| Summary: | N6-Isopentenyladenosine (<b>i6A</b>) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that <b>i6A</b> targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of <b>i6A</b> derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds <b>2a–m</b>) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds <b>2</b>, <b>2a</b> and <b>2c</b> showed a persistent antiproliferative effect on human CRC lines and compound <b>2f</b> exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of <b>2f</b> was related to the ability to inhibit FPPS activity.
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