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Design, Synthesis And Anticancer Activity Of PI3K Inhibitors

Posted on:2016-02-26Degree:DoctorType:Dissertation
Country:ChinaCandidate:J L GuoFull Text:PDF
GTID:1224330482454692Subject:Medicinal chemistry
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PI3K/Akt/m TOR is an important cell signal transduction pathways and involved in a diverse set of cellular functions, such as cell growth, proliferation, migration, differentiation, survival, angiogenesis, glucose metabolism and membrane ruffling. Aberrations of PI3 K signaling pathway are closely related to many diseases. With the advancement in understanding its structure and function, PI3 K pathway has been implicated in many diseases and proven to be an effective therapeutic target, especially for the treatment of various types of cancers.This work focused on the design and synthesis of novel inhibitors as potential anticancer agents by targeting PI3 K kinase. First, this thesis summarized the literature background of PI3 K. The design rationales for novel 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as PI3 K inhibitors was discussed by analyzing common structural features of reported PI3 K inhibitors and their interactions with PI3 K kinase. The synthetic routes of isoxazolopyrimidine scaffold was designed and developed. Using this method, 79 novel and structurally diverse derivatives were synthesized. The parts of them were evaluated for cytotoxicity against four cancer cell lines. The initial leads from the cellular screening were further evaluated for their inhibition of PI3 K delta kinase.In chapter one, the biological background of PI3 K was summarized. The composition of PI3 K signaling pathway and signal transduction were outlined, with focus on the PI3 K kinase and their related physiological activities. In addition, the research progress and clinical experiment of PI3 K inhibitors were also described.In chapter two, the design, synthesis and anticancer activity of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine were discussed in detail. By analyzing the common structural features of representative PI3 K inhibitors, we proposed a tri-substituted isoxazolo[4,5-d]pyrimidine pharmacophore hypothesis. Analysis of X-ray co-crystal structure or docking models of known inhibitors with PI3 K kinase indicating that the two side chains at X- and Y- have H-bond interaction with the kinase, while the side chain at Z-position is exposed to solvents. The central scaffold has no intermolecular interaction. Based on above analysis, the side chains with H-bond interaction are the key pharmacophore, while the central scaffold plays a supporting role. Therefore, we retained the key pharmacophore and designed the novel isoxazolopyrimidine scaffold. The novel isoxazolopyrimidine scaffold has the potential of displaying the substituents in the preferred positions, in addition to offer improved pharmacological properties.For this purpose, a facile synthesis of novel 3-(piperidin-4-yl)isoxazolo [4,5-d]pyrimidine derivatives was developed. Alpha-nitroketones were obtained from N-Boc-piperidine-4-carboxylic acid through a one-pot procedure. They were transformed to the corresponding oximes, which were then cyclized to furnish the isoxazole intermediate. Further functional group transformations including aminolysis of the ester, reduction of the nitro group afforded the 4-amino-2-isoxazolocarboxamide. Upon reaction with triphosgene, the carboxamide intermediate was cyclized to yield the isoxazolopyrimidine scaffold. Then chlorination of phosphorus oxychloride, morpholine replacement and Suzuki coupling were proceed to yield the key intermediate with isoxazolopyrimidine scaffold.Further structural modifications led to a diverse set of potential PI3 K inhibitors. Twenty-five 5-phenylurea derivatives were synthesized and their cytotoxicity against MCF-7, BT-474, U87-MG and PC-3 cells were evaluated. Most of them showed potent anticancer activities, with IC50 s in the sub-micromolar range. These compounds showed greater potency against PC-3 cell proliferations, most of them showed IC50 s below 500 n M, parts of them showed IC50 s in 100~200 n M range, of which the most potential one showed an IC50 value of 79 n M.Based on the initial structure-activity relationship, fixed phenyl methyl urea, forty-one additional derivatives were designed and synthesized, focusing on the modification of the piperidine fragment at the 3-position. Most of compounds showed improved activities, especially against PC-3 cell proliferation. Most of them against PC-3 cells showed IC50 s below 300 n M, of which four compounds showed IC50 s below 100 n M. These compounds were further evaluated in enzymatic assay for their inhibition of PI3Kδ kinase. Some of them showed potent inhibition of the PI3Kδ with IC50 s in the nanomolar range. These data indicate that the anti-proliferative properties these compounds exhibited could be contributed to their modulation of the PI3 K pathway.Besides, seven 5-derivatives were synthesized. The synthetic route of isoxazolopyrimidine scaffold was improved. And using this new route, three 5-(2- or 3-methyluera) phenyl derivatives were synthesized. The screening of these compounds is in progress.In chapter three, using the new route, three 3-isoxazolo[4,5-d]pyrimidine derivatives were designed and synthesized to investigate the effect of hydrophobicity increase and basicity decrease at 3-position.Chapter four provides the experimental details for the synthesis and biological evaluation of these isoxazolo[4,5-d]pyrimidine derivatives.In conclusion, this thesis presents the design and synthesis of seventy-nine isoxazolo[4,5-d]pyrimidine derivatives as novel PI3 K inhibitors. This novel class of compounds expanded the scope of structural diversity of PI3 K inhibitors and may offer improved pharmacological properties suited for further pharmaceutical development. Based on cell screening, most of them showed potential anticancer activities, of which five compounds showed greater potency, with IC50 s below 100 n M. Although the lead compounds were shown to be potential inhibitors of PI3K? kinase, indicating their anticancer activity could be through inhibition of PI3 K pathway, the further optimization and biological evaluation are underway. Additional investigation is also in progress to elucidate the mechanism of action for these novel isoxazolo[4,5-d]pyrimidine derivatives.
Keywords/Search Tags:PI3K, inhibitor, isoxazolopyrimidine, anticancer
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