• antitumor

Human farnesyl pyrophosphate synthase (hFPPS, also known as farnesyl diphosphate synthase, FDPS) belongs to the prenyltransferase family and it is an homodimeric enzyme constituted by 41 kDa subunits. This enzyme catalyzes the two-step synthesis of farnesyl pyrophosphate (FPP): isoprenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are coupled to produce geranylpyrophosphate (GPP), which subsequently is condensed with an additional IPP unit producing FPP. Condensing another unit of IPP with a FPP molecule geranylgeranyl pyrophosphate (GGPP) is obtained.
These sesquiterpene derivatives are crucial precursors in the synthesis of several classes of essential metabolites, including sterols, dolichols, ubiquinones and carotenoids. It is also used by farnesyltransferase (FT) to prenylate biomolecules as hormones, visual pigments, constituents of membranes and components of signal transduction.
FPP and GGPP are essential for the post-translational prenylation of small GTPases, a family of signaling proteins that are fundamentally important for cell survival. Farnesylated proteins (e.g., H-Ras, K-Ras, and N-Ras) are predominant in oncogenesis. In addition to down-regulating Ras prenylation, intracellular accumulation of IPP leads to the formation of an ATP derivative (ApppI), which induces apoptosis by inhibiting the mitochondrial adenine nucleotide translocase (ANT).
For this reason the development of farnesyltransferase inhibitors (FTI) as potential therapeutics is a new frontier for the treatment of cancer.
A recent study developed by the research group of Prof. Bifulco highlighted the capability of N6-isopenteniladenosine, an adenosine and isoprenoid (IPA) derivative, to arrest cell cycle at the G0-Gi phase. In particular the antiproliferative properties of this compound seem to be related to FPPS inhibition.
On the basis of these experimental data we have designed and synthesized adenosine and inosine derivatives as antitumor agents focusing on FPPS as biological target. These compounds have been designed with the aim to evaluate the influence of different substituents in position 6 of the adenosine and inosine core. Moreover compounds characterized by electron releasing or withdrawing groups in position 8 of inosine have been developed.