Design, Synthesis And Biological Evaluation Of PKB Inhibitors And Study On Synthesis Of Paclitaxel

Protein kinase B(PKB) is a serine threonine kinase belonging to the AGC superfamily of kinases.There are three isoforms of the enzyme with＞80%homology to one another.PKB,a critical downstream protein in the PI3K signal transduction pathway,plays a key role in the regulation of cell survival,proliferation and growth. PKB is considered as a novel and excellent target for antitumor chemotherapy and much attention have been paid to drug development based on PKB target.In this paper,hierarchical clustering and chemical space of 98 known PKBβinhibitors were constructed and three compound libraries were designed.58 2,4-Diamino-6-aryl-1,3,5-triazine derivatives were prepared in solution.24 Individual 2,4-diamino-6-aryl-1,3,5-triazine derivatives were synthesized by using a solid-supported approach with resin capture-release technique.35 Triazolo[4,3-α]pyrazine and 1H-benzo[d]imidazole heterocyclic compounds were prepared in solution.Most of the synthesized compounds have been used for the biological evaluation in vitro.From the biological evaluation results,a series of 2,4-diamino-6-aryl-1,3,5-triazine derivatives were found to have antiproliferative activities against the selected tumor cell lines.Five of these compounds were found to have more potent cytotoxicity against the selected tumor cell lines compared to IRESSA.Compound 2.83 exhibited the most potent inhibition activities against PC-3 and K562 cell lines with IC₅₀ values of 1.01 and 2.23μM,respectively.Compound 2.26 exhibited the most potent inhibition activities against A549 cell line with an IC₅₀ value of 1.99μM.The SAR studies demonstrated that the second position of triazine plays a crucial role for its antitumor activity.Some of these compounds have been selected for the further investigation.Paclitaxel(Taxol) has been recognized as one of the best anticancer drugs on the market in the past 20 years.It is currently employed in the treatment of advanced breast cancer,non-small-cell lung cancer and ovarian cancer.In this paper,using 1,1'-thiocarbonyldiimidazole as a regioselectively protecting reagent of the C-7 hydroxyl group of 10-DABâ…¢,an efficient semi-synthesis of paclitaxel was achieved in four steps starting from 10-DABâ…¢.Therefore,a novel and efficient approach to paclitaxle and its derivatives was provided.