Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase

Damian Kusy; Aleksandra Marchwicka; Joanna Małolepsza; Katarzyna Justyna; Edyta Gendaszewska-Darmach; Katarzyna Magdalena Błażewska

doi:10.3389/fchem.2020.596162

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase

Front Chem. 2021 Jan 6:8:596162. doi: 10.3389/fchem.2020.596162. eCollection 2020.

Authors

Damian Kusy¹, Aleksandra Marchwicka², Joanna Małolepsza¹, Katarzyna Justyna^{1

2}, Edyta Gendaszewska-Darmach², Katarzyna Magdalena Błażewska¹

Affiliations

¹ Faculty of Chemistry, Institute of Organic Chemistry, Lodz University of Technology, Łódź, Poland.
² Faculty of Biotechnology and Food Sciences, Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Łódź, Poland.

Abstract

Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa cell line. The esterification of carboxylic acid in the phosphonopropionate moiety turned the inhibitor into an inactive analog.

Keywords: RGGT; Rab geranylgeranyl transferase; imidazo[1, 2-a]pyridine; phosphonocarboxylate; phosphonocarboxylic acid; phosphonopropionate; phosphonopropionic acid; prenylation.