Synthesis of Nontoxic Protoflavone Derivatives through Selective Continuous‐Flow Hydrogenation of the Flavonoid B‐Ring

Abstract

Protoflavones are unique natural flavonoids with a non‐aromatic B‐ring, known for their potent antitumor properties. However, their cytotoxicity represents a strong limitation in the further exploration of their pharmacological potential. In the current study, we sought to selectively saturate the p‐quinol B‐ring of protoapigenone and that of its 1′‐O‐butyl ether, in order to obtain non‐toxic protoflavone analogues expressing the dihydro‐ or tetrahydroprotoflavone structure also occurring in nature. The benefits of a strictly controlled continuous‐flow environment in combination with on‐demand electrolytic H2 gas generation were exploited to suppress undesired side reactions and to safely and selectively yield the desired substances. The obtained tetrahydroprotoflavones were free of the cytotoxicity of their parent compounds, and, even though tetrahydroprotoapigenone 1‐O‐butyl ether showed a weak inhibition of DNA damage response through Chk1, neither compounds influenced the cytotoxicity of doxorubicin either.

Clara Immerwahr Award: T. L. Lohr / Head of the Chemical Division, Hungarian Academy of Sciences: F. Fülöp / JSPS 141st Committee on Microbeam Analysis Award: H.‐J. Freund / Distinguished Scientist, Chinese Academy of Sciences: M. T. Reetz

“…Fülöp's recent research has focused on enzymatic transformations, asymmetric syntheses, foldamer construction, and flow chemistry with respect to the development of pharmacologically active compounds and new synthetic methodologies. He has reported in the European Journal of Organic Chemistry on the dynamic resolution of ethyl 1,2,3,4‐tetrahydro‐β‐carboline‐1‐carboxylate, and in ChemPlusChem on the synthesis of nontoxic protoflavone derivatives …”

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle

“…During each transformation, the catalyst bed was placed in a thermostat to assure The hydrogenation of protoflavonoids' dienone moiety might result various products. Following our previously published procedure, the saturation of the protoflavone B-ring was achieved with high selectivity under mild reaction conditions while utilizing a modified H-cube ® continuous flow hydrogenation reactor [11]. Employing this device has several advantages when compared to traditional batch hydrogenation, i.e., the ease of handling of the explosive gas, precise control over the reaction conditions, instrumentally controlled gas pressure, sustainability, and safe applicability.…”

“…This allowed for us to obtain the rare, naturally occurring tetrahydroprotoflavone moiety, while also providing an effective tool to eliminate the cytotoxicity of the derivatives [11].…”

“…We recently reported a method for the highly selective saturation of the protoflavone B-ring by means of continuous flow hydrogenation under mild reaction conditions to overcome this limitation. This allowed for us to obtain the rare, naturally occurring tetrahydroprotoflavone moiety, while also providing an effective tool to eliminate the cytotoxicity of the derivatives [11].…”

Clara‐Immerwahr‐Preis: T. L. Lohr / Vorsitzender des Fachbereichs Chemie der Ungarischen Akademie der Wissenschaften: F. Fülöp / JSPS 141st Committee on Microbeam Analysis Award: H.‐J. Freund / Auszeichnung der Chinese Academy of Sciences: M. T. Reetz

“…Fülöps Forschung umfasst enzymatische Umwandlungen, asymmetrische Synthese, Foldamere sowie Flusschemie für die Entwicklung pharmakologischer Wirkstoffe und neuer Synthesemethoden. Er veröffentlichte im European Journal of Organic Chemistry einen Beitrag über die dynamische Racematspaltung von 1,2,3,4‐Tetrahydro‐β‐carbolinen‐1‐carbonsäureethylester und in ChemPlusChem über die Synthese ungiftiger Protoflavon‐Dderivate …”