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

6533b828fe1ef96bd1287ad3

RESEARCH PRODUCT

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

Hiremagalur N. Jayaram Riccardo Petrelli Fabio Del Bello Praveen Kusumanchi Maria Meli Loredana Cappellacci Patrizia Vita Arianna Ferro Munender Vodnala Mario Grifantini Anders Hofer Ilaria Torquati Manlio Tolomeo Palmarisa Franchetti Natale D'alessandro

subject

Deoxyribonucleoside triphosphate Adenosine Cell Survival Clinical Biochemistry Allosteric regulation Pharmaceutical Science Antineoplastic Agents Pharmacology Biochemistry Histone deacetylase (HDAC) inhibitor Histone Deacetylases Adenosine Triphosphate Allosteric Regulation Cell Line Tumor Drug Discovery Ribonucleotide Reductases medicine Valproic acid Humans Ribonucleotide reductase (RR) inhibitor Enzyme Inhibitors Molecular Biology 3′-C-methyladenosine Nucleoside analogue Kinase Chemistry Organic Chemistry Apoptosi Esters Settore CHIM/08 - Chimica Farmaceutica Hematological and solid tumor Histone Deacetylase Inhibitors Kinetics Ribonucleotide reductase Biochemistry Settore BIO/14 - Farmacologia Molecular Medicine Histone deacetylase Nucleoside Intracellular medicine.drug

description

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.

year	journal	country	edition	language
2014-01-01

10.1016/j.bmcl.2014.09.046 http://hdl.handle.net/11581/338581