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-1 alpha (HIF-1 alpha) Microscale thermophoresis analysis identified peptide [F-19]SFB-link-c-(Ppg)LLFVY 3 and small-molecule inhibitor 5 as potent HIF-1 alpha binding compounds with K-D values of 0.46 +/- 0.2 mu M and 7.8 3.4 mu M, respectively. Both compounds represent novel HIF-1 alpha targeting compounds that are predicted to interact with the PAS-B region of HIF-1 alpha, 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-1 alpha in vivo.

Automated summary

Eleven small-molecular-weight compounds and three cyclic peptides were synthesized and evaluated for their binding to HIF-1α. Peptide [F-19]SFB-link-c-(Ppg)LLFVY 3 and small-molecule inhibitor 5 showed potent binding to HIF-1α, with K-D values of 0.46 +/- 0.2 μM and 7.8 +/- 3.4 μM, respectively. Both compounds are novel HIF-1α targeting compounds predicted to interact with the PAS-B region of HIF-1α, as confirmed by molecular docking studies. Lead structures 3 and 5 were further radiolabelled with fluorine-18 for in vivo PET imaging targeting HIF-1α.