Dual-target dimeric molecules with antitumor properties. Synthesis and biological activity of 3’-C-methyladenosine-valproates

In recent years, together with development of new antitumor drugs, significant efforts have been directed toward the development of combination therapies in the treatment of different types of cancers. Some enzymes that play vital roles in DNA replication and transcription, such as ribonucleotide reductase (RR) and histone deacetylases (HDACs), are attractive targets for cancer chemotherapy. Many drugs exert their cytotoxic effects through inhibition of these enzymes’ activity. Moreover, several reports have suggested that HDAC inhibitors (HDACi) synergize with anticancer agents directed at other targets. Valproic acid (VPA), a short branched fatty acid used for the treatment of epilepsy, has emerged as a promising drug for cancer treatment showing antineoplastic activities against both solid and hematologic malignancies mediated by HDACs inhibition. A phase II multicenter study reported that the combination of VPA with 5-azacytidine, a DNA-methyltransferase inhibitor, is active and safe in patients with myelodysplastic syndromes (MDS) with a poor prognosis. In addition, the combination of VPA with either fludarabine or cladribine, two purine nucleoside analogues acting as RR allosteric inhibitors, greatly increased apoptosis in chronic lymphocitic leukaemia (B-CLL) cells. Even more interestingly, VPA induced apoptosis in poor prognosis patients resistant to different type of chemotherapy. In our previous work we found that 3’-C-methyl-adenosine (3’-Me-Ado),1 developed by us as a potent RR inhibitor with antitumor activity against both human leukaemia and carcinoma cell lines, has significant growth inhibitory and apoptotic synergistic effects in HL60 and NB4 promyelocytic leukaemia cells in combination with some hydroxamic acid–derived HDAC inhibitors2. On the basis of this result, we pursued the development of dual-target drugs by combining the structures of 3’-Me-Ado and VPA in a single molecule. This approach has high potential to improve therapeutic efficacy of the single drug and to reduce the probability of drug induced resistance and cross resistance. The 3’-C-methyladenosine-5’-O-valproic ester and the 2’,5’-diester analog were synthesized and evaluated for their antitumor potential against a panel of human cancer cell lines. The results of this study will be presented. References: 1-FRANCHETTI, P., et al., 2005. Antitumor activity of C-methyl-β-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors. Journal of Medicinal Chemistry, 48, 4983-4989. 2-GRIFANTINI, M., et al., 2009. Histone deacetylase (HDAC) inhibition modulates intracellular deoxynucleotides (DNTP) pools and potentiates the antitumor effects of the ribonucleotide reductase (RR) inhibitor 3’-methyl-adenosine (3’-Me-ADO) in promyelocitic leukaemia cell lines. 34° CONGRESSO NAZIONALE DELLA SOCIETÀ ITALIANA DI FARMACOLOGIA, P-2/4/16, Rimini, 14-17 Ottobre 2009.