title: Design and synthesis of 4-substituted indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives with antitumor activity.
abstract: New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The more active derivatives were shown to be 1eJ and 1eL, endowed with significant antiproliferative activity against the renal and CNS subpanels, respectively. A mechanism of action closely related to the DNA-interacting drugs can be supposed, although, alternative mechanisms, similar to those of the anthracyclines, can also operate.
authors.affiliation: Dipartimento Farmacochimico, Tossicologico e Biologico-Università di Palermo, Via Archirafi 32, Palermo, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.forename: Chiara
authors.initials: C
authors.lastname: Patella
authors.forename: Gaetano
authors.initials: G
authors.lastname: Dattolo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011744:Pyrimidinones; D004247:DNA