Chemical Graph Theory. V. On the Classification of Topological Biradicals

We have considered skeletal forms for topological (conjugated) biradicals and have examined alternative structural classification schemes for them. In particular, we have looked more closely at the classification proposed by Herndon and Ellzey, based on the multiplicity of the zero eigenvalue and have examined all acyclic forms having 12 or fewer carbon atoms, and all cyclic forms having 8 or fewer carbon atoms. Whlle the present work does not contribute to resolving the controversy as to which type of biradical can be expected to have the singlet, and which the triplet ground state, it provides the possibility of grouping compounds of the same expected ground state and thus allows the deduction of similar properties for members of the same group. Hence, definitive theoretical or experimental results obtained for a new standard species can then be applied to a wider body of biradicals. Examination of the distribution of »unpaired« spin density and the character of bonds which have a constant body type (so-called essentially single or essentially double CC bonds) provided guidance for deriving a number of rules for the construction of larger topological biradical forms by the combination (as fragments) of smaller-sized biradicals or other molecular fragments

Structure-based classification and ontology in chemistry

<p>Abstract</p> <p>Background</p> <p>Recent years have seen an explosion in the availability of data in the chemistry domain. With this information explosion, however, retrieving <it>relevant </it>results from the available information, and <it>organising </it>those results, become even harder problems. Computational processing is essential to filter and organise the available resources so as to better facilitate the work of scientists. Ontologies encode expert domain knowledge in a hierarchically organised machine-processable format. One such ontology for the chemical domain is ChEBI. ChEBI provides a classification of chemicals based on their structural features and a role or activity-based classification. An example of a structure-based class is 'pentacyclic compound' (compounds containing five-ring structures), while an example of a role-based class is 'analgesic', since many different chemicals can act as analgesics without sharing structural features. Structure-based classification in chemistry exploits elegant regularities and symmetries in the underlying chemical domain. As yet, there has been neither a systematic analysis of the types of structural classification in use in chemistry nor a comparison to the capabilities of available technologies.</p> <p>Results</p> <p>We analyze the different categories of structural classes in chemistry, presenting a list of patterns for features found in class definitions. We compare these patterns of class definition to tools which allow for automation of hierarchy construction within cheminformatics and within logic-based ontology technology, going into detail in the latter case with respect to the expressive capabilities of the Web Ontology Language and recent extensions for modelling structured objects. Finally we discuss the relationships and interactions between cheminformatics approaches and logic-based approaches.</p> <p>Conclusion</p> <p>Systems that perform intelligent reasoning tasks on chemistry data require a diverse set of underlying computational utilities including algorithmic, statistical and logic-based tools. For the task of automatic structure-based classification of chemical entities, essential to managing the vast swathes of chemical data being brought online, systems which are capable of hybrid reasoning combining several different approaches are crucial. We provide a thorough review of the available tools and methodologies, and identify areas of open research.</p

Organophosphorus Chemistry 2018

Organophosphorus chemistry is an important discipline within organic chemistry. Phosphorus compounds, such as phosphines, trialkyl phosphites, phosphine oxides (chalcogenides), phosphonates, phosphinates and >P(O)H species, etc., may be important starting materials or intermediates in syntheses. Let us mention the Wittig reaction and the related transformations, the Arbuzov- and the Pudovik reactions, the Kabachnik–Fields condensation, the Hirao reaction, the Mitsunobu reaction, etc. Other reactions, e.g., homogeneous catalytic transformations or C-C coupling reactions involve P-ligands in transition metal (Pt, Pd, etc.) complex catalysts. The synthesis of chiral organophosphorus compounds means a continuous challenge. Methods have been elaborated for the resolution of tertiary phosphine oxides and for stereoselective organophosphorus transformations. P-heterocyclic compounds, including aromatic and bridged derivatives, P-functionalized macrocycles, dendrimers and low coordinated P-fragments, are also of interest. An important segment of organophosphorus chemistry is the pool of biologically-active compounds that are searched and used as drugs, or as plant-protecting agents. The natural analogue of P-compounds may also be mentioned. Many new phosphine oxides, phosphinates, phosphonates and phosphoric esters have been described, which may find application on a broad scale. Phase transfer catalysis, ionic liquids and detergents also have connections to phosphorus chemistry. Green chemical aspects of organophosphorus chemistry (e.g., microwave-assisted syntheses, solvent-free accomplishments, optimizations, and atom-efficient syntheses) represent a dynamically developing field. Last, but not least, theoretical approaches and computational chemistry are also a strong sub-discipline within organophosphorus chemistry

Diversity-Oriented Synthetic Strategies Applied to Cancer Chemical Biology and Drug Discovery

How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery

A treatment of stereochemistry in computer aided organic synthesis

This thesis describes the author’s contributions to a new stereochemical processing module constructed for the ARChem retrosynthesis program. The purpose of the module is to add the ability to perform enantioselective and diastereoselective retrosynthetic disconnections and generate appropriate precursor molecules. The module uses evidence based rules generated from a large database of literature reactions. Chapter 1 provides an introduction and critical review of the published body of work for computer aided synthesis design. The role of computer perception of key structural features (rings, functions groups etc.) and the construction and use of reaction transforms for generating precursors is discussed. Emphasis is also given to the application of strategies in retrosynthetic analysis. The availability of large reaction databases has enabled a new generation of retrosynthesis design programs to be developed that use automatically generated transforms assembled from published reactions. A brief description of the transform generation method employed by ARChem is given. Chapter 2 describes the algorithms devised by the author for handling the computer recognition and representation of the stereochemical features found in molecule and reaction scheme diagrams. The approach is generalised and uses flexible recognition patterns to transform information found in chemical diagrams into concise stereo descriptors for computer processing. An algorithm for efficiently comparing and classifying pairs of stereo descriptors is described. This algorithm is central for solving the stereochemical constraints in a variety of substructure matching problems addressed in chapter 3. The concise representation of reactions and transform rules as hyperstructure graphs is described. Chapter 3 is concerned with the efficient and reliable detection of stereochemical symmetry in both molecules, reactions and rules. A novel symmetry perception algorithm, based on a constraints satisfaction problem (CSP) solver, is described. The use of a CSP solver to implement an isomorph‐free matching algorithm for stereochemical substructure matching is detailed. The prime function of this algorithm is to seek out unique retron locations in target molecules and then to generate precursor molecules without duplications due to symmetry. Novel algorithms for classifying asymmetric, pseudo‐asymmetric and symmetric stereocentres; meso, centro, and C2 symmetric molecules; and the stereotopicity of trigonal (sp2) centres are described. Chapter 4 introduces and formalises the annotated structural language used to create both retrosynthetic rules and the patterns used for functional group recognition. A novel functional group recognition package is described along with its use to detect important electronic features such as electron‐withdrawing or donating groups and leaving groups. The functional groups and electronic features are used as constraints in retron rules to improve transform relevance. Chapter 5 details the approach taken to design detailed stereoselective and substrate controlled transforms from organised hierarchies of rules. The rules employ a rich set of constraints annotations that concisely describe the keying retrons. The application of the transforms for collating evidence based scoring parameters from published reaction examples is described. A survey of available reaction databases and the techniques for mining stereoselective reactions is demonstrated. A data mining tool was developed for finding the best reputable stereoselective reaction types for coding as transforms. For various reasons it was not possible during the research period to fully integrate this work with the ARChem program. Instead, Chapter 6 introduces a novel one‐step retrosynthesis module to test the developed transforms. The retrosynthesis algorithms use the organisation of the transform rule hierarchy to efficiently locate the best retron matches using all applicable stereoselective transforms. This module was tested using a small set of selected target molecules and the generated routes were ranked using a series of measured parameters including: stereocentre clearance and bond cleavage; example reputation; estimated stereoselectivity with reliability; and evidence of tolerated functional groups. In addition a method for detecting regioselectivity issues is presented. This work presents a number of algorithms using common set and graph theory operations and notations. Appendix A lists the set theory symbols and meanings. Appendix B summarises and defines the common graph theory terminology used throughout this thesis

Eight-membered cyclic amines as novel scaffolds for drug discovery

The research conducted in this PhD thesis is one of the six projects of iDESIGN, an EU-funded European Industrial Doctorate Innovative Training Network (EU-EID-ITN). iDESIGN’s principal research objective was to design and synthesise novel compound libraries of structurally and functionally diverse, three-dimensional molecules with attractive physicochemical properties for early-stage drug discovery. Due to their conformational flexibility and presence in various bioactive natural products, eight-membered cyclic amine derivatives were considered valuable starting points for drug discovery as they represent an underexplored – and therefore underexploited – region of chemical space. Literature compound N-Boc-(Z)-5-oxo-3,4,5,8-tetrahydroazocine was synthesed in five steps, including an optimised ring-closing metathesis reaction as the key step, which was scaled up to gramme scale. By selectively manipulating the embedded enone functionality in this N-Boc-azacyclooctenone parent scaffold, three structurally distinct core scaffolds, comprising an azacyclooctylamine, a family of 8-5/8-6 fused aromatic heterocycles and an 8-5 fused pyrrolidine, were synthesised, each with multiple appendable handles. From these scaffolds, three diverse compound libraries were designed in silico and then prepared via parallel synthesis. Using KNIME and DataWarrior, the compound libraries were designed to display maximum diversity in drug-like physicochemical, structural and molecular shape space, which was validated using principal component analysis and Tanimoto similarity calculations. From the 200 synthesised library compounds, a representative selection was screened for hERG activity, whilst a broad range of measured ElogD values reflected the effort in maximising calculated physicochemical values (e.g., clogP) during in silico library design. All of the library compounds have been submitted to the Haworth Chemically Enabled Compound Collection (HC$^3$), a collaborative screening collection which is maintained by the Birmingham Drug Discovery Hub. Biological screening of these compounds against Mycobacteria and representative ESKAPE pathogens is planned for the near future

Celebrating Applied Sciences Reaches 20,000 Articles Milestone

To celebrate the publication of 20,000 articles in Applied Sciences, we launched this Special Issue “Celebrating Applied Sciences Reaching Its 20,000 Article Milestone: Feature Papers of the Applied Biosciences and Bioengineering Section”. We have invited well-known experts in different areas of interest covered in “Applied Biosciences and Bioengineering” to submit their original research papers and review articles of the highest quality in celebrating together with our readers on this special occasion. This Special Issue has collected more than 10 papers featuring important and recent developments or achievements in biosciences and bioengineering, with a special emphasis on recently discovered techniques or applications

Marine Drug Research in China: Selected Papers from the 15-NASMD Conference

The Book covers this whole field, from the discovery of structurally new and bioactive natural products (including biomacromolecules), from marine macro-/micro-organisms, to the pharmacodynamics, pharmacokinetics, metabolisms, and mechanisms of marine-derived lead compounds, both in vitro and in vivo, along with the synthesis and/or structural optimization of marine-derived lead compounds and their structure–activity relationships. Taken together, this Special Issue reprint not only provides inspiration for the discovery of marine-derived novel bioactive compounds, but also sheds light on the further research and development of marine candidate drugs