Synthesis, Binding Affinity Analysis, and ¹⁸ F 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 [¹⁹ F]SFB-link-c-(Ppg)LLFVY 3 and small-molecule inhibitor 5 as potent HIF-1α binding compounds with K_D 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 targeting HIF-1α in vivo.