Triazole-based inhibitors of geranylgeranyltransferase II

Abstract

A small set of triazole bisphosphonates has been prepared and tested for the ability to inhibit geranylgeranyltransferase II (GGTase II). The compounds were prepared through use of click chemistry to assemble a central triazole that links a polar head group to a hydrophobic tail. The resulting compounds were tested for their ability to inhibit GGTase II in an in vitro enzyme assay and also were tested for cytotoxic activity in an MTT assay with the human myeloma RPMI-8226 cell line. The most potent enzyme inhibitor was the triazole with a geranylgeranyl tail, which suggests that inhibitors that can access the enzyme region that holds the isoprenoid tail will display greater activity.

Figure 1

Two carboxy phosphonates that inhibit GGTase II and their parent bisphosphonates.

Figure 2

Retrosynthesis of a family of triazole bisphosphonates.

Figure 3

Synthesis of the target triazole bisphosphonates.