Design, Synthesis And Antitumor Study Of Pulsatilla Saponin A/d Derivatives; Applications Of Isocyanide Insertion In The Synthesis Of Diarylketones And 4-Amino-3-acyl-2-naphthols

The incidence rate of tumor is rapidly developing in world in recent 20 years and tumor is one of the major causes of human death. One of effective strategies is to identify and develop new antitumor agents from natural products. At least 150 kinds of natural saponins from more than 100 families of plants have been found to possess potential antitumor properties.Pulsatilla Saponin A/D have definite antitumor activities in vitro and in vivo. Their haemolytic toxicities are the main stumbling block for developing clinical antitumor agents. With Pulsatilla Saponin A/D as the leads, we designed, synthesized 22 derivatives and evaluated their antitumor activities. 1) the cytotoxic effect of 22 derivatives against the tumor cell lines A-549, Bel-7402, SMMC-7721 and the human normal cell line HL-7702 were determined employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. 2) The haemolytic activity of 22 derivatives against rabbit red blood cell was determined. 3) Study on the effect of the esterase on the 22 derivatives. 4) Study on the mice acute toxicity experience of PS-7 and PS-17. 5) Stduy on the pharmacokinetics of PS-7 and PS-17. 6) Study on the rat tissue distribution experience of PS-7. 7) Study on the antitumor effect of PS-7, PS-17 and PS-20 in mice model. Preliminary SAR(structure and activity relationship) and STR(structure and toxicity relationship) has been disclosed: 1) It indicated that 28-COOH of PSA was closely linked with the cytotoxicity. 2) It showed that esterification of 28-COOH of PSA was unfavorable to escaping haemolytic activity. 3) Cytotoxicity and haemolytic activity are two kinds of property of saponins. There is no necessary correlation between cytotoxicity and the haemolytic activity for the derivatives. 4) 28-amidoacetic acid is a good modification fragment for PSA/PSD. Compared to the model, compound PS-7 has no obvious effect on body weight, viscera index and blood biochemical criterion of mice. Intervention was kept for 14 continuous days and there were no death and no hematuriesis for mice. The Inhibition ratio of compound PS-7 was 35.63% on H22 hepatocarcinoma-bearing mice. Compared to PSA, the toxicity of PS-7 was significantly decreased and the antitumor activity remained partly. It is a topic which is worth studying.“Palladium catalyzed cross coupling reaction” was an exquisite tool. Chemists can use it to engrave and connect building blocks(small groups), and produce beautiful articles(organic complex chemical moleculars) like artists. Based on the principle of “Palladium catalyzed cross coupling reaction”, we can insert tert-Bu isocyanide into substrates, synthesized suscessfuly diarylketones and 4-amino-3-acyl-2-naphthols. 1) With Pd Cl2/PPh3 as catalysis system and with tert-Bu isocyanide as C1 building block, a simple and effective “carbonyl Suzuki cross coupling reaction” was built in order to synthesis 17 kinds of diarylketones. It provided a new example of building intermolecular C-C bond by insertion isocyanides. 2) There are important values in medicines, argicultures and materials for 4-amido-3-acyl-2-naphthols, but the synthesis methods are limited. With Pd Cl2(PPh3)2 as catalysis system, tert-Bu isocyanide was successfully inserted into the active methylene and intramolecular C-C bond was construct. Later, the object product was synthesized by cyclization and isomerization. This method characterized with cheap materials, simple and effective reaction process, according with “atom economy”, is suitable to construct the compound library.