Design, Synthesis And Study Of Antitumor Activity Of Novel Small Molecular Inhibitors Of PKB

Protein kinase B (PKB or Akt) is a serine/threonine kinase that functions as a central knot in the PI3K.-PKB-mTOR signalling cascade and plays essential roles in regulating cell growth, survival, cell-cycle progression, transcription and motility, making it an attractive target for cancer therapy. Several promosing candidates targeting PKB/Akt are currently under clinical trials.A series of diphenylmethanamine derivatives were designed and synthesized in the first chapter of this disseration using{(4-chlorophenyl)[4-(9H-purin-6-yl)phenyl]methyl}amine as the lead compound, based on the following conceptions: 1 Retaining the diphenylmethanamine scaffold,2) introducing different alkyl and aromatic substituents to the amino-group; 3) replacing the purine substituent with pyrazole and pyridyl substituents to investigate its impact on binding mode with Akt.35 novel compounds were synthesized and structurally,characterized by 1H NMR and MS. All compounds were tested for their in vitro cytotoxic activities against four human tumor cell lines. Most compounds showed potent cytotoxic activities. Among them, compound Wd3 displayed potent cytotoxic activities against all tested cell lines (IC50 from 5.3 to 15.4μM), high inhibition rate of 92.45% against Akt kinase, IC50 value of 43nM over Akt kinase, resepectively. These results suggested the desirable antitumor activities of target compounds, further tests are in progress.The second series of derivatives were designed and synthesized using (1R)-1-(4-chlorobenzyl)-2-oxo-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl] et hylamine as the lead compound, based on the following concepts:1)changing the amino acid substitutes,2)changing piperazine to 1,4-diazepane; 3) replacing the 7H-pyrrolo[2,3-d]pyrimidine substitute with pyrazole and purine substituents to investigate its impact on binding mode with Akt.21 novel compounds were synthesized and structural characterized by 1H NMR and MS. All compounds were tested for their in vitro cytotoxic activities against four human tumor cell lines. However, most compounds showed weak cytotoxic activities.