Many analogues of the natural nucleosides modified at nucleobase or at sugar moiety have been developed on the basis of their therapeutic potential as antitumor antiviral and antiprotozoal agents. Among the N6-modified adenosine analogues, N6-hydroxy, N6-methoxy, and N6-amino derivatives have proved to be potent cytotoxic agents acting through letal mutagenesis. Moreover, modification at the ribose moiety of purine nucleosides resulted in potent antitumor agents, such as in the case of 3'-C-methyladenosine (3'-MeAdo), recently developed by us as a mechanism-based ribonucleotide reductase (RR) inhibitor, that displayed a significant cytotoxicity against a panel of human leukemia and carcinoma cell lines.1 We now report on the synthesis and antitumor activity of a series of 3'-C-methyladenosine derivatives substituted at N6 with a hydroxy, methoxy or amino group. Furthmore, azinyl hydrazone containing a N*-N*-N* structural motif able to inhibit RR were also prepared starting from N6-.amino-adenosine or N6-amino-3'-C-methyladensine. The stereochemistry of these compounds was established to be Z by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented. 1 (a) Franchetti P et al J Med Chem 2005, 48, 4983-89; (b) Cappellacci et al J Med Chem 2008, 51, 4260-69

New N6-substituted adenosine and 3’-C-methyl-adenosine derivatives as antitumor agents

CAPPELLACCI, Loredana;PETRELLI, Riccardo;VITA, PATRIZIA;FRANCHETTI, Palmarisa;GRIFANTINI, Mario
2009-01-01

Abstract

Many analogues of the natural nucleosides modified at nucleobase or at sugar moiety have been developed on the basis of their therapeutic potential as antitumor antiviral and antiprotozoal agents. Among the N6-modified adenosine analogues, N6-hydroxy, N6-methoxy, and N6-amino derivatives have proved to be potent cytotoxic agents acting through letal mutagenesis. Moreover, modification at the ribose moiety of purine nucleosides resulted in potent antitumor agents, such as in the case of 3'-C-methyladenosine (3'-MeAdo), recently developed by us as a mechanism-based ribonucleotide reductase (RR) inhibitor, that displayed a significant cytotoxicity against a panel of human leukemia and carcinoma cell lines.1 We now report on the synthesis and antitumor activity of a series of 3'-C-methyladenosine derivatives substituted at N6 with a hydroxy, methoxy or amino group. Furthmore, azinyl hydrazone containing a N*-N*-N* structural motif able to inhibit RR were also prepared starting from N6-.amino-adenosine or N6-amino-3'-C-methyladensine. The stereochemistry of these compounds was established to be Z by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented. 1 (a) Franchetti P et al J Med Chem 2005, 48, 4983-89; (b) Cappellacci et al J Med Chem 2008, 51, 4260-69
2009
273
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/200013
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact