The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/

Abstract:The discovery of novel chemical reactions or reaction sequences that are able to generate useful chemical products may be regarded as the heart of organic chemistry. We present here concepts and methods on how to find and explore new multi component reactions, especially with automated combinatorial methods. This "combinatorial reaction finding" provides also a powerful tool to the understanding of the rules of organic chemistry, especially structure-reactivity relationships.

The oncoprotein Mdm2, and the recently intensely studied, homologues protein Mdmx, are principal negative regulators of the p53 tumor suppressor. The mechanisms by which they regulate the stability and activity of p53 are not fully established. We have determined the crystal structure of the N-terminal domain of Mdmx bound to a 15-residue p53 peptide. The structure reveals that although the principle features of the Mdm2-p53 interaction are preserved in the Mdmx-p53 complex, the Mdmx hydrophobic cleft on which the p53 peptide binds is significantly altered: a part of the cleft is blocked by sidechains of Met and Tyr of the p53-binding pocket of Mdmx. Thus specific inhibitors of Mdm2-p53 would not be optimal for binding to Mdmx. Our binding assays show indeed that nutlins, the newly discovered, potent antagonists of the Mdm2-p53 interaction, are not capable to efficiently disrupt the Mdmx-p53 interaction. To achieve full activation of p53 in tumor cells, compounds that are specific for Mdmx are necessary to complement the Mdm2 specific binders.

A novel three-component, one-pot condensation yielding 3-amino-substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines and imidazo[1,2-a]pyrimidines from aldehydes, isonitriles and 2-aminopyridine, 2-amino-pyrazine or 2-amino-pyrimidine is described.Combinatorial chemistry has recently gained much attention in pharmaceutical research. 1 The discovery of highly versatile and efficient synthetic methods for a broad variety of chemical structures is a prerequisite for the synthesis of large and diverse compound libraries. Multicomponent condensations (MCC's) constitute an especially attractive synthetic strategy for rapid and efficient library generation since the number of possible products grows exponentially with the number of the components involved and also because of their convergent nature. 2Here we present a facile three-component, one-pot condensation reaction yielding 3-amino-substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines and imidazo[1,2-a]pyrimidines.The imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine and imidazo [1,2-a]pyrimidine structural moieties can be found in pharmacologically active compounds such as benzodiazepine receptor agonists, 3 antiinflammatory agents, 4 inhibitors of gastric acid secretion, 5 calcium channel blockers 6 and antibacterials. 7 The classical synthesis of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines and imidazo[1,2-a]pyrimidines involves the condensation of α-haloketones with 2-amino-pyridines, 2-amino-pyrazines or 2-amino-pyrimidines, respectively. 8 Being only a two-component condensation, this reaction is less suitable for the generation of a large compound library. To our knowledge only a single example for the formation of one of the said heterocyclic systems by a three-component reaction is reported in the literature, namely the synthesis of 3-amino-imidazo[1,2-a]pyrazine by condensation of 2-aminopyrazine, formaldehyde and sodium cyanide. 9The use of Ugi-type multicomponent reactions for the generation of compound libraries both by solution and solid phase chemistry has been reported by several groups. 2,10-15 Various heterocycles have been synthesized by this highly versatile condensation, including benzodiazepines, 11 pyrroles, 12 lactams, 13 hydantoins, 2,14 tetrazoles 14 and diketopiperazines. 15 In the course of our own studies of the Ugireaction using a broad variety of isonitriles 1, aldehydes 2, amines 3 and carboxylic acids we observed that the structure of the product formed depends strongly on the structure of the primary amine involved. We found now that the condensation with 6-membered heteroaromatic amines containing a H 2 N-C=N substructure leads smoothly to the generation of imidazo[1,2-a]-annulated heterobicyclic compounds. Thus, 2-amino-pyridine, 2-amino-pyrazine or 2-amino-pyrimidine gave 3-amino-imidazo[1,2-a]pyridines 4, 3-amino-imidazo[1,2-a]pyrazines 5 and 3-amino-imidazo[1,2-a]pyrimidines 6, respectively (Scheme 1).This reaction may be regarded as a special type of the Ugi four component reaction. 2 Thus, the reaction proce...

Artificial evolutionary synthesis can be used to find biologically active compounds out of a library of 160000 possible Ugi‐type reaction products by using an enzymatic assay (thrombin) as the feedback loop function. Thus, a reaction in generation 18 gave compound 1, which exhibits the structural features of known thrombin inhibitors and inhibits the enzyme effectively (Ki = 0.22 μM).