Structure-based design and efficient synthesis of kinase inhibitors via palladium catalysis = 구조에 기반한 키나아제 저해제의 설계와 팔라듐 촉매 반응을 이용한 효율적인 합성법 연구

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Part 1. Discovery of Novel Kinase inhibitors for Overcoming Drug Resistance The drug resistance mainly occur through reactivation of cell signaling by other signaling pathway or struc-tural mutation of target. We designed the novel inhibitors to study the cross talk between Trk and PI3K signal-ing and overcome the point mutation of Bcr-Abl. These inhibitor were designed through rational approach using structured-based design. 1.1 Discovery of new aminopyrimidine-based phosphoinositide 3-kinase beta (PI3K $\beta$) inhibitors with selectivity over PI3K $\alpha$ Phosphatidylinositol-3-kinase beta (PI3K $\beta$) selective inhibitor over PI3K$\alpha$ was designed because PI3K $\beta$ has not been extensively studied despite the therapeutic potential since the tool compound was limited in comparison with PI3K$\alpha$. In this study, a new series of aminopyridine-based PI3K$\beta$ inhibitors have been de-veloped by the structure-based design strategy. When incorporated with the naphthyl ring on sulfonamide moiety, aminopyrimidine analogs showed good potency on PI3Kβ and selectivity over PI3K$\alpha$. These results clearly provide useful insight in the design of new PI3Kβ inhibitors with high potency and selectivity. 1.2 Design, Synthesis and Evaluation of 3,5-Disubstituted 7-Azaindoles as Trk Inhibitors with Anticancer and Antiangiogenic Activities Tropomyosin-related kinase A (TrkA) is an upstream effector of PI3K and considered a promising target in the development of a therapeutic treatment of cancer and pain. In this study, we designed and synthe-sized a series of novel 7-azaindole-based Trk kinase inhibitors. By varying the functional groups at the 3 and 5 positions of a 7-azaindole scaffold, we studied the structure- activity relationships (SAR) profiles and identified a series of potent Trk inhibitors. Representative derivatives showed desirable activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity. 1.3 Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase In-cluding the T315I Mutant The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative ef-fects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl. Part 2. Development of Palladium Catalyzed C-H activation Reaction for Efficient Synthesis of Privileged Scaffolds It is important to efficiently diversify chemical entities into a panel of closedly related analogues to opti-mize biologically active compounds such as kinase inhibitors. In synthetic approach, palladium catalyzed C-H activation reactions were developed for efficient synthesis of privileged scaffolds. 2.1 A Pd-Catalyzed one-pot dehydrogenative aromatization and ortho-functionalization We developed a palladium catalyzed one pot method for synthesis of quinolinone. The one-pot dehydro-genation and ortho-functionalization sequence provides access to highly functionalized arylamine-containing derivatives and quinolinone from readily accessible cyclic N-acetyl enamides. 2.2 Asymmetric C-H Functionalization of Cyclopropanes Using an Isoleucine-NH2 bidentate Directing Group The systematic investigation of substrate-bound a-amino acid auxiliaries has resulted in catalytic asym-metric C-H functionalization of cyclopropanes enabled by amino acid amides as chiral bidentate directing groups. The use of an Ile-NH2 auxiliary embedded in the substrate provided excellent levels of asymmetric induction (diastereomeric ratio of up to 72 : 1) in the Pd(II)-catalyzed b-methylene C(sp3)-H bond activation of cyclopropanes and cross-coupling with aryl iodides.
Hong, Sungwooresearcher홍승우researcher
한국과학기술원 :화학과,
Issue Date

학위논문(박사) - 한국과학기술원 : 화학과, 2016.2 ,[vi, 94 p. :]


Kinase Inhibitor; Structure-Based Design; Targeted Therapy; C-H Activation; Palladium Catalysis; 키나아제 저해제; 구조기반 약물 설계; 표적 치료; 탄소 수소 활성화 반응; 팔라듐 촉매 반응

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