Synthesis and in vitro activities of new anticancer duplex drugs linking 2′-deoxy-5-fluorouridine (5-FdU) with 3′-C-ethynylcytidine (ECyd) via a phosphodiester bonding

Two isomeric cytostatic duplex drugs 2′-deoxy-5-fluorouridylyl-(3′→5′)-3′-C-ethynylcytidine [5-FdU(3′→5′)ECyd] and 2′-deoxy-5-fluorouridylyl-(5′→5′)-3′-C-ethynylcytidine [5-FdU(5′→5′)ECyd] were designed and synthesized at gram scale according to the hydrogenphosphonate method in an overall yield of about 40%. The in vitro evaluation of the anticancer effects indicated highly varying sensibilities of the panel of 60 tested tumor cell lines against the duplex drugs. 5-FdU(3′→5′)ECyd had a 50% growth inhibition (IC50 ⩽ 10−8 M) in 44/58 cell lines. However, only 25/53 of those cell lines showed corresponding IC50 values when the isomeric 5-FdU(5′→5′)ECyd was tested. Total growth inhibition was achieved using micromolar concentrations of the duplex drugs. The 5-FdU residue of the duplex drug can cause very different effects like additive, synergistic, antagonistic as well as sequence-depending activities, which drastically changed efficiency as well as specificity of the anticancer activities of the duplex drugs, in comparison to those of the monomeric drugs.

Antitumor active duplex drugs linking 2′-deoxy-5-fluorouridine with 3′-C-ethynylcytidine via a 5′→5′ (A) or a 3′→5′ (B) phosphodiester bonding.Figure optionsDownload as PowerPoint slide