# Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
## 3 GGDPS Inhibitors
Figure 3: Synthetic sequences to dialkyl (**17**) and alkyl/alkoxy (**22**) bisphosphonates. More recently, a novel series of GGDPS inhibitors containing a triazole moiety has been reported (Table 1). The synthesis of these triazoles takes advantage of an azide-acetylene cycloaddition or \"click reaction\" [42]. As shown in Figure 4, click chemistry involves the cycloaddition of an azide (**23**) with a terminal acetylene (**24**), resulting in an efficient synthesis of the 1,2,3-triazole (**25**). As both the acetylene and the azide components can carry substituents, this allows for a combinatorial approach to drug development. The process is highly reliable and quite efficient for preparation of triazoles with simple alkyl or aryl substituents. However, with allylic azides, the reaction can be more complicated because of a rapid sigmatropic rearrangement which gives a mixture of \(E\)- and \(Z\)-olefins (e.g., **26** and **27**) [43]. Thus, the first triazole examples bearing geranyl or nervl substituents derived from the azide component gave a mixture of olefin isomers in a 2:1 ratio irrespective of the olefin stereochemistry in the initial azide. Upon bioassay it was noted that a 2:1 mixture of the geranyl and nervl triazole bisphosphonates (7) globally disrupted cellular geranylgeranylation, even though it showed no activity as an inhibitor of GGTase II [39; 44]. To circumvent the olefin isomerization and prepare the individual isomers, it has proven possible to mask the olefins as an epoxide (e.g., **28**), conduct the cycloaddition with the acetylene bisphosphonate **29**[42] to obtain the triazole **30**, and then reduce the epoxide to regenerate the original olefin stereochemistry (**31**) (Figure 5) [39]. This approach was utilized to generate the individual geranyl (**32**) and nervl (**33**) isomers. When the two compounds were tested in vitro against \begin{table}
\begin{tabular}{l c c c} \hline
**Alkyl Group** & **GGDPS IC\({}_{\textbf{50}}\) (uM)** & **FDPS IC\({}_{\textbf{50}}\) (uM)** & **Cell Activity (uM)** \\ \hline premyl [36] & 38 & \textgreater{}100 & none \\ homoprenyl [37] & 0.43 & 6.6 & \textgreater{}1 \\ bishomoprenyl [38] & 3.6 & \textgreater{}100 & \textgreater{}5 \\ geranyl/neryl (2:1) (**7**) [39] & 2.2 & 84 & \textgreater{}10 \\ geranyl (**32**) [39] & 17 & 57 & \textgreater{}10 \\ neryl (**33**) [39] & 0.38 & 79 & \textgreater{}1 \\ geranyl epoxide [39] & 23 & 33 & none \\ neryl epoxide [39] & 17 & 47 & none \\ homogeranyl/homomeryl (3:1) (**8**) [37] & 0.045 & 28 & \textgreater{}0.03 \\ homogeranyl [40] & 0.17 & 8.2 & \textgreater{}0.09 \\ homomeraryl [40] & 0.075 & 5.6 & \textgreater{}0.03 \\ bishomogeranyl [38] & 2.6 & 33 & \textgreater{}5 \\ bishomomeryl [38] & 1.3 & 30 & \textgreater{}0.5 \\ farnesyl [41] & 40 & 58 & none \\ homofarnesyl [36] & 0.82 & 43 & \textgreater{}1 \\ geranylgeranyl [41] & 120 & 100 & none \\ homogeranylgeranyl [36] & 56 & 63 & \textgreater{}100 \\ \hline \end{tabular}
\end{table} 
Table 1: Summary of alkyl-substituted triazole bisphosphonates. Figure 4: A convergent synthesis to triazole bisphosphonates. purified enzymes, the nervl isomer **33** was found to be approximately 40-fold more potent than the geranyl isomer **32** (IC\({}_{50}\) 375 nM versus 17 nM), suggesting that the olefin stereochemistry has a significant impact on inhibitory activity against GGDPS [39]. The nervl isomer was also 10-fold more potent than the geranyl isomer in cellular assays, highly specific for GGDPS, and showed no activity against any of the prenyltransferasees [39]. Additional structure-function work led to the development of homoisoprenoid triazole bisphosphonates [37]. In all tested cases, the elongation of the alkyl chain length by one-carbon enhanced activity of the compound as a GGDPS inhibitor (Table 1). The most potent of this homologated series of compounds was a mixture of homogeranyl and homoneryl triazole bisphosphonates (8, Figure 2, Table 1). This mixture inhibits GGDPS with an IC\({}_{50}\) value of 45 nM, the lowest IC\({}_{50}\) value reported to date [37].