Synthesis of Selagibenzophenone A and Its Derivatives for Evaluation of Their Antiproliferative, RORγ Inverse Agonistic, and Antimicrobial Effect

• Published in: ChemistrySelect (Weinheim) 2023-02, Vol.8 (7), p.n/a
• Main Authors: Lapinskaite, Ringaile, Atalay, Hazal Nazlıcan, Malatinec, Štefan, Donmez, Serhat, Cinar, Zeynep Ozlem, Schwarz, Patrik F., Perhal, Alexander F., Císařová, Ivana, Labanauskas, Linas, Karpiński, Tomasz M., Dirsch, Verena M., Tumer, Tugba Boyunegmez, Rycek, Lukas
• Format: Article
• Language: English
• Subjects: antiproliferation; biological activity; drug discovery; medicinal chemistry; natural products
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202204816

We report a modular synthetic approach towards novel derivatives of the naturally occurring arylated benzophenone selagibenzophenone A. The initial strategy for the construction of the carbon framework of the derivatives relied on the Suzuki reaction of 2,4,6‐tribromobenzonitrile, and the addition of the aryl lithium species to nitrile to generate imine. However, the formed imines showed remarkable stability toward hydrolysis. Therefore, Suzuki cross‐coupling was carried out with 2,4,6‐tribromobenzaldehyde and the subsequent addition of organometallic species to the aldehyde. Oxidation of the resulting alcohol ensured the access to desired ketones. The importance of the developed modular strategy is underlined by the discovery of several derivatives with selective cytotoxic effects and potential anti‐inflammatory activity superior to the effect of the natural product. We report a modular synthesis of unnatural variously substituted derivatives of the natural product selagibenzophenone A. We discovered, that some of the derivatives show promising antiproliferative and potential anti‐inflammatory activity. For both biological effects, the activity of some derivatives is superior to that of the natural compound, underling the importance of the synthesis.