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.