Application Of Combination Principles In The Research Of 20s Proteasome Inhibitors

Objective: The harm of tumors has seriously affected people health and became a nightmare in people life.In order to reduce its damage,many scientific researchers in various fields have been seeking new targets and high-efficiency and low-toxic anti-tumor medicine.Peptide boric acid and peptide epoxy ketone proteasome inhibitors have become the hot spots of research.In this paper,peptide boric acid(bortezomib)and peptide epoxy ketone(carfilzomib)proteasome inhibitors are regarded as lead compounds and are designed as twin drugs by using the method of the combination principle,which is comprehensively described.The specific process is to adopt((a R,3a S,4S,6S,7a R)-hexahydro-3a,8,8-trimethyl-alpha-(2-methylpropyl)-4,6-methyl bridge-1,3,2-benzodioxane-2-methylamine 2,2,2-trifluoroacetate)and((S)-2-amino-4-methyl-1-((R)-2-methyloxirane-2-yl)-1-pentanone trifluoroacetate)linking to the peptide fragment by the method of chemical synthesis,and a twin drug with two pharmacophores is designed.Thus,a twin drug of a 20 s proteasome inhibitor with twice the potency is obtained.At the same time,we hope to obtain proteasome inhibitors with less drug dosage,convenience,and lower toxicity,which will provide a certain basis for the clinical treatment research of the development of 20 s proteasome inhibitors as anti-tumor.Methods: 1.Obtain,((a R,3a S,4S,6S,7a R)-hexahydro-3a,8,8-trimethyl-alpha-(2-methylpropyl)-4,6-methyl bridge-1,3,2-benzodioxaborole-2-methylamine 2,2,2-trifluoroacetate)and((S)-2-amino-4-methyl-1-((R)-2-methyloxirane-2-yl)-1-pentanone trifluoroacetate)was obtained.2.The currently proven P2,P3 fragments,leucine and phenylalanine were regarded as replacements for amino acid fragments.Through dehydration condensation,the dipeptide was linked.Furthermore,it reacted with succinic anhydride to form the main skeleton,a total of 2 series of compounds were designed and synthesized.Results: Eight target compounds and intermediates were successfully synthesized.By 1H-NMR,13C-NMR and MS,structural characterization was carried out.