Novel synthetic molecules bioinspired in natural phenolic compounds for anticancer drug discovery

Limited effectiveness, toxicity and eventual resistance remain serious problems of the available anticancer drugs [1]. Over the last few years, our organic chemistry group have been focused on the development of new eco-friendly synthetic methods for bioactive heterocyclic compounds, including the preparation of chalcones, flavonols, and chromene derivatives. These scaffolds are widely present in plants and well recognized for the diverse pharmacological properties, including anticancer activity [2]. Here, the cytotoxicty of several bioinspired molecules was evaluated against cancer cell lines and some revealed superior activity when compared with the natural counterparts. A brominated flavonol was found to be 6 times more active than quercetin against colorectal HCT116 cancer cells (Fig. 1) and to induce significant cell cycle arrest and cell death by apoptosis [3]. Novel chromene derivatives incorporating the imidazo[1,2-a]pyridine nucleus were also synthesized and presented potent inhibition of cell growth as assessed by the MTT assay. Interestingly, two analogs of the chromene derivatives revealed to have different mechanisms of action, showing opposing effects on p53 levels and apoptosis mechanisms. These compounds may be relevant for further development of drugs acting on distinct molecular targets useful in the treatment of cancers with different genetic profiles. Novel molecules synthesized using EGCG as lead showed also improved activity. In conclusion, novel bioinspired molecules were prepared by eco-friendly synthetic approaches and showed that they can be successfully used for anticancer drug discovery.

Fig. 1: Structure and cytotoxicity of a brominated flavonol as compared with quercetin.

Acknowledgements: This work was supported by national FCT funds through the strategic project grants PEst-OE/AGR/UI4033/2014 and PEst-C/QUI/UI0686/2011. MC and TAD are supported by the FCT grants SFRH/BPD/79609/2011 and SFRH/BD/88245/2012, respectively.

Keywords: Natural compounds as leads, novel synthetic molecules, cancer, apoptosis, cytotoxicity, cell cycle arrest, p53, bioactive heterocyclic compounds

References:

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[2] Ravishankar D, Rajora AK, Greco F, Osborn HM (2013), Flavonoids as prospective compounds for anti-cancer therapy. The International Journal of Biochemistry and Cell Biology, 45: 2821 – 2831.

[3] Dias TA, Duarte CL, Lima CF, Proença MF, Pereira-Wilson C (2013), Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin. European Journal of Medicinal Chemistry, 65: 500 – 510.