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

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

  • Bioorg Med Chem Lett. 2014 Nov 15;24(22):5304-9. doi: 10.1016/j.bmcl.2014.09.046.
Riccardo Petrelli 1,  Maria Meli 2,  Patrizia Vita 1,  Ilaria Torquati 1,  Arianna Ferro 2,  Munender Vodnala 3,  Natale D'Alessandro 2,  Manlio Tolomeo 4,  Fabio Del Bello 1,  Praveen Kusumanchi 5,  Palmarisa Franchetti 1,  Mario Grifantini 1,  Hiremagalur N Jayaram 5,  Anders Hofer 3,  Loredana Cappellacci 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
  • 2 Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile-Sezione di Farmacologia, Università di Palermo, 90127 Palermo, Italy.
  • 3 Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden.
  • 4 Centro Interdipartimentale di Ricerca in Oncologia Clinica, Policlinico 'P. Giaccone', Università di Palermo, 90127 Palermo, Italy.
  • 5 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Richard Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
  • 6 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: loredana.cappellacci@unicam.it.
PMID: 25304896 DOI: 10.1016/j.bmcl.2014.09.046
Abstract

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.

Keywords

3′-C-Methyladenosine; Apoptosis; Hematological and solid tumors; Histone deacetylase (HDAC) inhibitors; Ribonucleotide reductase (RR) inhibitors; Valproic acid.

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