Medicinal Chemistry Laboratories Research Articles

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.

Advances in Development of Dopaminergic Aporphinoids

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTAdvances in Development of Dopaminergic AporphinoidsAo Zhang, Yi Zhang, Alan R. Branfman, Ross J. Baldessarini, and John L. NeumeyerView Author Information Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, The Branfman Family Foundation, 418 Queen Anne Road, Cherry Hill, New Jersey 08003, Department of Psychiatry & Neuroscience Program, Harvard Medical School, Boston, Massachusetts 02114, Neuropharmacology Laboratory Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts 02478-9106, and Medicinal Chemistry Laboratory, Alcohol & Drug Abuse Research Center, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts 02478-9106. Cite this: J. Med. Chem. 2007, 50, 2, 171–181Publication Date (Web):December 16, 2006Publication History Received8 August 2006Published online16 December 2006Published inissue 1 January 2007https://doi.org/10.1021/jm060959iCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1448Altmetric-Citations90LEARN 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 (213 KB) Get e-AlertsSUBJECTS:Agonists,Antagonists,Receptors,Rodent models,Selectivity Get e-Alerts

Recent Trends in Microwave‐Assisted Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Metal-ligand bifunctional catalysis: a nonclassical mechanism for asymmetric hydrogen transfer between alcohols and carbonyl compounds.

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTMetal−Ligand Bifunctional Catalysis: A Nonclassical Mechanism for Asymmetric Hydrogen Transfer between Alcohols and Carbonyl CompoundsRyoji Noyori, Masashi Yamakawa, and Shohei HashiguchiView Author Information Department of Chemistry and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan, Kinjo Gakuin University, Omori, Moriyama, Nagoya 463-8521, Japan, and Medicinal Chemistry Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85 Juso-honmachi, Yodogawa, Osaka 532-8686, Japan Cite this: J. Org. Chem. 2001, 66, 24, 7931–7944Publication Date (Web):November 3, 2001Publication History Received16 July 2001Published online3 November 2001Published inissue 1 November 2001https://doi.org/10.1021/jo010721wCopyright © 2001 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views11468Altmetric-Citations739LEARN 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 (688 KB) Get e-AlertsSUBJECTS:Alcohols,Anions,Hydrocarbons,Ketones,Ligands Get e-Alerts

Synthesis and Photochemical Activity of Designed Enediynes

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis and Photochemical Activity of Designed EnediynesGraham B. Jones, Justin M. Wright, Gary Plourde, Ajay D. Purohit, Justin K. Wyatt, George Hynd, and Farid FouadView Author Information Bioorganic and Medicinal Chemistry Laboratories Department of Chemistry, Northeastern University Boston, Massachusetts, 02115 Cite this: J. Am. Chem. Soc. 2000, 122, 40, 9872–9873Publication Date (Web):September 23, 2000Publication History Received2 March 2000Revised23 August 2000Published online23 September 2000Published inissue 1 October 2000https://doi.org/10.1021/ja000766zCopyright © 2000 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views534Altmetric-Citations46LEARN 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 (58 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Degradation,Hydrocarbons,Irradiation,Materials,Peptides and proteins Get e-Alerts

Molecular Flexibility Profiling Using NMR Spectroscopy

Molecular flexibility is a factor that is not extensively studied in most pharmaceutical research efforts. When it is, the level of effort is high involving the preparation of detailed models supported by either molecular dynamics simulations and/or Nuclear Magnetic Resonance data. While these studies are both powerful and illuminating, they cannot be routinely applied in a drug discovery setting as they are time and expertise intensive. Yet there seems to be little doubt that at least in some cases, molecular flexibility plays a key role in complex formation. A simple, rapid and generally applicable flexibility profiling protocol was applied to two model systems and data describing the internal mobility of carbon atoms were obtained. The protocol utilizes the Model Free approach and NMR data to characterize the internal molecular dynamics of these compounds. The first model system consisted of fluorene and diphenylmethane where the anticipated flexibility trends were observed in the data providing a link between chemical intuition and the experimental results. Data on a second model system, which consisted of two Paclitaxel analogs, showed predictable patterns including dynamical phenyl and methyl groups and a relatively immobile taxane core. Subtle differences in the internal dynamics within the taxane core suggest that it cannot be considered as a rigid structure. Key advantages of using this approach are that no prior knowledge or supposition of dynamical features is required, the protocol can be carried out in most medicinal chemistry laboratories and the data obtained provide a common, empirically derived reference point to discuss the effects of molecular flexibility on activity.