Total Synthetic Of Baicalein And Structure Design Of Acylation Mannich Base Derivatives

Cyclin-dependent kinase (CDK) 1 is the only necessary in the process of cell proliferation and has become the latest target for anti-cancer drugs. Natural flavonoids are some CDK1 selective inhibitors, and activity of Baicalein is strongest. Baicalein does not directly kill cells, but selectively induced apoptosis in tumor cells through different mechanisms of redox state normal cells and tumor cells and regulation of intracellular reactive oxygen species, without affecting normal cell function. However, its poor solubility and low bioavailability limited its clinical application. Therefore, structure modification of Baicalein used as leading compounds aroused people's concern.In this paper, Phloroglucinol dihydrate and Acetonitrile as material, Phosphorus oxychloride as catalyst, Trihydroxy benzene ethylene imine was synthesized by Hoesch reaction, and then Trihydroxy acetophenone monohydrate was synthesized by hydrolysis (yield 85.5%, purity 98.0%).6-Acetyl-Chrysin was synthesized by depressor reaction, using Trihydroxy acetophenone monohydrate and Benzoyl acetic acid ethyl ester as the raw material (yield 65.0%, purity 95.0%).6-Acetyl Chrysin as material, after 4% NaOH dissolution, oxidation of H2O2 and acidification of acetic acid, Baicaleinwas totally synthesized (yield 86.6%, purity 96.0%). Three new compounds:6-Acetyl-Baicalein,6-Benzoyl-Baicalein and 6-Butyryl-Baicalein were synthesized by acylation, using Baicalein as material.Baicalein,6-Acetyl-Chrysin and acylation of Baicalein used as lead compounds,6 Flavone Mannich base derivatives were semi-synthesized by Mannich condensation reaction with organic amines and formaldehyde in organic solvents:8-Hydroxypiperidine-methyl-Baicalein (BA-j),6-Acetyl-8-Hydroxypiperidine-methyl-Chrysin (CH-j),6-Acetyl-8-Hydroxypiperidine-methyl-Baicalein (ACBA-j),6-Acetyl-8-Hydroxyprolinol-methyl-Baicalein,6-Butyryl-8-Hydroxypiperidine-methyl-Baicalein and 6-Benzoyl-8-Hydroxypiperidine-methyl-Baicalein.5 of them were new structures by spectroscopy characterization.The effect on intracellular H2O2 levels of these Mannich bases derivatives were evaluated by intracellular H2O2 selective fluorescent probe PF1 method combined with fluorescence imaging. The results showed that BA-j, CH-j and ACBA-j could raise H2O2 levels in tumor cells. BA-j and ACBA-j could raise H2O2 levels in activated lymphocytes (B/T), and the activity of ACBA-j was about one times stronger than BA-j. BA-j and ACBA-j had no effect on Peripheral Blood Mononuclear Cells (PBMCs). CH-j had no effect on H2O2 levels in activated lymphocytes (B/T) and PBMCs. Anti-tumor cell proliferation activity in vitro was evaluated by MTT method. The results showed that IC50 of BA-j, ACBA-j and CH-j was 12.5?M,11.36?M and 6.25?M, respectively. The results showed that anti-tumor cell proliferation activity in vitro of CH-j was about one times stronger than BA-j and ACBA-j.In summary, Baicalein, BA-j and 5 new Mannich base derivatives were designed and totally synthesized by using Phloroglucinol, Benzoyl acetic acid ethyl ester and 4-Piperidinol as the main raw materials. Activity evaluation shown that CH-j as candidate compounds may have some application on solid tumor.