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

Abstract

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 (IC(50) < or = 10(-8) M) in 44/58 cell lines. However, only 25/53 of those cell lines showed corresponding IC(50) 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.