Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives

Abstract

Two series of 12 novel thioxoflavones Mannich base derivatives 5a-f and 6a-f were synthesized via Mannich reaction of 4',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 IC values ranging from 9.16 to 55.50 μM. 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 NMR, C NMR, IR, and MS techniques.

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…[54] Aminomethylation of dihydroquercetin with secondary cyclic amine N-oxides, whose use as amine reagents in the Mannich reaction was primarily intended to improve the substrate's antioxidant activity, afforded compounds 42 (Figure 5) with claimed selective cytotoxicity against various tumor cells, although no actual data has been made available. [55] Other examples of Mannich bases of flavonoids with antiproliferative activity include aminomethyl derivatives of thioxoflavones 43 (several compounds had IC 50 values around 10 μM against HeLa and HCC1954 cells and IC 50 values around 20 μM against SK-OV-3 cells), [56] aminomethylated naringenins 44 (lack of cytotoxicity), [57] and Mannich bases 45 of bergenin with a 1,2,3-triazole appendage (compound 45 (R = 3,5-(CF 3 ) 2 ) was the most potent in the series with IC 50 values of 1.86 μM and 1.33 μM against A-549 and HeLa cells, respectively) [58] (Figure 5).…”

Centennial Anniversary of Mannich's Report on the Formation of β‐Amino‐Ketones in the Archiv der Pharmazie

“…According to late results by Li et al entitled “Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives”, the title compounds exhibited potential antiproliferative activities on the tested cancer cell lines and are expected worthy of further investigation, as well.…”