Studies On The Synthesis And Bioactivity Of Natural Prenylated Flavonoids And Flavonoid Mannich Base Derivatives

Flavonoids are phenolic secondary metabolites which are widely distributed throughout the plant kingdom. They have been isolated from various plant, and are a class of importance natural products. These compounds have a variety biological activities and potent medical applications, such as anti-tumor and anti-cancer activity,antibacterial and antiviral activity, anti-cardiovascular disease, enzyme inhibitory activity, anti-free radical and antioxidant activity, etc.Prenylated flavonoids are a unique class of naturally occurring flavonoids characterised by the presence of a prenylated side chain on the flavonoid skeleton.C-prenylation of flavonoids can enhance binding affinity toward p-glycoprotein and increase ability to permeate cell membranes, which can significantly improve the biological activity of flavonoids. Thus, prenylated flavonoids show promise as lead compounds for the development of nutraceuticals in plants and as new pharmacological agents for the treatment of human diseases. On the other hand, natural resources of flavonoids and prenylflavonoid are limited due to the low contents in the plants kingdom. They were negatively influenced their further bioactivity evaluation.Therefore, chemical synthesis of flavonoids and prenylflavonoid will be a very important alternative approach for addressing the problem of its availability.Mannich reaction is an effective method for the synthesis of β-amino ketones and phenols such as O-amino nitrogen compounds, it is widely used in the synthesis of natural products and organic drug molecules. Mannich base structure containing amine moiety is an important class of pharmacological active groups, which can effectively improve the biological activity, bioavailability, and water-soluble of compounds.Therefore, the synthesis of bioactive flavonoids Mannich base derivatives has great significance. In this thesis, the synthesis and bioactivity of prenylated flavonoids natural products and flavonoid Mannich base derivatives have been studied.1. The novel total synthesis of icaritin（1a）, a naturally occurring with importance bioactive 8-prenylflavonoid, was performed via a reaction sequence of 8 steps including Baker-Venkataraman reaction, chemoselective benzyl or methoxymethyl protection, dimethyldioxirane（DMDO） oxidation, O-prenylation, Claisen rearrangement and deprotection, starting from 2,4,6-trihydroxyacetophenone and4-hydroxybenzoic acid in overall yields of 23%. The key step was Claisen rearrangement under microwave irradiation.2. The first total synthesis of Sophoflavescenol（1b）, Flavenochromane C（2b） and Citrusinol（3b）, three naturally occurring prenylated or prenyl-cyclizen flavonoids have importance activities such as cytotoxicity against some cancer cell lines and treatment for erectile dysfunction, were achieved through methoxymethyl protection,aldol condensation, cyclization, DMDO oxidation, O-prenylation, microwave assistance Claisen rearrangement, deprotection, cyclization of prenyl group and DDQ dehehydrogenation, starting from 2,4,6-trihydroxyacetophenone and substituted benzaldehydes with overall yields 23%, 17% and 16%, respectively. The key step of the synthetic route is regioselective microwave assistance Claisen rearrangement formed 8-prenylated flavonoids from 5-O-prenylflavonoids.3. Preylated flavonoid icaritin（1a） upon treatment with formic acid under microwave assistance gave another natural product β-anhydroicaritin（2c） in good yield（89%）. Based on Mannich reaction of 1a or 2c with various secondary amines and formaldehyde, two series eighteen new 6-aminomethylated flavonoids Mannich base derivatives 3c-11 c and 12c-20 c were synthesized. Furthermore, their cytotoxic potential against cervical carcinoma Hela cell line were evaluated by the standard CCK-8 assay, the results showed that most of the target compounds exhibit moderate to potent cytotoxicity against Hela cells comparable with the positive control cis-Platin（DDP）.4. Kaempferide（3,5,7-trihydroxy-4’-methoxyflavone, 1d）, a naturally occurring flavonoid with potent anticancer activity in a number of human tumour cell lines, was first semisynthesized from naringin. Based on Mannich reaction of kaempferide with various secondary amines and formaldehyde, nine novel kaempferide Mannich base derivatives 2d-10 d were synthesized. The aminomethylation occurred preferentially in the position at C-6 and C-8 of the A-ring of kaempferide. All the synthetic compounds were tested for antiproliferative activity against cervical carcinoma Hela cell line by the standard CCK-8 assay, the results showed that all target compounds exhibited moderate to potent cytotoxicity against Hela cells with IC50 values of 12.48-70.52 μM,and compounds 1d, 2d, 5d, 6d, 7d, 8d, 9d and 10 d were better than or equal to the activities of positive control cis-Platin（DDP）.5. The efficient hydrolysis of flavonoid glycosides hesperidin（1e）, naringin（1f）and rutin（1g） to corresponding flavonoid aglycone hesperetin（2e）, naringnin（2f） and quercetin（2g） respectively by employing microwave irradiation method was studied.The test was designed to investigate the influential factors of the hydrolysis process under a microwave irradiation such as power of microwave, reaction temperature andirradiation time. The optimized parameters are: power 500-600 W, irradiation time30-45 min, reaction temperature 80-90 o C. The yields of flavonoid aglycone are90-95%. The results show that microwave assistance can greatly accelerate the hydrolysis rate of flavonoid glycosides, shorten the reaction time, increase the yield of flavonoid aglycone and product purities.6. Fifty-five prenylated flavonoids and flavonoids Mannich base derivatives were synthesized totally in this thesis, and twenty-six of them were new compounds. The structures of all the synthesized compounds have been confirmed by IR, 1H NMR, ¹³ C NMR and MS or HRMS techniques.