Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.

Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure-activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels.

α-Amino bisphosphonate triazoles serve as GGDPS inhibitors.

Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and in vivo activities.

Conjugate reduction of vinyl bisphosphonates.

Vinyl bisphosphonates can be readily prepared by condensation of an aromatic aldehyde with the tetraester of a methylenebisphosphonate, and reduction of the resulting olefin is an attractive strategy for the preparation of monoalkyl geminal bisphosphonates. Conjugate reduction through use of variations on the Stryker approach has proven to be an efficient method for that reduction, even in the presence of aromatic substituents that also could be reduced. Furthermore, remote olefins in an isoprenoid chain survive this conjugate reduction unaffected, allowing access to isoprenoid-substituted triazole bisphosphonates of interest as potential inhibitors of terpenoid biosynthesis.