A small set of triazole bisphosphonates has been prepared and tested for the ability to inhibit geranylgeranyl transferase 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.

The α–trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups, and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. To advance studies of this unique functionality, a general route to alkyl derivatives of the parent system (R = H) has been developed. A set of new α-alkyl-1,1,1-trisphosphonate esters has been prepared through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of these new compounds has been studied in representative reactions that afford additional examples of this functionality.

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Reaction of the [trans-B(20)H(18)](2-) ion with the n-butoxide ion, formed in situ from reaction of n-butanol and NaH, in tetrahydropyran (THP) produces in good yield an unexpected and isolable solvent-coordinated polyhedral borane anion, [ae-B(20)H(17)O(CH(2))(5)](3-). The anticipated product of nucleophilic attack, [ae-B(20)H(17)On-Bu](4-), is not observed under the reaction conditions. The solvent-coordinated product is also formed in the presence of either ethoxide or carbamate ion but is not observed if the ethoxide or carbamate ion is not present in stoichiometric amounts. In the presence of the n-butanethiol anion, the coordinated THP ring undergoes a ring-opening reaction, yielding the [ae-B(20)H(17)O(CH(2))(5)Sn-Bu](4-) anion. Ring opening is also observed in the presence of the ethoxide ion in refluxing THP. Isolation of the previously proposed analogous solvent-coordinated tetrahydrofuran (THF) product, [ae-B(20)H(17)O(CH(2))(4)](3-), was unsuccessful; however, the product resulting from ring opening of THF by the n-butanethiol anion is reported.

At the branch point of the isoprenoid biosynthetic pathway, squalene synthase (SQS) is an enzyme that utilizes farnesyl diphosphate (FPP) to make squalene, which is first committed step in the biosynthesis of cholesterol. A recombinant form of human SQS has been purified and in vitro assays have been established to measure enzyme activity. We have evaluated structure activity relationships among more than 30 novel bisphosphonates and have identified 9‐biphenyl geranyl bisphosphonate (BPGB) as a potent inhibitor of SQS (IC50 = 10 nM). Western blot analysis of farnesylated and geranylgeranylated proteins from HepG2 cells indicates that treatment with BGBP is specific for the sterol branch of the pathway and not other isoprenoid enzymes (i.e., farnesyl diphosphate synthase or geranylgeranyl diphosphate synthase). The coadministration of lovastatin with BGBP can prevent lovastatin‐induced inhibition of protein prenylation. BGBP at 25 μM for 24 hours resulted in more than 20 fold accumulation of the substrate FPP. In conclusion, this data identifies a novel and specific inhibitor of SQS and evaluates some of the cellular effects of squalene synthase inhibition. Research support comes from the Roy J. Carver Charitable Trust and the Roland W. Holden Family Program for Experimental Cancer Therapeutics.