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ANTONINO LAURIA

Lead optimization through VLAK protocol: New annelated pyrrolo-pyrimidine derivatives as antitumor agents

  • Autori: Lauria, A; Patella, C; Abbate, I; Martorana, A; Almerico, AM
  • Anno di pubblicazione: 2012
  • Tipologia: Articolo in rivista (Articolo in rivista)
  • Parole Chiave: Anticancer drugs; VLAK protocol; Developmental Therapeutics Program (DTP); Annelated pyrrolo-pyrimidines
  • OA Link: http://hdl.handle.net/10447/64282

Abstract

The chemometric protocol VLAK was applied to predict improvement of the biological activity of pyrrolo-pyrimidine derivatives as anticancer agents, by using the NCI ACAM Database as depository of antitumor drugs with a known mechanism of action. Among the selected compounds two of these showed a good increase in the antitumor activity. These new pyrrolo-pyrimidine compounds were demonstrated effective against the full panels of NCI DTP tumour human cell lines. The derivative 8-[3-(piperidino)propyl]-4,10-dimethyl-9-phenyl-6-(methylsulfanyl)-3,4-dihydropyrimido[1,2-c]pyrrolo[3,2- e]pyrimidin-2(8H)-one reveled efficacious against the leukemia subpanel, in particular the RPMI cell line resulted the most sensitive (pGI50 ¼ 6.68). Moreover the derivative 7-(3-Chloropropyl)-9-methyl-5- (methylsulfanyl)-8-phenyl-3H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-2(7H)-one showed a good antitumor activity against the leukemia subpanel with a low cytotoxic activity, above all against the HCT11 human tumour cell line. The VLAK protocol revealed a good method to design new molecules with good antitumor activity, starting from low active compounds. Moreover this protocol focused on the pyrrolo-pyrimidine derivatives as useful starting point for further development to obtain more potent antitumor agents.