Studies On The Synthesis And Bioactivity Of Stilbenes And Flavones Mannich Base Derivatives

Stilbene compounds and flavonoids are important parts of natural products, and are abundant in nature. Many research showed that stilbene compounds and flavonoids have desirable biological activity. They played marvelous roles on treatment and prevention of human diseases. Based on Mannich reaction of stilbene compounds and flavones with various secondary amines and formaldehyde in acidic methanol solvent under microwave assistanced,twenty-nine novel Mannich base derivatives were synthesized, and the antiproliferative activity against human cervical carcinoma Hela cells had been evaluated.1. Two stilbene derivatives 1 and 2 were synthesized in reaction steps including methylation, LiAlH4 reduction, bromization, Arbuzov rearrangement, MOMO hydroxyl protection and Wittig-Horner reaction respectively using 3, 5-dihydroxy- benzoic acid as the starting material. Fourteen novel pterostilbene(1)and 3′-methoxy pterostilbene(2)Mannich base derivatives( 3-16) were synthesized through Mannich reaction of 1 or 2 with various secondary amines and formaldehyde. The regioselectivity of the reaction oICurred preferentially at C-3′(and/or C-5′)position of B-ring of stilbene structure.2. Natural ocurring flavones, apigenin-5,4′-dimethy ether( 1a) and lutedin-5,3′,4′-trimethyl ether(2a), were synthesized through I2/Py dehydrogenation, O-methylation and glycoside hydrolysis reaction, starting from naringin and hesperidin respectively. Based on Mannich reaction of flavones 1 or 2 with various secondary amines and formaldehyde in acidic alcohol solvent under microwave assistanced, fifteen novel flavones Mannich base derivatives 3a-17 a.3. All the 29 synthetic compounds were tested for anti-proliferative activities on human cervical carcinoma Hela cells by the CCK-8 method. The results showed that 20 compounds exhibited distinct cytotoxicity against Hela cells. Compounds 3, 5, 7, 11, 12, 13, 16, 10 a, 12 a and 17 a displayed higher(lower IC50 values)activity than the positive control cis-Platin( DDP). Among them, the compound 3( IC50=23.26 μmol·L-1), characterized by dimethylaminomethyl group in C-3′ position, was more active than parent compound pterostilbene(IC50=28.46 μmol·L-1), the compound 17 a exhibited the highest distinct cytotoxicity(IC50 = 9.14 μmol·L-1) against Hela cells, Almost 7 times higher than its parent flavone 2a(IC50 = 59.62 μmol·L-1), and nearly 5 times higher than the positive control drug cis-platin(DDP).The thesis synthesized thirty-three compounds included pterostilbene, 3′-methoxy pterostilbene, apigenin-5,4′-dimethy ether, lutedin-5,3′,4′-trimethyl ether and their Mannichbase derivatives. Among them, twenty-nine are new compounds,and their structures have been confirmed by 1H NMR, 13 CNMR and MS.