From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3’-C-methyladenosine

We synthesized a series of serum-stable covalently linked drugs derived from 3'-C-methyladenosine(3'-Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase(HDAC) inhibitors, respectively. While the combination of free VPA and 3'-Me-Ado resulted in a clear synergisticapoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the correspondingapoptotic activity. Two of the analogs, 2',5'-bis-O-valproyl-3'-C-methyladenosine (A160) and5'-O-valproyl-3'-C-methyladenosine (A167), showed promising cytotoxic activities against humanhematological and solid cancer cell lines. A167 was less potent than A160 but had interesting featuresas an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantlyreduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novellead compound, which in contrast to previously used RR nucleoside analogs does not require intracellularkinases for its activity and therefore holds promise against drug resistant tumors with downregulatednucleoside kinases.