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

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)5304-5309
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2014

Fingerprint

Ribonucleotide Reductases
Esters
Pharmaceutical Preparations
nucleoside phosphotransferase
Valproic Acid
Deoxyribonucleosides
Lead compounds
Histone Deacetylase Inhibitors
Histone Deacetylases
Nucleosides
Human Activities
Tumors
Neoplasms
Phosphotransferases
Down-Regulation
Adenosine Triphosphate
Cells
3'-C-methyladenosine
calcium ascorbate
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase : Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine. / Petrelli, Riccardo; Meli, Maria; Vita, Patrizia; Torquati, Ilaria; Ferro, Arianna; Vodnala, Munender; D'Alessandro, Natale; Tolomeo, Manlio; Del Bello, Fabio; Kusumanchi, Praveen; Franchetti, Palmarisa; Grifantini, Mario; Jayaram, Hiremagalur N.; Hofer, Anders; Cappellacci, Loredana.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 22, 15.11.2014, p. 5304-5309.

Research output: Contribution to journalArticle

Petrelli, R, Meli, M, Vita, P, Torquati, I, Ferro, A, Vodnala, M, D'Alessandro, N, Tolomeo, M, Del Bello, F, Kusumanchi, P, Franchetti, P, Grifantini, M, Jayaram, HN, Hofer, A & Cappellacci, L 2014, 'From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 22, pp. 5304-5309. https://doi.org/10.1016/j.bmcl.2014.09.046
Petrelli, Riccardo ; Meli, Maria ; Vita, Patrizia ; Torquati, Ilaria ; Ferro, Arianna ; Vodnala, Munender ; D'Alessandro, Natale ; Tolomeo, Manlio ; Del Bello, Fabio ; Kusumanchi, Praveen ; Franchetti, Palmarisa ; Grifantini, Mario ; Jayaram, Hiremagalur N. ; Hofer, Anders ; Cappellacci, Loredana. / From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase : Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 22. pp. 5304-5309.
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