Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, Chemistry, N6-benzyladenosine derivatives, colorectal cancer, FPPS, ISOPRENOID END-PRODUCT, FARNESYL DIPHOSPHATE SYNTHASE, TRANSFER DIFFERENCE NMR, BIOLOGICAL EVALUATION, N6-ISOPENTENYLADENOSINE, CYTOKININ, CELLS, APOPTOSIS, NUCLEOSIDES, LIGAND, Adenosine, Animals, Antineoplastic Agents, Apoptosis, Cell Proliferation, Cell Survival, Colorectal Neoplasms, Computer Simulation, Drug Screening Assays, Antitumor, Geranyltranstransferase, HCT116 Cells, Humans, Mevalonic Acid, Mice, Structure-Activity Relationship, User-Computer Interface, CELL-PROLIFERATION, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 0307 Theoretical and Computational Chemistry, Organic Chemistry, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

N6-Isopentenyladenosine (i6A) 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 i6A 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 i6A 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 2a-m) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds 2, 2a and 2c showed a persistent antiproliferative effect on human CRC lines and compound 2f exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of 2f was related to the ability to inhibit FPPS activity.