Synthesis of Icaritin and β-anhydroicaritin Mannich Base Derivatives and Their Cytotoxic Activities on Three Human Cancer Cell Lines

Background: Prenyl flavonoid icaritin (1) and β-anhydroicaritin (2) are two natural products with important biological and pharmacological effects. such as antiosteoporosis, estrogen regulation and antitumor properties. </p> <p> Objective: The present study investigates the synthesis and cytotoxic activities on three Human cancer cell lines (Hela, HCC1954 and SK-OV-3) of icaritin and &#946;-anhydroicaritin Mannich base derivatives in vitro models. </p> <p> Method: Preylated flavonoid icaritin (1) upon treatment with formic acid under microwave assistance gave another natural product &#946;-anhydroicaritin (2) in good yield (89%). Based on Mannich reaction of 1 or 2 with various secondary amines and formaldehyde, two series eighteen new 6-aminomethylated flavonoids Mannich base derivatives 3-11 and 12-20 were synthesized. Their cytotoxic potential against three human cancer cell lines (Hela, HCC1954 and SK-OV-3) were evaluated by the standard MTT method with cis-Platin and Paclitaxel as positive control. </p> <p> Results: Our research showed that most of these flavonoid Mannich base derivatives displayed equal or higher (lower IC₅₀ values) cytotoxic activities than the positive control cis-Platin. Some compounds possess the IC₅₀ value below 10&#181;M. Compounds 6-(diisopropylamino)methyl- and 6-morpholinylmethyl substituted &#946;-anhydroicaritin (15 and 19) showed selective cytotoxicity against HCC1954 cells (IC₅₀ 12.688 &#181;M) and Hela cells (IC₅₀ 6.543 &#181;M) respectively. </p> <p> Conclusion: Our finding most of icaritin and &#946;-anhydroicaritin Mannich base derivatives possessing moderate to potent cytotoxicity against these three cancer cells (Hela, HCC1954 and SK-OV-3). Compound 15 and 19 showed selective cytotoxicity against HCC1954 cells and Hela cells respectively, they are potential and selective anticancer agent and worthy of further development.