Design Of Furoxan Analogues Targeted On SjTGR And Design Of Thiazolo [3,2-a] Pyrimidine Analogues Targeted On The Antiapoptotic Bcl-2 Family Proteins

1. Design of furoxan analogues targeted on SjTGRSchistosomiasis is a chronic parasitic disease. And it is one of the most burdensome and neglected tropical diseases, accounting for an extraordinarily high level of suffering around the world. It has been estimated that more than 200 million people are infected worldwide with an estimated 200,000-280,000 deaths occurring annually in sub-saharan Africa alone as a result of this disease.There is currently no vaccine for schistosomiasis. And treatment of the disease is accomplished solely on praziquantel. Unfortunately, given its widespread use, drug-resistant parasites may become more prevalent and PZQ-resistant isolates have already been identified. Therefore, it is important to find new structure type of antischistosomal or new antischistosomal target. The majority of eukaryotes contain two native mechanisms by which they detoxify reactive oxygen species, the tripeptide glutathione (GSH) and the protein thioredoxin (Trx). It has been proved that reduction of both glutathione and thioredoxin in schistosomes is dependent upon a single multifunctional selenocysteine-containing flavoenzyme designated thioredoxin glutathione reductase (TGR). Oxadiazole 2-oxides, identified from a quantitative high-throughput screen, were shown to be inhibitors of a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Then more and more 1,2,5-oxadiazole-2-oxide (Furoxan) analogues have been synthesized, and most of them showed good activities.My work is focused on the synthesis and structure modification of a class of derivatives based on the lead compound furoxan. Five compounds containing different functional groups were obtained and have been tested the activity on the SjTGR. And bio-assay showed that five compounds exhibit good Inhibition rate to the SjTGR. Three analogues have the similar inhibition rate (70-80%) with the lead compound when the drug concentration was 12.5 μM. And two compounds exhibit good inhibition rate (over 90%) with higher activity than the lead compound.2. Design of thiazolo[3,2-a]pyrimidine analogues targeted on the antiapoptotic Bcl-2 family proteinsApoptosis is a spontaneous cell-suicide process triggered in response to physiological and pathological stress stimuli. It is an initiative, tightly regulated and gene controlled process with the participation of a series of enzymes. Disorder of apoptosis may occur with many diseases such as cancer, autoimmune diseases. The imbalance between cell proliferation and apoptosis is a major reason for the occurrence and progression of tumors.Apoptosis is a very complex process. This process is positively or negatively regulated by specific genes. And Bcl-2 family proteins play an important role in the process of apoptosis. Based on their structure and function, the Bcl-2 family of proteins is divided into three groups:anti-apoptotic Bcl-2 family proteins、Pro-apoptotic proteins and BH3-only proteins. The research showed that anti-apoptotic Bcl-2 family proteins are over-expression in many tumor cells. They inhibit the apoptosis of normal cancer cells in order to keep the integrity of mitochondrial membrane. And this will result to the produce the drug resistant of tumor cells. Thus, it is a novel strategy to develop small-molecule inhibitors of Bcl-2 family protein to restore the apoptosis process in tumor cells. A range of small-molecule inhibitors of Bcl-2 family proteins have been reported in recent years, such as Oblimersen, ABT-263, ApoG2, TW-37, GX15-070, BI-97C1. Some of them, for example, ABT-263, Oblimersen, GX15-070, GX15-070, have already entered clinical trials. And these small-molecule inhibitors are superior to traditional cytotoxic drugs own to their good cell permeability and easy absorption.A series of thiazolo [3,2-a] pyrimidine compounds have been synthesized by our group, and the most effective compound (BCL-LZH-40) exhibits the competitive inhibition constant Ki values of 17,530 and 200 nM on BcI-xL, Bcl-2 and Mcl-1 proteins. My work is that use this compound as lead compound to get more active compounds according to the theory of drug molecular design.I have got a total of 8 Biginelli precursor compounds and 22 thiazolo [3,2-a] pyrimidine compounds through the Biginelli reaction and the thiazolo [3,2-a] pyrimidine reaction. The antitumor activities of synthesized compounds were evaluated against H1299, MDA-MB-231, Hela and A549 in vitro by MTT assay, and nearly all of the compounds exhibited week inhibitory activities on MDA-MB-231, Hela and A549. Encouragingly, most of them exhibited good inhibitory activities on H1299, and four potent compounds exhibited IC50 values of 2.2,3.2,7.4 and 12μM on H1299. So it is worthy to study further.