Modular Approach for the Synthesis and Bioactivity Profiling of 8,8'-Biflavones

Moritz K T Klischan; Flaminia Mazzone; Lena Berning; Julian Greb; Max Schlamkow; Mona Haase; Wolfgang Frey; Björn Stork; Klaus Pfeffer; Jörg Pietruszka

doi:10.1021/acsomega.3c06503

Modular Approach for the Synthesis and Bioactivity Profiling of 8,8'-Biflavones

ACS Omega. 2023 Oct 27;8(44):41816-41834. doi: 10.1021/acsomega.3c06503. eCollection 2023 Nov 7.

Authors

Moritz K T Klischan¹, Flaminia Mazzone², Lena Berning³, Julian Greb¹, Max Schlamkow^{1

4}, Mona Haase¹, Wolfgang Frey⁵, Björn Stork³, Klaus Pfeffer², Jörg Pietruszka^{1

4}

Affiliations

¹ Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf, Forschungszentrum Jülich, Stetternicher Forst, Geb.15.8, 52426 Jülich, Germany.
² Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
³ Institute of Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
⁴ Institut für Bio- und Geowissenschaften (IBG-1: Bioorganische Chemie) Forschungszentrum, 52428 Jülich, Germany.
⁵ Institute of Organic Chemistry, University of Stuttgart, 70569 Stuttgart, Germany.

Abstract

In this work, we report the scalable and modular synthesis of a library of 55 monomeric and dimeric flavonoids including 14 8,8'-biflavones. The sterically demanding tetra-ortho-substituted axis of an acetophenone dimer key intermediate was constructed in a regioselective manner using Fe-mediated oxidative coupling. This step was systematically optimized and performed on up to multigram scale. The biological activities of this compound library were evaluated, including cytotoxicity against healthy and malignant human cell lines, antimicrobial activity against the apicomplexan parasite Toxoplasma gondii, and antioxidant capacity. A marked increase in activity for the 8,8'-dimeric structures compared to that of their monomeric counterparts was observed. Several biflavones were identified with high selectivity indices (low cytotoxicity and high antiprotozoal activity), showing that this class of natural products may serve as lead structures for further investigations.