title: Synthesis of short retinoidal amides related to fenretinide: antioxidant activities and differentiation-inducing ability.
abstract: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, β-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect.
  
  
  
  The antiproliferative activity and triggering of apoptosis of our short retinoids were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4'-6-diamidino-2-phenylindole staining and microscope evaluation after 3- or 6-day exposure, while their differentiating activity was established by the analysis of the expression of the CD11b marker of differentiation in treated HL60 target cells and by the superoxide production assayed colorimetrically by the nitro blue tetrazolium-reducing activity assay. Finally, the antioxidant activity was determined by the 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt radical cation decolourisation assay utilizing the antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) as reference (Trolox equivalent antioxidant capacity, or TEAC). Docking analysis was performed to study the binding features to the Retinoic Acid Receptor alpha (RARα).
  
  
  
  While no pharmacologically relevant antiproliferative activity was evidenced, some of our short retinoids showed a differentiating and antioxidant activity similar to that of 4-HPR. In particular, compound 2b6 displayed a scavenging activity two times more efficient than 4-HPR itself. Finally, the docking analysis showed that these short retinoids, like 4-HPR, bind to the RARα protein with good fitness scores.
  
  
  
  Our data could pave the way for the design of new potent and less toxic antioxidant and differentiating compounds related to 4-HPR.
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV, 3, 16132, Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anzaldi
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, U.O.C. Bioterapie, L.go R. Benzi, 10, 16132, Genoa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Viale
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV, 3, 16132, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Macciò
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, U.O.C. Bioterapie, L.go R. Benzi, 10, 16132, Genoa, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Castagnola
authors.affiliation: Dipartimento di Scienze Chimiche, University of Catania, Viale A. Doria, 6, 95125, Catania, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Oliveri
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, U.O.S. Biopolimeri e Proteomica, L.go R. Benzi, 10, 16132, Genoa, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV, 3, 16132, Genoa, Italy. balbi@unige.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Balbi
mesh_terms: D000577:Amides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000737:chemistry; D017313:Fenretinide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D013481:Superoxides / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D000975:Antioxidants; D039481:CD11b Antigen; D002839:Chromans; D016166:Free Radical Scavengers; C509295:ITGAM protein, human; D013481:Superoxides; D017313:Fenretinide; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: 4-HPR; Antioxidant; Differentiation; Retinoidal amides