| Abstract |
The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.
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| MeSH term(s) |
Adamantane/analogs & derivatives ; Adamantane/chemical synthesis ; Adamantane/chemistry ; Adamantane/therapeutic use ; Amino Acid Sequence ; Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/therapeutic use ; Capsid Proteins/chemistry ; Capsid Proteins/metabolism ; Drug Delivery Systems ; Gene Expression Regulation ; Gene Products, gag/chemistry ; Gene Products, gag/metabolism ; HIV-1/drug effects ; HIV-1/genetics ; Humans ; Hydrochloric Acid/pharmacology ; Magnetic Resonance Spectroscopy ; Molecular Sequence Data ; Nucleocapsid Proteins/chemistry ; Nucleocapsid Proteins/metabolism ; Oligopeptides/chemistry ; Oligopeptides/metabolism ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/therapeutic use ; RNA Viruses/drug effects ; RNA, Viral/drug effects ; RNA, Viral/genetics ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/metabolism ; Spectrophotometry, Infrared ; Temperature ; Transcriptional Activation ; Viral Proteins/antagonists & inhibitors ; Viral Proteins/chemistry ; Vitamin B 6/administration & dosage ; Vitamin B 6/analogs & derivatives ; Zinc Fingers/drug effects ; Zinc Fingers/genetics ; gag Gene Products, Human Immunodeficiency Virus |
