Protoflavones express a non-aromatic, p-quinol B ring that confers them a unique 3D structure among natural flavonoids. Anticancer activity of these compounds is intensively studied, but their cytotoxicity is a strong limitation for investigating their other possible uses [1].
Our group identified protoapigenone 1’-O-propargyl ether as the first non-planar flavonoid that is a strong inhibitor of xanthine oxidase (XO), however its cytotoxicity was similarly strong. XO plays a crucial role in the pathomechanism of gout, and it also significantly contributes to oxidativ e stress [2]. Recently, our group reported a selective method to saturate the protoflavone B ring of protoapigenone and its 1’-O-butyl ether through continuous flow chemical hydrogenation to obtain non-cytotoxic derivatives with the rare, naturally occurring tetrahydroprotoflavone moiety [3].
In our present work, we aimed to investigate the structure-activity relationships of differently substituted 1’-O-alkyl tetrahydroprotoapigenone derivatives concerning their potential to inhibit XO. We utilized both batch and continuous flow chemical approaches for the preparation. With an aim to investigate the isotope effects on the XO-inhibition protoapigenone analogues, selective deuteration of the B ring was also achieved. Our preliminary studies on the obtained derivatives indicated that saturation of the p-quinol B ring could not only eliminate the cytotoxicity, but it could also further increase the XO-inhibition potential of protoflavones as compared to their parental compounds. Related pharmacological studies are currently ongoing, and results of these will also be presented.
[1] Hunyadi et al., Phytochem Rev (2014) 13 69-77.
[2] Hunyadi et al., Tetrahedron Letters (2013) 54 6529-6532.
[3] Ötvös et al., ChemPlusChem (2018) 83 72-76.
Acknowledgments
This work was supported by the National Research, Development and Innovation Office, Hungary (NKFIH; K119770) A.H. acknowledges the János Bolyai fellowship of the Hungarian Academy of Sciences and the Kálmán Szász Prize.