1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs

Nathalie M Grob; Roger Schibli; Martin Béhé; Ibai E Valverde; Thomas L Mindt

doi:10.1021/acsmedchemlett.0c00636

1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs

ACS Med Chem Lett. 2021 Mar 16;12(4):585-592. doi: 10.1021/acsmedchemlett.0c00636. eCollection 2021 Apr 8.

Authors

Nathalie M Grob¹, Roger Schibli^{1

2}, Martin Béhé², Ibai E Valverde³, Thomas L Mindt^{4

5

6}

Affiliations

¹ Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland.
² Center for Radiopharmaceutical Sciences, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland.
³ Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR CNRS 6302, Université de Bourgogne Franche-Comté, 21000 Dijon, France.
⁴ Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, 1090 Vienna, Austria.
⁵ Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.
⁶ Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

Abstract

1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle¹⁵]MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH₂) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle¹⁵]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, plasma stability, and biodistribution) were evaluated and compared with [Nle¹⁵]MG11 as well as their previously reported analogs bearing 1,4-disubstituted 1,2,3-triazoles. Our investigations led to the discovery of novel triazole-modified analogs of [Nle¹⁵]MG11 with nanomolar CCK2R-binding affinity and 2-fold increased tumor uptake. This study illustrates that substitution of amides by 1,5-disubstituted 1,2,3-triazoles is an effective strategy to enhance the pharmacological properties of biologically active peptides.