Synthesis of a New Class of Furan-Fused Tetracyclic Compounds Using o-Quinodimethane Chemistry and Investigation of Their Antiviral Activity

Abstract

The synthesis and evaluation of antiviral activity of new furan-fused tetracyclic compounds are described. The syntheses were satisfactorily achieved on the basis of o-quinodimethane chemistry, using furan-containing benzocyclobutene derivatives as a substrate, in high generality and stereoselectivity. The various derivatives thus synthesized were examined on their inhibitory activity on virus growth using a hemagglutinin (HA) method, leading to a discovery of promising candidates for new antiviral drugs having high activity and good therapeutic index.

Die Synthese von naturstoffinspirierten Verbindungsbibliotheken

“…Ausgehend von einer tetracyclischen furanhaltigen Leitstruktur [44] synthetisierten Nemoto und Mitarbeiter eine Bibliothek aus mehrfach anellierten Furanderivaten mit naturstoffähnlicher Architektur. [45] Das Strukturgerüst wurde über eine intramolekulare [4+2]-Cycloaddition von o-Chinodimethanen synthetisiert, wobei letztere durch thermische Ringöffnung von Benzocyclobutanderivaten zugänglich sind (Schema 12). [46] Mit [42,43,47] manche hemmen außerdem auch die Cdc25B-Phosphatase.…”

Synthetic Organic Chemistry Based on Small Ring Compounds

“…This new finding inspired us to examine the structure-activity relationships of its congeners, aiming at the discovery of new candidates for antiviral drugs. 91) As a preliminary study, the antiviral activity was surveyed using the assay method of hemagglutinin (HA) titers. 92) HVJ in LLC-MK2 cells was used for the assay, and the inhibitory activity on the virus growth was assessed as minimum inhibitory concentrations (MIC), which are summarized in Fig.…”

“…96) For example, bafilomycin A1 has been reported to exert inhibitory effects on influenza virus growth through specific inhibition of vacuolar-type proton pump to raise the pH in endosomes and lysosomes. 91) To examine whether drug 10 could exert a similar effect, acidification of intracellular compartments under influence of the drug was monitored by vital fluorescence microscopy with acridine orange. 97) This examination revealed that the amount and intensity of fluorescence in the drugtreated cells were almost identical with the control cells, implying that the drug did not affect the acidic environment of intracellular compartments, which causes the uncoating process.…”

“…In the course of our continuous research on o-quinodimethane chemistry, 90,91,105) we focused our interest on the substituent effect for the thermal cleavage of benzocyclobutenes, especially on the silyl substituents 106) in conjunction with recent reports on their rate enhancement effects for that of monocyclic cyclobutenes. 107,108) The compounds 112a-c and 113a-c were conducted to thermal electrocyclic reaction involving concurrent [4ϩ2] cycloaddition with maleic anhydride.…”

Approach to a New Dihydrofuran‐Fused Cyclic System by a Remarkable Switching of endo/exo Selectivity of a [4+2] Cyclo­addition Reaction

“…[1] In the course of our model studies on the synthesis of furan-fused polyketides, halenaquinone, and xestoquinone, [2] we found that dihydrofuran-fused tetracyclic compounds, represented by general structure 1, exert notable antiproliferative effects against viruses, including influenza A and B. [3] More recently, we also reported that this class of compounds can enhance hyperthermiainduced apoptosis in human lymphoma U937 cells. [4] Novel structural characteristics make them a promising lead compound for the discovery of a new type of therapeutic agent.…”