| Methyl-lysine recognition proteins, have become another hot spot in theepigenetics field.53BP1(p53binding protein1) is a class of DNA repairing factorsand a member of the methyl-lysine recognition proteins.53BP1contains canonicaltandem Tudor domains which recognize the methyl-lysine residues. Upon DNAdamage, the tumor suppressor p53undergoes dimethylation atLys382(p53K382me2), and this posttranslational modification is recognized by thetypical tandem Tudor domains of53BP1. Binding of the53BP1Tudor domains top53K382me2may facilitate p53accumulation at DNA damage sites. A directinteraction between53BP1Tudor domains and H4K20me2contributes to therelocation of53BP1to DNA damage sites. These bindings promote DNA repair assuggested by chromatin immunoprecipitation and DNA repair assays, and regulategene expression, for instance, activation or silencing.53BP1protein plays an important role in the process of cell growth anddevelopment in humans. It exsits aberrant reduction or loss of53BP1in subsets ofhuman carcinomas including breast and lung cancer, while it is expressed in allnormal tissues[34]. Furthermore,53BP1could inhibit invasion and metastasis in breastcancer[31], and could suppress tumor growth and promote susceptibility to apoptosisin ovarian cancer[32], etc. All of these fndings imply that53BP1is very likely to be animportant therapeutic target for cancers.Although53BP1protein takes an unnegligible role in regulation of geneexpression and treatment of cancer and other diseases, currently, research concerningbiological activity of its small molecular ligands, is not widely reported in theliterature(only one related publication).53BP1protein ligand could be regarded as a biological probe, which facilitates the comprehension over53BP1protein biologicalfunctions. And in the point of view of drug discovery, developing small moleculecompounds to disrupt the protein-protein interaction would be a significantbreakthrough.In this thesis, based on the interaction between53BP1tandem Tudor domainsand its known ligands and using the strategy of rational drug design, we designedand synthesized eleven amide compounds of spiro cyclic and fused amines directedat the53BP1protein. We used2-amino-acetaldehyde dimethylacetal as a startingmaterial to synthesize cyclic-fused amines through6-7reaction steps. And werespectively used N-benzyl-3-piperidone and N-benzyl-4-piperidone as startingmaterials, and obtain three additional products of spiro amines through7-8reaction steps.Our collabortator, professor Frye’s group, tested these compounds in primaryscreen of biological activity by Alpha Screen. Three compounds from fusedamines(2-7b,2-7c and2-7d) showed micromolar affinity for53BP1. We speculatethat these cyclic-fused amine moieties may form hydrogen bond with polar aminoacid residues in the binding pocket, therefore enhancing their activity. Furthermore,the benzene ring may also bind to aromatic amino acid residues around the pocketthrough π-π function.Retaining the key group--2-methyl-2,7-diaza-bicyclo[3.3.0]octane, wedesigned and synthesized additional21amides by replacing the aromatic ringposition of active compounds. It is expected to get compound with higher activityand selectivity. This study may lay a foundation for more in-depth study of53BP1protein ligands in the future. |
