers and the full complement of all possible stereoisomers of a given compound are present in the collection. The S/SAR viewer allows rapid identification of both structure/activity relationships and stereo-structure/activity relationships present in HTS data from the DOS collection. Together, these tools enable the prioritization and analysis of hits from diverse compound collections, and enable informed decisions for follow-up biology and chemistry efforts.     

Versatile 2‐aminothiazoles,building blocks for highly functionalised heterocycles

The reactions of quantitatively available 4‐phenyl‐ and 4‐(4‐antipyrinyl)‐2‐aminothiazole [“4‐antipyrinyl‐” is used as a short‐term for “4‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1‐H‐pyrazol‐4yl)‐”] with chloroacetyl chloride, acetic anhydride, ethyl cyanoacetate and carbon disulphide are reported. The products are transformed further by Knoevenagel condensations and coupling reactions with aromatic diazonium salts. The latter occur both at the thiazole ring and at the active methylene sites. The tautomerism of these products is studied on the basis of density functional theory calculations at the B3LYP/6‐31G* level.     

A quantum chemical study of three isomers of N20

Ab initio molecular orbital (MP2) and density functional theory (B3LYP) calculations using different basis sets have been employed to study the structures, energetics and vibrational frequencies of the large homonuclear polynitrogen compound, N₂₀. In the present study, three distinct forms were found to represent local minima on the potential energy surface. They are the fullerene-type cage form of I_h symmetry, a corannulene-like bowl form of C_5v symmetry, and a ring isomer with D₅ symmetry of which the cage form turns out to be the highest energy form. Both the bowl and ring forms are calculated to be more stable than the cage form by about 200 kcal/mol. The molecular properties calculated for these isomers may serve as valuable predictions for future experimental searches for new high energy density materials (HEDM).     

高中生“芳香烃”心智模型的测评及其教学启示*

采用二阶式纸笔测验以及半结构化访谈法对高中生持有的“芳香烃”心智模型进行测评,并重点分析了学生建构的与“芳香烃和苯的同系物的概念”“芳香烃的结构”“苯及其同系物的化学性质”等概念群相关的缺陷模型。研究发现学生建构的有关“芳香烃”缺陷模型包括3大类共计11种;学生对有机物空间结构的想象力和建构能力较为薄弱;学生对“有机化合物结构内基团之间相互作用对其化学性质的影响”认识不足,“性质结构”模型不完善;学生建构的有机化学的心智模型尚不具备整体性。     

Triple Click Reaction Strategy for Macromolecular Diversity

This Feature Article focuses on the rapidly emerging concept of the “triple click reactions” towards the design and synthesis of macromolecules with well‐defined topology and chemical composition, and also precise molecular weight and narrow molecular weight distribution. The term “triple click reaction” used in this feature article is based on the utilization of three chemically and mechanistically different click reactions for polymer–polymer conjugation and post‐modification of the polymers. Three sequential click reactions of which two are identical should not be considered to be triple click reactions. The triple click reaction strategy for polymer conjugation and post‐modification of polymers is classified in this article based on the resultant architectures: linear and non‐linear structures.