title: Synthesis and evaluation of the cytotoxic activity of novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives in myeloid and lymphoid leukemia cell lines.
abstract: Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Among heterocyclic compounds that attracted a lot of attention because of its wide spread biological activities, the pyrrolo[1,2-a]quinoxaline heterocyclic framework has been identified as interesting scaffolds for antiproliferative activity against various human cancer cell lines. In the present study, novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives 1a-l have been designed and synthesized. Their cytotoxicities were evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines), and K562, U937, HL60 (myeloid cell lines), as well as normal human peripheral blood mononuclear cells (PBMNCs). Then, apoptosis study was performed with the more interesting compounds. The new pyrrolo[1,2-a]quinoxaline series showed promising cytotoxic potential against all leukemia cell lines tested, and some compounds showed better results than the reference compound A6730. Some compounds, such as 1a, 1e, 1g and 1h are promising because of their high activity against leukemia and their low activity against normal hematopoietic cells. Structure-activity relationships of these new synthetic compounds 1a-l are here also discussed.
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, Cellules souches hématopoïétiques normales et leucémiques, F-33076 Bordeaux cedex, France; INSERM U1035, Cellules souches hématopoïétiques normales et leucémiques, F-33000 Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France; Department of Pharmacy and CIRPeB, University of Naples "Federico II", Via Mezzocannone, 16 80134 Naples, Italy.
authors.forename: Marian
authors.initials: M
authors.lastname: Vincenzi
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Moreau
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Savrimoutou
authors.affiliation: Univ. Bordeaux, ISM - CNRS UMR 5255, 351 cours de la Libération, F-33405 Talence cedex, France.
authors.forename: Noël
authors.initials: N
authors.lastname: Pinaud
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Lesbordes
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Peyrilles
authors.affiliation: Univ. Bordeaux, ICMCB CNRS-UPR 9048, 87, Avenue du Docteur Schweitzer, F-33608 Pessac cedex, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marchivie
authors.affiliation: Institut de Chimie Organique et analytique Univ. Orleans, CNRS UMR 7311, ICOA, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
authors.affiliation: Université de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressouces, UMR CNRS 7378, UFR de Pharmacie, 1 rue des Louvels, F-80037 Amiens cedex 01, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
authors.affiliation: Department of Pharmacy and CIRPeB, University of Naples "Federico II", Via Mezzocannone, 16 80134 Naples, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ronga
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France. Electronic address: jean.guillon@u-bordeaux.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D011810:Quinoxalines; C000612562:phenylpyrrolo(1,2-a)quinoxaline
keywords: Cancer; Cytotoxic activity; Leukemia; Pyrrolo[1,2-a]quinoxaline; Synthesis