Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives

Two series of 12 novel thioxoflavones Mannich base derivatives 5a-f and 6a-f were synthesized via Mannich reaction of 40,7-dimethoxy-5-hydroxyflavothione (3) or 3',4',7-trimethoxy-5-hydroxyflavothione (4) with appropriate aliphatic amines or alicyclic amines and formaldehyde. Thioxoflavones 3 and 4 were prepared from 4',7-dimethoxy-5-hydroxyflavone (1) and 3',4',7-trimethoxy-5-hydroxyflavone (2) with Lawesson's reagent, respectively. Their antiproliferative activities in vitro were evaluated on a panel of three human cell lines (HeLa, HCC1954, and SK-OV-3) by CCK-8 assay. The results showed that most of the thioxoflavones and their Mannich base derivatives exhibited potential antiproliferative activities on the tested cancer cell lines, with IC50 values ranging from 9.16 to 55.50 mu M. In particular, thioxoflavone 4 and the thioxoflavone Mannich base derivatives 5a and 5d showed the best antiproliferative activity on all three human cancer cell lines; they are promising candidates worthy of further development. The structures of all synthesized compounds were confirmed by H-1 NMR, C-13 NMR, IR, and MS techniques.