title: Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents.
abstract: A new series of indole-based analogues were recently identified as potential anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b.
authors: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. Electronic address: andrea.spallarossa@unige.it.
authors: Andrea
authors: A
authors: Spallarossa
authors: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
authors: Chiara
authors: C
authors: Caneva
authors: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
authors: Matteo
authors: M
authors: Caviglia
authors: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
authors: Silvana
authors: S
authors: Alfei
authors: European Research Centre for Drug Discovery & Development, Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Stefania
authors: S
authors: Butini
authors: European Research Centre for Drug Discovery & Development, Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Giuseppe
authors: G
authors: Campiani
authors: European Research Centre for Drug Discovery & Development, Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Sandra
authors: S
authors: Gemma
authors: European Research Centre for Drug Discovery & Development, Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Margherita
authors: M
authors: Brindisi
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: Daniela M
authors: DM
authors: Zisterer
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: Sandra A
authors: SA
authors: Bright
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: Clive D
authors: CD
authors: Williams
authors: Institute of Molecular Genetics IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors: Emmanuele
authors: E
authors: Crespan
authors: Institute of Molecular Genetics IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors: Giovanni
authors: G
authors: Maga
authors: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, s.p. 8, Km 0.700, I-09042 Monserrato, Cagliari, Italy.
authors: Giuseppina
authors: G
authors: Sanna
authors: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, s.p. 8, Km 0.700, I-09042 Monserrato, Cagliari, Italy.
authors: Ilenia
authors: I
authors: Delogu
authors: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, s.p. 8, Km 0.700, I-09042 Monserrato, Cagliari, Italy.
authors: Gabriella
authors: G
authors: Collu
authors: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, s.p. 8, Km 0.700, I-09042 Monserrato, Cagliari, Italy.
authors: Roberta
authors: R
authors: Loddo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles
keywords: Antiproliferative agents; Indoles; Pro-apoptotic agents; Tubulin immunostaining