The Study Of The Synthesis Of Small-moleculer HSP90 Inhibitor Ganetespib

HSP(Heat Shock Protein)is a kind of highly conservative protein which exist in most eukaryotic cells.90%of human cells contain HSP.HSP90 is chaperone in cells and helps client proteins regulating folding and stabling the conformation.It is reported that HSP90 occurs in normal cells as a latent form,but an activated form in cancer cells.So inhibiting HSP90 will cause cancer cells cannot obtain proteins with stable conformation and inhibit the growth of cancer cells to inhibit cancer.HSP90 has three parts:N-terminal domains,C-terminal domains and middle domains.Most HSP90 inhibitors in clinical now focused on N-terminal domains.There are lots of inhibitors are developed since HSP90 becomes target,and these inhibitors can be divided into two generations.The first generation is Geldanamycin and it's derivatives,but the clinical study has been stopped because of the side effects.The second generation inhibitor is resorcinol and it's derivatives.Apart from these,there are some inhibitors from purine and pyrimidine derivatives.The best one is Ganetespib(Ganetespib)which was found by Synta Pharmaceutical.Ganetespib has entered phase III clinical trials for non-small-cell lung cancer and leukemia and it performs very good in phase I and II clinical trials.First,the project studied the synthesis of Ganetespib.We found two routes to synthesize Ganetespib by reading references and chose one route by comparing the reactants?the conditions and the toxicity of reaction.We optimized the most of reactions in the route.At last,the project studied the design and synthesis of HDC drugs.HDC means HSP90 inhibitors-drug conjugates.HDC drugs have some good properties such as the better targeting,the lower toxicity,the better treatment effects etc.The project designed the synthesis route under this thought,and we have the most important intermediate D7.The intermediate is the most important part to link HD AC inhibitors.