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

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

doi:10.3389/fchem.2020.596162

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.

Highlights

Rab geranylgeranyl transferase (RGGT) constitutes a potential therapeutic target, as it is responsible for posttranslational prenylation of Rab GTPases (Kelly et al, 2012)
We have previously demonstrated that phosphonocarboxylates with imidazo[1,2-a]pyridine ring substituted in the C6 position of the heterocycle show activity toward RGGT (Kazmierczak et al, 2017)
We synthesized a set of 12 new phosphonocarboxylate derivatives of a previously described potent RGGT inhibitor, namely 3-IPEHPC (McKenna et al, 2010; Błazewska et al, 2011)

Summary

INTRODUCTION

Rab geranylgeranyl transferase (RGGT) constitutes a potential therapeutic target, as it is responsible for posttranslational prenylation of Rab GTPases (Kelly et al, 2012). The analogs bearing C3-substituted pyridine (Coxon et al, 2001; Marma et al, 2007; Baron et al, 2009) and Nsubstituted benzimidazole (Bhuiyan et al, 2019) are less active against RGGT, the latter were tested only as the socalled desoxy analogs, which are known to be less active than Cαfluorinated analogs (Marma et al, 2007; Coxon et al, 2014). As these compounds bear two ionic groups, we have undertaken the effort to synthesize their prodrug analogs. Besides the varied character of substituents in terms of bulkiness, length, and geometry, we studied the influence of the basic and acidic nature of introduced groups on the activity of these compounds against RGGT

RESULTS AND DISCUSSION

CONCLUSIONS

General Procedure for the Hydrolysis With HCl

DATA AVAILABILITY STATEMENT