Study On The Synthesis Of Novel Matrine Derivatives

Matrine is one of the major active alkaloids isolated from the sophora alopecuroides. Matrine possesses good biological activities. For example, matrine has been used for the treatment of anti- inflammatory, antipyretic, immune, cardiac arrhythmia treatment, LPS-induced liver injury; Matrine also could increase the number of white blood cells and inhibit the growth of tumor cells and further effect on cervical, hepatic and gastric carcinomas. With the in-depth study of matrine alkaloids, the matrine alkaloids have been used in the prevention and treatment of viral diseases of hepatitis B, hepatitis C, HIV and anti- HBV with greater inhibitory activity than both matrine and sophocarpine. The biological evaluation showed that nitric oxide-releasing matrine derivatives had stronger cytotoxic activities than 5-fluorouracil against human hepatoma cells (HepG2) in vitro. Therefore, the study of biological activity and application of matrine analogues is continuing to expand, showing a good development prospects. The purpose of this paper consists of three parts. Firstly, introducting of the nitrogen-containing groups at the 13 position by dithiophosphate in view of the nitrogen atom and the sulfur atom play an important role in the organism of the composition, and aspects of the physiologically active drug metabolism. Secondly, the widespread use of matrine is limited because its water-solubility is not really ideal. We designed and synthesized a number of water-soluble matrine derivatives. Finally, part of the target compounds were preliminary antitumor activity experiments on three typical tumor cells.In the synthesis process, sophocarpine was used as the starting material via the classic Michael addition reaction matrine and we have designed and synthesized of 13 novel matrine derivatives. We also have successfully cultured three new compound single crystal structure and obtained accurate data of the crystal structure. The chemical structures of them were further confirmed by 1HNMR,13CNMR and HRMS. Particularly, the structures of some compound were characterized by X-diffraction and partly crystalline structure exists intermolecular hydrogen bonds which are play an important role in the single crystal growth process. The methods of synthesis target compounds are simple, easy and organic solvents, expensive catalysts are not needed by generated a new chiral carbon atom. Finally, water-soluble target compounds are evaluated for their activity on human colon cancer cells (SW480), lung cancer cells (A549) and epidermal squamous cells (A431). We expect these compounds will have good pharmacological activity. This thesis is comprised of five parts as follows:In the chapter one:We described the status of research matrine derivatives mainly tends to progress of matrine derivatives modified structure. The biologically active portion of matrine derivatives were introduced. Based on structure-activity relationships, this paper design ideas and research methods have been proposed.In the chapter two:The 13-position of sophocarpine was introduced three kinds of nitrogen-containing heterocyclic compounds by the Michael addition reaction. The three kinds of matrine derivatives were successfully obtained. The method was confirmed to be novel for one-pot preparation of matrine derivatives. The target compound were characterized by 1H NMR,13C NMR,HR-MS and X-ray. At last, these three compounds were made bioassay experiments.In the chapter three:As sophocarpine with the starting material, several nitrogen-containing heterocyclic derivative of matrine were designed and synthesized in the aqueous phase. Synthesis method is simple, high yield and avoidinguse of methanol and other organic solvent. We successfully synthesized five novel nitrogen-containing heterocyclic group matrine derivative and the structure of products were characterized, especially 13-piperidine derivatives matrine crystal analysis, analysis of its structure by X-ray.In the chapter four:A series of amine derivatives matrine were synthesized and new compounds have good solubility in water compared with matrine. Some strong activity group is introduced during the synthesis. We designed and synthesized a number of water-soluble matrine derivatives.In the chapter fifth:We make a summary of the full text of the new compound synthesis, characterization and preliminary activity tests, outlook late work.