Abstract
Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, β- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 μM. Four conjugates 51 and 69–71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 μM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.
Highlights
Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus
To pursue our research interests in natural products with significant anti-influenza activity, we planned to synthesize a series of multivalent BA derivatives based on CD scaffolds linked by a variable length oligo(ethylene glycol)norbomene (OEG)
poly(ethylene glycol) (PEG) and OEGs are ubiquitously used in the pharmaceutical industry and biomedical research for the modification of proteins, peptides or nonpeptides
Summary
The multivalent presentation of bioactive molecules to polymers, such as poly(ethylene glycol) (PEG), has aroused extensive interest and been widely applied in many different fields [26,27], especially in drug delivery systems [28]. Difficulties in loading a quantitative amount of drugs at a specific position of polymeric carriers, such as polymethyl methacrylate, make drug delivery systems hard to work with. To pursue our research interests in natural products with significant anti-influenza activity, we planned to synthesize a series of multivalent BA derivatives based on CD scaffolds linked by a variable length OEG chain via click chemistry. Three natural CD scaffolds and six OEG linkers were selected because of their beneficial effects on the grafted ligands, such as water solubility and good biocompatibility and immune compatibility [29]
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