Design, synthesis, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo

Abstract

Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. N-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity in vitro and in vivo. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds B-11 and C-27 demonstrated significant anticancer activity in vivo in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.