Studies On The Synthesis And Bioactivity Of Prenylated Flavonoids And Thioxoflavonoids As Well As Their Mannich Bases Derivatives

Flavonoids are main active components in many medicinal plants,which possess a variety of biological activities such as anti-inflammatory,antibacterial,antioxidant,anti-cancer and so on.To enhance their biological activity,solubility and biological conductivity,which is more conducive for absorption,the structure of flavonoids were modified.In this paper,isopentyl groups,sulfur elements and nitrogen-containing base groups were introduced on the structure of flavonoids.The synthesis and biological activity of natural isopentyl flavonoids,thioxoflavonoids and thioxoflavones Mannich base derivatives were studied.1.The total synthesis of three prenylflavonoid natural products,8-prenylluteolin（1）,8-prenylquerccetin-3,7,3’,4’-tetramethyl ether（2）and Artochamin C（3）were achieved through methoxymethyl protection,aldol condensation,iodine catalytic cyclization,DMDO oxidation,O-prenylation,microwave promoted Claisen rearrangement,deprotection,O-methylation and prenyl group side chain cyclization,staring from commercially available2,4,6-trihydroxyacetophenone and 3,4-dihydroxy benzaldehyde in 16-23%overall yield.The key step of microwave promoted Claisen rearrangement formed 8-C-prenylflavonoids from5-O-prenylflavonoids was investigated.2.8-Prenylated flavonoids 28-31,6-prenylated flavonoids 32-35 and dihydropyranflavonoids 36-39 were synthesized through methoxymethyl protection,O-prenylation,intramolecular[1,3]or[1,5]shift reaction with the catalysis of acid clays and deprotection reaction from commercially available diosmetin and quercetin.The key step of intramolecular[1,3]or[1,5]shift reaction was discussed.The assembly of 8-prenylated flavonoids were obtained with the catalysis of Florisil,and 6-prenylated flavonoids were obtained with the catalysis of Montmorillonite K10.Their in vitro antiproliferative activities were evaluated on a panel of three human cancer cell lines（Hela,HCC1954 and SK-OV-3）using CCK-8 assay.The result showed that 6-prenylated flavonoids exhibited excellent antiproliferative activities on three human cancer cell lines.3.Fifteen novel thioxoflavonoids were synthesized from commercially available apigenin,luteolin and quercetin under the catalysis of Lawesson’s reagent in 65-86%yield.Their in vitro antiproliferative activities were evaluated on a panel of three human cancer cell lines（Hela,HCC1954 and SK-OV-3）using cell counting kit-8（CCK-8）assay.The results showed that some thioxoflavonoids exhibits the superior antiproliferative activities than positive control cis-Platin against the three human cancer cell lines.In particular,thioxoflavonoids 45 and 46 showed the best antiproliferative activity on all three human cancer cell lines(IC₅₀<5μM),53 showed the best antiproliferative activity on Hela cells(IC₅₀ 2.30μM),44 showed the best antiproliferative activity on HCC1954 cells(IC₅₀ 2.13μM)and SK-OV-3 cells(IC₅₀ 2.33μM).4.Twelve thioxoflavones Mannich base derivatives 57-68 were synthesized in good yield via Mannich reaction of 4’,7-dimethoxy-5-hydroxyflavothione（55）or3’,4’,7-trimethoxy-5-hydroxyflavothione（56）with the hydrochloric acid catalytic,appropriate aliphatic amines or alicyclic amines and formaldehyde.Their antiproliferative activities in vitro were evaluated on a panel of three human cell lines（Hela,HCC1954 and SK-OV-3）by CCK-8 assay.The results showed that most thioxoflavones Mannich base derivatives exhibited potential antiproliferative activities on tested cancer cell lines with IC₅₀values ranging from 9.16 to 55.50μM.In particular,thioxoflavone 56,thioxoflavone Mannich base derivatives 57 and 60 showed the superior antiproliferative activities than positive control cis-Platin on all the three human cancer cells.The structures of all synthesized compounds have been confirmed by ¹H NMR,¹³C NMR,MS and HR-MS.