Lead optimization through VLAK protocol: new annelated pyrrolo-pyrimidine derivatives as antitumor agents.
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 (pGI(50) = 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.
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari STEMBIO, Sezione di Chimica Farmaceutica e Biologica, Università di Palermo, Via Cipolla 74D, I-90123 Palermo, Italy. antonino.lauria@unipa.it
Antonino
A
Lauria
Chiara
C
Patella
Ilenia
I
Abbate
Annamaria
A
Martorana
Anna Maria
AM
Almerico
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D048088:Informatics / Q000379:methods*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; C030986:pyrimidine