Five-membered heteroaromatic ring fused-pyrimidine derivatives: design, synthesis, and hedgehog signaling pathway inhibition study. 2014

Liandi Zhang, and Minhang Xin, and Han Shen, and Jun Wen, and Feng Tang, and Chongxing Tu, and Xinge Zhao, and Ping Wei
The College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, No. 30 Puzhu Road, Nanjing 211800, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.

A series of novel five-membered heteroaromatic ring fused-pyrimidine derivatives including purines, pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and furo[3,2-d]pyrimidines have been identified to be potent inhibitors of hedgehog signaling pathway. The synthesis and SAR of these compounds are described. Among this new series of hedgehog signaling pathway inhibitors, most compounds exhibited significant inhibitory activity compared to vismodegib, indicating that the five-membered heteroaromatic ring fused-pyrimidines stand out as encouraging scaffolds among the currently reported structural skeletons for hedgehog signaling pathway inhibitors, deserving more exploration and further investigation.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006576 Heterocyclic Compounds, 4 or More Rings A class of heterocyclic compounds that include four or more fused rings. Both aromatic or non-aromatic ring structures are included in this category. Heterocyclic Compounds with 4 or More Rings,Five Ring Heterocyclic Compounds,Four Ring Heterocyclic Compounds,Fused Heterocyclic Compounds, Five-Ring,Fused Heterocyclic Compounds, Four-Ring,Heterocyclic Compounds with Four or More Rings,Heterocyclic Compounds, 4-Ring,Heterocyclic Compounds, 5-Ring,Heterocyclic Cpds, 4 Ring,Heterocyclic Cpds, 4 or More Rings,Heterocyclic Cpds, 5 Ring,4-Ring Heterocyclic Compounds,5-Ring Heterocyclic Compounds,Fused Heterocyclic Compounds, Five Ring,Fused Heterocyclic Compounds, Four Ring,Heterocyclic Compounds, 4 Ring,Heterocyclic Compounds, 5 Ring
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D053823 Hedgehog Proteins A family of intercellular signaling proteins that play an important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action. Hedgehog Protein,Hedgehog Protein, Vertebrate,Banded Hedgehog Protein,Desert Hedgehog Protein,Indian Hedgehog Protein,Sonic Hedgehog Protein,Vertebrate Hedgehog Protein,Hedgehog Protein, Banded,Hedgehog Protein, Desert,Hedgehog Protein, Indian,Hedgehog Protein, Sonic,Protein, Hedgehog

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