Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment.

ABSTRACT: To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1- and unfolded protein response (UPR)-dependent reporter assays and selective cytotoxicity assay under low glucose conditions. Homologation studies of aryl-(CH₂)_n-biguanides (n = 0-6) yielded highly potent derivatives with an appropriate alkylene linker length (n = 5, 6). The o-chlorophenyl derivative 7l (n = 5) indicated the most potent inhibitory effects on HIF-1- and UPR-mediated transcriptional activation (IC₅₀; 1.0 ± 0.1 μM, 7.5 ± 0.1 μM, respectively) and exhibited s

SUBMITTER: Sakai T 

PROVIDER: S-EPMC7921556 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature