Human immunodeficiency virus (HIV) integrase (IN) catalyzes the integration of HIV DNA copy into the host cell DNA. Such integration is essential for the production of progeny viruses, and therefore therapeutic agents that can inhibit this process should be effective anti-HIV agents. We have previously reported the inhibitory activity of dicaffeoylglucosides against HIV IN. In the present study, we have synthesized and tested dicaffeoyl or digalloyl compounds joined through a five-membered heterocyclic ring as HIV IN inhibitors to explore the SARs of this family of compounds. The starting heterocyclic diols were prepared from l-tartaric acid, diethyl l-tartarate or d-(+)-ribonic γ-lactone. We found that the HIV IN inhibitory activities of dicaffeoyl derivatives were comparable to that of l-chicoric acid (IC50=24.9 μM). On the other hand, digalloyl derivatives were more potent than l-chicoric acid with IC50 values of 4.7–15.6 μM.

HIV protease inhibitors containing 6-hydroxy-1,3-dioxin-4-one ring system as a new scaffold have been prepared. Among them, compound 4d showed potent HIV protease inhibitory activity (IC50=0.01 μM) and antiviral activity in cell culture (EC50=0.96 μM, SI=65.69).

Lysophosphatidic acid (LPA) is a lipid metabolite that induces the activation of mitogen-activated protein kinase (MAPK) through binding to the G protein-coupled receptor in a number of cell lines and cultures. Recent studies have revealed that LPA is able to rapidly induce the phosphorylation of MAPK through an epidermal growth factor (EGF) receptor-dependent pathway. We investigated the role of the EGF receptor in the signaling pathway initiated by LPA stimulation in nerve growth factor (NGF)-responsive PC12 cells well known to transiently retract their own neurites upon LPA stimulation. LPA-stimulated MAPK signaling was suppressed by the selective EGF receptor inhibitor and in the dominant negative mutant EGF receptor cell line. As in the EGF signaling pathway, the complex of EGF receptor with adapter proteins Shc and Sos was formed in response to LPA stimulation, suggesting there is an intracellular mechanism for transactivation. A neurite retraction assay was also performed to examine the role of the EGF receptor in PC12 cell differentiation, which related to the involvement of LPA-induced neurite retraction. These results suggest that the receptor tyrosine kinase can be activated in a ligand-independent manner through intracellular crosstalk between the signaling pathways.

Caffeoylglucosides, which have a glucose ring as a central linker, were synthesized from methyl d-glucosides, and their anti-HIV-1 activities were tested. Among them, four dicaffeoylglucosides (IC50=29.1–35.1 μM), 6a, 6b, 9b and 10b, showed HIV-1 integrase inhibitory activity as potent as l-chicoric acid.

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTChiral Synthesis of trans-1-Aminoindolo[2,3-a]quinolizidine and trans-1-Aminobenzo[a]quinolizidine Derivatives from l-Pyroglutamic AcidYong Sup Lee, Dae Joo Cho, Sun Nam Kim, Jung Hoon Choi, and Hokoon ParkView Author Information Medicinal Chemistry Research Center, Korea Institute of Science & Technology, P.O. Box 131 Cheongryang, Seoul 130-650, Korea, and Department of Chemistry, Hanyang University, Seoul 133-791, Korea Cite this: J. Org. Chem. 1999, 64, 26, 9727–9730Publication Date (Web):November 25, 1999Publication History Received27 July 1999Published online25 November 1999Published inissue 1 December 1999https://doi.org/10.1021/jo9911950Copyright © 1999 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views824Altmetric-Citations23LEARN 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 (180 KB) Get e-AlertsSUBJECTS:Amides,Cyclization,Ions,Organic compounds,Redox reactions Get e-Alerts