title: Synthesis and evaluation of the antiproliferative activity of novel pyrrolo[1,2-a]quinoxaline derivatives, potential inhibitors of Akt kinase. Part II.
abstract: Attenuation of protein kinases by selective inhibitors is an extremely active field of activity in anticancer drug development. Therefore, Akt, a serine/threonine protein kinase, also known as protein kinase B (PKB), represents an attractive potential target for therapeutic intervention. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel inhibitors with various heterocycle scaffolds. Based on previous results obtained on the antiproliferative activities of new pyrrolo[1,2-a]quinoxalines, a novel series was designed and synthesized from various substituted phenyl-1H-pyrrole-2-carboxylic acid alkyl esters via a 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. The first biological evaluation of our new substituted pyrrolo[1,2-a]quinoxalines showed antiproliferative activity against the tested cell lines. From a general SAR point of view, these preliminary biological results highlight the importance of substitution at the C-4 position of the pyrroloquinoxaline scaffold by a benzylpiperidinyl fluorobenzimidazole group, and also the need for a functionalization on the pyrrole ring.
authors.affiliation: PPF Médicaments-Parasitologie, UFR des Sciences Pharmaceutiques, Université Bordeaux 2, Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.forename: Stephane
authors.initials: S
authors.lastname: Moreau
authors.forename: Aurore
authors.initials: A
authors.lastname: Gay
authors.forename: Solene Belisle
authors.initials: SB
authors.lastname: Fabre
authors.forename: Denis
authors.initials: D
authors.lastname: Thiolat
authors.forename: Stephane
authors.initials: S
authors.lastname: Massip
authors.forename: Gregory
authors.initials: G
authors.lastname: Macky
authors.forename: Frederic
authors.initials: F
authors.lastname: Godde
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: D001562:Benzimidazoles / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D004952:Esters; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011810:Quinoxalines; D051057:Proto-Oncogene Proteins c-akt