Synthesis of new, potentially bioactive chalcones as protoflavone analogues

Protoflavones represent a rare, unique class of naturally occurring bioactive flavonoid derivatives. Recent publications revealed their antiviral, anti-angiogenic and cytotoxic activity, moreover they have also been found to interfere with crucial DNA damage response mechanisms^{[1 – 3]}. The pharmacophore of these compounds is the non-aromatic B-ring – the unusual p-quinol moiety^[3]. The formation of this moiety can be synthetically achieved from 4 ′ -hydroxyflavones applying hypervalent iodine reagents.

Chalcones – also abundant in nature – exert anti-inflammatory, antioxidant, antibacterial and anticancer activity; anti-angiogenic effect of 4-hydroxychalcone 3 was reported lately^[4].

Fig. 1

During the current project our aim is – in order to broaden our knowledge on structure-activity relationships concerning protoflavones – to build a compound library by synthesizing and characterizing variously substituted chalcone analogues bearing the p-quinol moiety.

The key intermedier 4-hydroxychalcone 3 was synthesysed via Claisen-Schmidt condensation. Seven new compounds (4-10) were subsequently obtained by oxidative dearomatization performed with PIFA in various solvent mixtures. These compounds are expected to exert potent antitumor activity; their bioactivity testing is currently in progress.

This work was supported by the NKFIH, Hungary (K119770), the EU-funded Hungarian grant EFOP-3.6.1 – 16 – 2016 – 00008, and GINOP-2.3.2 – 15 – 2016 – 00012. A.H. acknowledges the János Bolyai fellowship of the Hungarian Academy of Sciences and the Kálmán Szász Prize.

[1] Danko B et al. Anticancer Res 2012; 32: 2863 – 2870.

[2] Wang HC et al. Mol. Cancer Ther 2012; 11:1443 – 1453.

[3] Hunyadi A et al. Phytochem Rev 2014; 13: 69 – 77.

[4] Varinska L et al. Eur J Pharmacol 2012; 691: 125 – 133.