title: Synthesis of new pyrrolo[1,2-a]quinoxaline derivatives as potential inhibitors of Akt kinase.
abstract: Akt kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel Akt kinase inhibitors, based on a quinoxaline or pyrazinone scaffold. A series of new substituted pyrrolo[1,2-a]quinoxaline derivatives, structural analogues of these active quinoxaline or pyrazinone pharmacophores, was synthesized from various substituted 2-nitroanilines or 1,2-phenylenediamine via multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937 and HL60, and the breast cancer cell line MCF7. Three of these human cell lines (K562, U937 and MCF7) exhibited an active phosphorylated Akt form. The most promising active pyrroloquinoxalines were found to be 1a that inhibited K562 cell line proliferation with an IC(50) of 4.5 microM, and 1h that inhibited U937 and MCF7 cell lines with IC(50) of 5 and 8 microM, respectively. These two candidates exhibited more potent activities than the reference inhibitor A6730.
authors.affiliation: PPF Médicaments-Parasitologie, UFR des Sciences Pharmaceutiques, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.forename: Ambre
authors.initials: A
authors.lastname: Geneste
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Begorre
authors.forename: Solene Belisle
authors.initials: SB
authors.lastname: Fabre
authors.forename: Stephane
authors.initials: S
authors.lastname: Brajot
authors.forename: Stephane
authors.initials: S
authors.lastname: Massip
authors.forename: Denis
authors.initials: D
authors.lastname: Thiolat
authors.forename: Djavad
authors.initials: D
authors.lastname: Mossalayi
authors.forename: Christian
authors.initials: C
authors.lastname: Jarry
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055808:Drug Discovery; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011758:Pyrroles; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011810:Quinoxalines; D051057:Proto-Oncogene Proteins c-akt