From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3'-C-methyladenosine
2014 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 24, no 22, 5304-5309 p.Article in journal (Refereed) Published
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 synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2',5'-bis-O-valproyl-3'-C-methyladenosine (A160) and 5'-O-valproyl-3'-C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases.
Place, publisher, year, edition, pages
2014. Vol. 24, no 22, 5304-5309 p.
Histone deacetylase (HDAC) inhibitors; Ribonucleotide reductase (RR) inhibitors; Hematological and solid tumors; Apoptosis; 3 '-C-Methyladenosine; Valproic acid
Other Basic Medicine
IdentifiersURN: urn:nbn:se:umu:diva-94711DOI: 10.1016/j.bmcl.2014.09.046ISI: 000343901400035PubMedID: 25304896OAI: oai:DiVA.org:umu-94711DiVA: diva2:755767