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Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards this enzyme compared to prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS inhibitor is reported.

Type

Journal article

Journal

European journal of medicinal chemistry

Publication Date

09/2014

Volume

84

Pages

77 - 89

Addresses

Musculoskeletal Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.

Keywords

Cell Line, Hela Cells, Animals, Cattle, Humans, Alkyl and Aryl Transferases, Enzyme Inhibitors, Cell Survival, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Organophosphonates