Design, Synthesis And Antitumor Activities Study Of Nitrogen-containing Flavonoids

Flavonoids, such as quercetin, genistein, baicalein and Flavopiridol have antitumor activity, in which only a few compounds present cytotoxic properties in cells that do not proliferate. These beneficial properties prompted study and synthesis of flavonoid derivatives. Flavopiridol is a synthetic flavone that has been studied extensively recently;furthermore, its analogues and some SAR also have been reported. Generally, these compounds show antitumor activity against various tumor cell lines Flavopiridol's antitumor activity is related to its inhibition of CDK 1, 2,4, and 7, which has been shown to induce arrest in both G₁/S and G₂/M phases of cell cycle. In addition, it has been shown to induce apoptosis in cell cycle.In continuation of our search for more potent antitumor agents, flavopiridol was chosed as a lead compound. Take account of structure-activity relationship of flavopiridol, the 4-keto plus 5-hydroxy groups of the compounds and the o-chlorophenyl ring in position 2 of the chromenone moiety were essential for the activity, however, chlorophenyl ring could also be replaced by other substituted groups such as trifluoromethylphenyl or methylsulfonylphenyl. The above two pharmacophore plus different amino units via three carbon atom were connected with the flavonoid backbone. Thus, eleven chalcone and thirty-eight flavone derivatives were designed and synthesized. The structure of target compounds was confirmed by IR, ¹H-NMR. The key intermediate 4a was also confirmed by NOESY so as to determine the position of allyl group.The IC₅₀ values of the target chalcone and flavone derivatives were determined in vitro against human cancer cell lines by the microculture tetrazolium assay. 34 compouds have been evaluated against the ECA-109, All tested chalcones showed significant inhibitory activity at IC₅₀ values of <10μg/mL. Among them, a representative member, chalcone 12 showed the most potent activity (IC₅₀ =1.0 μg/mL). The structure-activity relationship is studied, and their further pharmacological evaluation is under way.