Synthesis, binding affinity analysis, and 18F-radiosynthesis of small molecular weight HIF-1α binding compounds.

Eleven small molecular weight compounds and three cyclic peptides were synthesized and evaluated for binding to hypoxia-inducible factor-1α (HIF-1α). Microscale thermophoresis analysis identified peptide [19F]SFB-link-c-(Ppg)LLFVY 3 and small-molecule inhibitor 5 as potent HIF-1α binding compounds with KD values of 0.46 ± 0.2 μM and 7.8 ± 3.4 μM, respectively. Both compounds represent novel HIF-1α targeting compounds that are predicted to interact with the PAS-B region of HIF-1α, as confirmed with molecular docking studies. Lead structures 3 and 5 were further radiolabelled with fluorine-18 for positron emission tomography (PET) imaging agents targetting HIF-1α in vivo.