title: Synthesis of mono- and bisdihydrodipyridopyrazines and assessment of their DNA binding and cytotoxic properties.
abstract: Aminoalkyl-substituted monomeric and dimeric dihydrodipyridopyrazines have been synthesized and evaluated as antitumor agents. Potent cytotoxic compounds were identified in both series. Biochemical and biophysical studies indicated that all these compounds strongly stabilized the duplex structure of DNA and some of them elicited a selectivity for GC-rich sequences. Sequence recognition by of the dimeric dihydrodipyridopyrazines is reminiscent of that of certain antitumor bisnaphthalimides. Compared to monomers, corresponding dimeric derivatives showed higher affinity for DNA. This property was attributed to a bisintercalative binding to DNA. This assumption was indirectly probed by electric linear dichroism and DNA relaxation experiments. DNA provides a bioreceptor for these dihydrodipyridopyrazine derivatives, but no poisoning of human topoisomerases I or II was detected. Most of the compounds efficiently inhibited the growth of L1210 murine leukemia cells and perturbed the cell cycle progression (with a G2/M block in most cases). A weak but noticeable in vivo antitumor activity was observed with one of the dimeric compounds. This studies identifies monomeric and dimeric dihydrodipyridopyrazines as a new class of DNA-targeted antitumor agents.
authors.affiliation: Institut de Chimie Organique et Analytique UMR-CNRS 6005, UFR de Sciences, Université d'Orléans, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Ivan
authors.initials: I
authors.lastname: Rodriguez
authors.forename: Christelle
authors.initials: C
authors.lastname: Tardy
authors.forename: Brigitte
authors.initials: B
authors.lastname: Baldeyrou
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Pierre
authors.initials: P
authors.lastname: Colson
authors.forename: Claude
authors.initials: C
authors.lastname: Houssier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Paul
authors.initials: P
authors.lastname: Caubère
authors.forename: Gérald
authors.initials: G
authors.lastname: Guillaumet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D004095:Dihydropyridines; D007364:Intercalating Agents; D011719:Pyrazines; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II