RESUMO
Natural products, which are enzymatically biosynthesized, have a broad range of biological activities. In particular, many flavonoids are known to contribute to human health with low toxicity. We previously reported that novel benzo[b]thiophenyl (BT) flavones with a 10π-electron BT ring B replacing the usual 6π-electron phenyl ring showed potent antiproliferative activity against human tumor cell lines. Interestingly, the activity profiles against cell cycle progression of the BT-flavones totally changed depending on the combination of substituents at the C-3 and C-5 positions. This finding encouraged an extension of these studies on the impact of BT to related flavonoids, such as chalcones, isoflavones, and aurones. Accordingly, 10 isoflavones, 29 chalcones, and four aurones were synthesized and evaluated for antiproliferative activity against five human tumor cell lines including a multi-drug-resistant cell line. Among these compounds, BT-isoflavone 7, BT-chalcones 48, 52, 57, 66, and 77, and BT-aurone 80 displayed significant antiproliferative effects against all tested tumor cell lines. The structure-antiproliferative activity relationships clearly demonstrated the importance of BT instead of phenyl as ring B for the isoflavone and chalcones, but not the aurones. Flow cytometry and immunocytochemical studies demonstrated that the active BT-flavonoids led to cell cycle arrest at the prometaphase by induction of multipolar spindle formation. The present studies should contribute greatly to the synthesis and functional analysis of biologically active flavonoid derivatives for chemical space expansion.
Assuntos
Flavonoides/química , Mitose/efeitos dos fármacos , Tiofenos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Elétrons , Flavonoides/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[b]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC50 values of 0.05-0.08 µM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20, with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with topoisomerase I.