Synthesis of mono- and bisdihydrodipyridopyrazines and assessment of their DNA binding and cytotoxic properties.
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.
Blanchard
Stéphanie
S
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.
Rodriguez
Ivan
I
Tardy
Christelle
C
Baldeyrou
Brigitte
B
Bailly
Christian
C
Colson
Pierre
P
Houssier
Claude
C
Léonce
Stéphane
S
Kraus-Berthier
Laurence
L
Pfeiffer
Bruno
B
Renard
Pierre
P
Pierré
Alain
A
Caubère
Paul
P
Guillaumet
Gérald
G
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
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