Studies on the C(sp2)-C(sp2) bond formation via palladium catalyzed C-H activation and the application to synthesis of the biologically active compounds

Abstract

Part 1. Development of New Fluorescent Xanthines as Kinase Inhibitors via Direct C-H Activation

An understanding of intracellular drug distribution and its fate in biological systems is of enormous value to confirm their desired target of drug molecules. This also gives the knowledge of drug concentration and metabolism for optimizing treatment time, determining the selectivity of the drug for various sites and customizing medicine for therapy. In addition, information regarding the receptors and particular subcellular compartments with which drugs are associated is useful to reveal mechanisms and to provide a biological rationale for the design of new therapeutics with improved properties and fewer side effects. We have developed an efficient route for the preparation of direct N7- and C8-arylation on the xanthine (theophylline) core as fluorophore to monitor its subcellular localization and ATP hinge binder to PI3 kinase. N7- aryl group was introduced by Chan-Lam coupling reaction using Cu(OAc)2 and pyridine, which is not moisture sensitive and mild condition. C8- aryl group was introduced via Pd-catalyzed direct C-H activation, which is effective to make C(sp2)-C(sp2) bond without pre-activating group. N7- and C8- aryl xanthine derivatives can act as a family of potent fluorescent PI3Kα inhibitors in which part of the fluorophore was engineered to be a pharmacophore capable of inhibiting PI3Kα. These xanthine derivatives are characterized by a donor-acceptor molecular structure, and changes in the electronic properties of the two variation points at N7- and C8-aryl group give rise to notable bathochromic shifts in the λem, λabs and increase the value of ΦF (fluorescent quantum yield). Further, we illustrated the use of E2 (PI3Kα/IC50 = 0.068 μM, T47D cell viability: IC50 = 0.9 μM) to block cancer cell proliferation and to monitor its subcellular localization by fluorescence microscopy.

Part 2. Pd-Catalyzed C-C Bond Formation of Bio-Active Flavonoids via ...