Structure-based design and efficient synthesis of kinase inhibitors via palladium catalysis

Abstract

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.