Polyoxygenated flavones; Synthesis, cytotoxicities and antitumor activity against ICR mice carrying S-180 cells

Abstract

Fifty two flavones were synthesized from polyoxygenated dibenzoylmethanes which were obtained by a modified Baker-Venkataraman rearrangement, of 2-benzoyl oxyacetophenones. The following flavones among then showed good cytotoxic activities against L1210 and HL-60 cells; 2′-benzyloxy-5-methoxyflavone [ED50(L1210)=4.9 μg/ml) ED50(HL-60)=3.1 μg/ml] 2′-benzyloxy-5,7-dimethoxyflavone (8.2 μg/ml, 5.0 μg/ml), 2′-benzyloxy-5,7,8-trimethoxyflavone (5.9 μg/ml, 11.0 μg/ml), 2′-hydroxy-5,7-dimethoxyflavone (8.3 μg/ml 4.9 μg/ml) 2′-hydroxy-5-methoxyflavone (4.2 μg/ml, 2.7 μg/ml), 2′-hydroxy-5,7,8-trimethoxyflavone (9.8 μg/ml, 6.2 μg/ml), 2′-benzyloxy-5-hydroxyflavone (5.2 μg/ml, 3.6 μg/ml), and 5,2′-dihydroxyflavone (5.1 μg/ml, 4.0 μg/ml). Presence of 5-methoxy group potentiated the cytotoxic activity, while the existence of 7-methoxy group decreased the activity. 5-Hydroxy or methoxy, activates 4-carbonyl group, while 7-methoxy group deactivates the carbonyl group. From these observation it was concluded that the activation of carbonyl group at C-4 of a flavone is important for the enhancement of the cytotoxic activity. The presence of both 5-hydroxy and 2′-benzyloxy- or 2′-hydroxy group enhanced the antitumor activity; 2′-benzyloxy-5-hydroxy-7-methoxyflavone (T/C=144%), 5,2′-dihydroxy-7-methoxyflavone (T/C=132%), and 5,2′-dihydroxy-6,7,8,6′ tetramethoxyflavone (T/C=172%). 2′-Hexanoylation of 5,2′-dihydroxy-flavones did not improve the antitumor activity; 2′-hexanoyloxy-5-hydroxy-7-methoxyflavone showed T/C=132%, about the same as that of 5,2′-dihydroxy-7-methoxyflavone (T/C=130%)