Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy.

The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.

Nickel-catalyzed Chan-Lam cross-coupling: chemoselective N-arylation of 2-aminobenzimidazoles.

A complementary set of Ni- and Cu-based catalyst systems for the selective N-arylation of 2-aminobenzimidazoles have been developed. Selective N-arylation of the primary amine (C-NH2) group was achieved by Ni-catalyzed, boronic acid promoted cross-coupling reactions in air, whereas, selective N-arylation of the azole nitrogen was achieved with Cu-catalysis and aryl halides. These protocols are general and give rapid access to an array of both the N-arylated isomers of 2-aminobenzimidazoles.

Palladium-catalyzed arylation of 2H-chromene: a new entry to pyrano[2,3-c]carbazoles.

Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.