title: From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: synthesis and biological evaluation of valproic esters of 3'-C-methyladenosine.
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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.affiliation: Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile-Sezione di Farmacologia, Università di Palermo, 90127 Palermo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Meli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vita
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torquati
authors.affiliation: Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile-Sezione di Farmacologia, Università di Palermo, 90127 Palermo, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Ferro
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Munender
authors.initials: M
authors.lastname: Vodnala
authors.affiliation: Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile-Sezione di Farmacologia, Università di Palermo, 90127 Palermo, Italy.
authors.forename: Natale
authors.initials: N
authors.lastname: D'Alessandro
authors.affiliation: Centro Interdipartimentale di Ricerca in Oncologia Clinica, Policlinico 'P. Giaccone', Università di Palermo, 90127 Palermo, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Tolomeo
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Richard Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kusumanchi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Palmarisa
authors.initials: P
authors.lastname: Franchetti
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Grifantini
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Richard Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
authors.forename: Hiremagalur N
authors.initials: HN
authors.lastname: Jayaram
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hofer
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: loredana.cappellacci@unicam.it.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014635:Valproic Acid / Q000737:chemistry*
chemical_list: C502992:3'-C-methyladenosine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004952:Esters; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D000255:Adenosine Triphosphate; D012264:Ribonucleotide Reductases; D006655:Histone Deacetylases; D000241:Adenosine
keywords: 3′-C-Methyladenosine; Apoptosis; Hematological and solid tumors; Histone deacetylase (HDAC) inhibitors; Ribonucleotide reductase (RR) inhibitors; Valproic acid