The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds.

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.

Protein kinases c-Abl, b-Raf, and p38alpha are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38alpha inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets. Although the discovery of this class of kinase inhibitors has increased the level of emphasis on the design of DFG-out inhibitors, the structural determinants for their binding and stabilization of the DFG-out conformation remain unclear. To improve our understanding of these determinants, we determined cocrystal structures of Imatinib and Sorafenib with p38alpha. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38alpha in comparison with BIRB-796, including binding kinetics, binding interactions, the solvent accessible surface area (SASA) of the ligands, and stabilization of key structural elements of the protein upon ligand binding. Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases.

A sequence of two known reactions, palladium catalyzed arylboronation of arybromide and subsequent oxidation of arylboronate with oxone, has been carried out to prepare functionalized phenols and pyridin-2(1H)-one which were later loaded on to resin for solid-phase synthesis. Using these resin-bound templates, a number of solid-phase methods were developed to generate libraries of substituted phenols and pyridin-2(1H)-one.

Combinatorial chemistry, combined with recent advances in robotic screening, which enable the testing of a large number of compounds in a short period of time, is becoming an important tool in accelerating drug discovery. This technique involves the preparation of a large number of structurally related compounds either as mixtures in the same reaction vessel or individually by parallel synthesis. In this manner large pools of similar compounds can be synthesized within a short period of time. Combinatorial libraries have been prepared using both solution chemistry and by solid phase synthesis; however, solid phase synthesis allows the use of excess reagents to drive the reaction to completion and easy removal of the reagents and side-products by simple filtration of the polymeric support and washing with solvent. Therefore, solid phase synthesis offers a more attractive approach to the generation of chemical libraries for screening purposes.

A number of arylsilane-based linkers are prepared for traceless solid-phase synthesis. General methodologies for introduction of the silyl group and various functional groups to aromatic, polyaromatic, and heteroaromatic rings are developed. Also, broad utilities of the linkers are demonstrated by on-resin preparation of small organic molecules and subsequent cleavage of the products either by protiodesilylation (TFA) or ipso-substitution (Br2).

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTEfficient Solid-Phase Synthesis of Compounds Containing Phenylalanine and Its Derivatives via Side-Chain Attachment to the Polymer SupportYounghee Lee and Richard B. SilvermanView Author Information Department of Chemistry, Northwestern University Evanston, Illinois 60208-3113 Cite this: J. Am. Chem. Soc. 1999, 121, 36, 8407–8408Publication Date (Web):August 31, 1999Publication History Received20 May 1999Published online31 August 1999Published inissue 1 September 1999https://doi.org/10.1021/ja991679dCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views648Altmetric-Citations26LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (33 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Monomers,Organic compounds,Organic polymers,Peptides and proteins,Solid phase synthesis Get e-Alerts