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Lead Molecule (lead + molecule)
Selected AbstractsChemInform Abstract: A General and Versatile Synthesis of 3-Phenylthio ,-Lactams as Lead Molecules for 3-Methyl-2-azetidinones.CHEMINFORM, Issue 3 2008Seema Kanwar Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] 1,3-Diaryl-2-propenones and 2-Benzylidene-1,3-indandiones: A Quest for Compounds Displaying Greater Toxicity to Neoplasms than Normal CellsARCHIV DER PHARMAZIE, Issue 9 2010Hari N. Pati Abstract A series of 1,3-diaryl-2-propenones 2a,j and analogous 2-benzylidene-1,3-indandiones 3a,j were evaluated against various neoplasms and normal cells. In general, greater cytotoxic potencies and selective toxicity to human malignant cells were observed by the compounds in series 2 rather than 3. In particular, 2i emerged as a lead molecule having an average CC50 figure of 8.6,µM and a selective index value of 18. Various physicochemical features of 2a,j were correlated with the cytotoxic potencies to neoplastic cell lines which provide guidelines for expansion of this series of compounds. The enone 2i induced internucleosomal DNA fragmentation and activated caspase-3 in HL-60 cells suggesting that one of the ways in which the cytotoxicity of the compounds in series 2 is mediated towards some of the cell lines used in this study is by apoptosis. Neurotoxicity in mice was generally lower in series 2 than 3a,j. [source] Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesisACTA CRYSTALLOGRAPHICA SECTION D, Issue 12 2007Günter Pappenberger Fatty-acid synthesis in bacteria is of great interest as a target for the discovery of antibacterial compounds. The addition of a new acetyl moiety to the growing fatty-acid chain, an essential step in this process, is catalyzed by ,-ketoacyl-ACP synthase (KAS). It is inhibited by natural antibiotics such as cerulenin and thiolactomycin; however, these lack the requirements for optimal drug development. Structure-based biophysical screening revealed a novel synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds to Escherichia coli KAS I with a binding constant of 25,µM as determined by fluorescence titration. A 1.35,Ĺ crystal structure of its complex with its target reveals noncovalent interactions with the active-site Cys163 and hydrophobic residues of the fatty-acid binding pocket. The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding. This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction. The structural information on the protein,ligand interaction offers strategies for further optimization of this low-molecular-weight compound. [source] In-vitro and in-vivo assays for angiogenesis-modulating drug discovery and developmentJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2006Michelle W. Phung In the past 35 years, significant findings have been made in relation to angiogenesis, and how this usually normal physiological function is converted into an abnormal state in cancer. To search for agents that can inhibit angiogenesis, and thereby prevent a tumour from proliferation and spread that is ultimately fatal to the patient, various in-vitro assays have been developed. In addition, older assays have been refined usually into high throughput screening formats, mainly by the biopharmaceutical industry in their attempts to develop novel therapeutic molecules and maintain a pipeline of lead candidates. The central aim is to extract more accurate data that would facilitate the birth of innovative mechanisms to defeat aberrant angiogenesis in-vivo. At the same time, better in-vivo models have been established, with the goal to mimic as close as possible the natural progression of various types of neoplasms in response to a good angiogenic response. More clinically relevant models are needed as anti-angiogenesis drug discovery and drug development companies fast track their lead molecules from preclinical investigations to phase I clinical trials. [source] Intracellular antibodies and cancer: New technologies offer therapeutic opportunitiesBIOESSAYS, Issue 7 2010David Pérez-Martínez Abstract Since the realisation that the antigen-binding regions of antibodies, the variable (V) regions, can be uncoupled from the rest of the molecule to create fragments that recognise and abrogate particular protein functions in cells, the use of antibody fragments inside cells has become an important tool in bioscience. Diverse libraries of antibody fragments plus in vivo screening can be used to isolate single chain variable fragments comprising VH and VL segments or single V-region domains. Some of these are interfering antibody fragments that compete with protein-protein interactions, providing lead molecules for drug interactions that until now have been considered difficult or undruggable. It may be possible to deliver or express antibody fragments in target cells as macrodrugs per se. In future incarnations of intracellular antibodies, however, the structural information of the interaction interface of target and antibody fragment should facilitate development of binding site mimics as small drug-like molecules. This is a new dawn for intracellular antibody fragments both as macrodrugs and as precursors of drugs to treat human diseases and should finally lead to the removal of the epithet of the ,undruggable' protein-protein interactions. [source] | ||||||||||