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

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.

Targeting Small GTPases and Their Prenylation in Diabetes Mellitus

“…This class of inhibitors prohibits the introduction only of the second geranylgeranyl group to Rabs, leaving the monogeranylated Rabs unaffected. Among the currently known phosphonocar- boxylates, the most active ones contain imidazo[1,2-a] 282,283,281 or the imidazole ring. 284,285 Another strategy is based on the direct targeting of Rab GTPases.…”

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI(d2)

“…It has become clear and evident that phosphonate chemistry plays a crucial role in drug research and development [1][2][3][4]. There are several phosphonate-containing compounds under research or already in clinical use as antiviral or anticancer drugs [2,5,6]. Bisphosphonates (BPs), the stable analogues of the natural pyrophosphate (Figure 1) found in cells, have been used for decades in the treatment of bone-related diseases, such as osteoporosis [7,8].…”