Studies On The Synthesis And Bioactivity Of Polymethoxy Flavonoids And Aminoalkyl-substituted Derivatives

Chalcones are a class of flavonoids that exist widely in the nature. Due to the flexible structure of chalcones and the combination with different receptors, they have a large number of biological activities including antibacterial, antiallergy, antiviral, antiulcer and so on. Some have been used in clinical fields. Mannich reaction and Hofmann alkylation reaction can introduce nitrogen-containing groups to the parent compound, which can improve its pharmacological properties and expand its scope of application. In order to get the compounds with better pharmacological properties, we used phloroglucinol, gallic acid and the mixture of tangeretin and nobiletin as starting materials and synthesized a series of aminoalkyl-substituted polymethoxy chalcone derivatives and polymethoxy flavones.1?2-Hydroxy-4,6-dimethoxyacetophenone (2) was synthesisd through Friedel-Crafts acetylization and O-methylation, with phloroglucinol as starting compound. 3,4,5-Trimethoxybenzaldehyde (5) was synthesized through hydrazidation and K3[Fe(CN)e] oxidation from methyl 3,4,5-trimethoxybenzate which was prepared from gallic acid. 2'-Hydroxy-3,4,5,4',6'-pentamethoxy chalcone (6) was synthesized through the Claisen-Schmide condensation reaction between compounds 2 and 5. With acetonitrile as solvent, we introduced aminoalkyl groups at the 2'-0-position of compound 6, and synthesized two series of sixteen novel aminoalkyl-substituted polymethoxy chalcone derivatives 8a-8h and 9a-9h that were all new compounds.2?With methanol as solvent and concentrated HC1 as catalyst, based on Mannich reaction with Microwave heating technology, we introduced the aminomethyl groups at 3'-position of compound 6 to afford Mannich base derivatives 10a-10h that were all new compounds.3?2-Hydroxy-3,4,5,6-tetramethoxyacetophenone (13) was synthesized by tangeretin and nobiletin, then Claisen-Schmidt condensation with 3,4,5-trimethoxybenzaldehyde achieved 2'-hydroxy-3,4,5,3',4',5',6'-heptamethoxy chalcone (14). Polymethoxy chalcones oxidative cyclization could afford polymethoxy flavones and flavonols, the flavonols could also be synthesized by flavones through DMDO oxidation.4?he antiproliferative activity against three cancer cell lines (Hela, HCC 1954, and SK-OV-3) of the synthesized compounds, were evaluated by CKK-8 assay with cw-platin and paclitaxel as positive controls. The results showed that most of the compounds showed a broad range of growth inhibitory effect on all three cancer cell lines. Among them, compounds 8a-8g markedly inhibited the proliferation of Hela cells with IC50 values below 10 ?M. In the case of HCC 1954 cell line, compounds 8e and 8f were 7 and 8 times more potent than positive control cis-Platin. Compounds 6 and 8a-8e markedly inhibited the proliferation of SK-OV-3 with IC50 values below 10 ?M. Compound 10b displayed antiproliferative activities against these three human cancer cells.5?This thesis synthesized twenty-four aminoalkyl-substituted polymethoxy chalcone derivatives and four polymethoxy flavones, among which twenty-six were new compounds. The structures of all synthesized compounds have been confirmed by more than one of the!H NMR,13C NMR, MS and so on.