Synthesis of novel benzothiazole amides: Evaluation of PPAR activity and anti-proliferative effects in paraganglioma, pancreatic and colorectal cancer cell lines

被引：18

作者：

Ammazzalorso, Alessandra ^{[1
]}

De Lellis, Laura ^{[2
,3
]}

Florio, Rosalba ^{[2
]}

Laghezza, Antonio ^{[4
]}

De Filippis, Barbara ^{[1
]}

Fantacuzzi, Marialuigia ^{[1
]}

Giampietro, Letizia ^{[1
]}

Maccallini, Cristina ^{[1
]}

Tortorella, Paolo ^{[4
]}

Veschi, Serena ^{[2
]}

Loiodice, Fulvio ^{[4
]}

Cama, Alessandro ^{[2
,3
]}

Amoroso, Rosa ^{[1
]}

机构：

[1] Univ G dAnnunzio, Unita Chim Farmaceut, Dipartimento Farm, Chieti, Italy

[2] Univ G dAnnunzio, Unita Patol Gen, Dipartimento Farm, Chieti, Italy

[3] Univ G dAnnunzio, Aging Res Ctr CeSI, Chieti, Italy

[4] Univ Bari Aldo Moro, Dipartimento Farm Sci Farmaco, Via Orabona 4, I-70126 Bari, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 16期

关键词：

PPAR antagonists; Benzothiazoles; Amides; Anti-proliferative; Paraganglioma; Cytotoxicity; IN-VITRO; PEROXISOME; PROLIFERATION; FAMILY;

D O I：

10.1016/j.bmcl.2019.06.020

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The reduced activation of PPARs has a positive impact on cancer cell growth and viability in multiple preclinical tumor models, suggesting a new therapeutic potential for PPAR antagonists. In the present study, the benzothiazole amides 2a-g were synthesized and their activities on PPARs were investigated. Transactivation assay showed a moderate activity of the novel compounds as PPAR alpha antagonists. Notably, in cellular assays they exhibited cytotoxicity in pancreatic, colorectal and paraganglioma cancer cells overexpressing PPAR alpha. In particular, compound 2b showed the most remarkable inhibition of viability (greater than 90%) in two paraganglioma cell lines, with IC50 values in the low micromolar range. In addition, 2b markedly impaired colony formation capacity in the same cells. Taken together, these results show a relevant anti-proliferative potential of compound 2b, which appears particularly effective in paraganglioma, a rare tumor poorly responsive to chemotherapy.

引用

页码：2302 / 2306

页数：5

共 26 条

[11] Potential of Peroxisome Proliferator-Activated Receptor Gamma Antagonist Compounds as Therapeutic Agents for a Wide Range of Cancer Types [J].

Burton, Jack D. ;

Goldenberg, David M. ;

Blumenthal, Rosalyn D. .

PPAR RESEARCH, 2008, 2008

[12] Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling [J].

Cama, Alessandro ;

Verginelli, Fabio ;

Lotti, Lavinia Vittoria ;

Napolitano, Francesco ;

Morgano, Annalisa ;

D'Orazio, Andria ;

Vacca, Michele ;

Perconti, Silvia ;

Pepe, Felice ;

Romani, Federico ;

Vitullo, Francesca ;

di Lella, Filippo ;

Visone, Rosa ;

Mannelli, Massimo ;

Neumann, Hartmut P. H. ;

Raiconi, Giancarlo ;

Paties, Carlo ;

Moschetta, Antonio ;

Tagliaferri, Roberto ;

Veronese, Angelo ;

Sanna, Mario ;

Mariani-Costantini, Renato .

ACTA NEUROPATHOLOGICA, 2013, 126 (04) :575-594

[13] The Anticancer Potential of Peroxisome Proliferator-Activated Receptor Antagonists [J].

De Lellis, Laura ;

Cimini, Annamaria ;

Veschi, Serena ;

Benedetti, Elisabetta ;

Amoroso, Rosa ;

Cama, Alessandro ;

Ammazzalorso, Alessandra .

CHEMMEDCHEM, 2018, 13 (03) :209-219

[14] PPAR modulators and PPAR pan agonists for metabolic diseases: The next generation of drugs targeting Peroxisome Proliferator-Activated Receptors? [J].

Feldman, P. L. ;

Lambert, M. H. ;

Henke, B. R. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (09) :728-749

[15] Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells [J].

Florio, Rosalba ;

De Lellis, Laura ;

Veschi, Serena ;

Verginelli, Fabio ;

di Giacomo, Viviana ;

Gallorini, Marialucia ;

Perconti, Silvia ;

Sanna, Mario ;

Mariani-Costantini, Renato ;

Natale, Angelica ;

Arduini, Arduino ;

Amoroso, Rosa ;

Cataldi, Amelia ;

Cama, Alessandro .

SCIENTIFIC REPORTS, 2018, 8

[16] Effects of PPARα inhibition in head and neck paraganglioma cells [J].

Florio, Rosalba ;

De Lellis, Laura ;

di Giacomo, Viviana ;

Di Marcantonio, Maria Carmela ;

Cristiano, Loredana ;

Basile, Mariangela ;

Verginelli, Fabio ;

Verzilli, Delfina ;

Ammazzalorso, Alessandra ;

Prasad, Sampath Chandra ;

Cataldi, Amelia ;

Sanna, Mario ;

Cimini, Annamaria ;

Mariani-Costantini, Renato ;

Mincione, Gabriella ;

Cama, Alessandro .

PLOS ONE, 2017, 12 (06)

[17]

ISSEMANN I, 1990, NATURE, V347, P645, DOI 10.1038/347645a0

[18] A Selective Novel Peroxisome Proliferator-Activated Receptor ( PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo [J].

Messmer, Davorka ;

Lorrain, Kymmy ;

Stebbins, Karin ;

Bravo, Yalda ;

Stock, Nicholas ;

Cabrera, Geraldine ;

Correa, Lucia ;

Chen, Austin ;

Jacintho, Jason ;

Chiorazzi, Nicholas ;

Yan, Xiao Jie ;

Spaner, David ;

Prasit, Peppi ;

Lorrain, Daniel .

MOLECULAR MEDICINE, 2015, 21 :410-419

[19] Targeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of Modulators [J].

Pirat, Celine ;

Farce, Amaury ;

Lebegue, Nicolas ;

Renault, Nicolas ;

Furman, Christophe ;

Millet, Regis ;

Yous, Said ;

Speca, Silvia ;

Berthelot, Pascal ;

Desreumaux, Pierre ;

Chavatte, Philippe .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (09) :4027-4061

[20] Structural Insight into Peroxisome Proliferator-Activated Receptor γ Binding of Two Ureidofibrate-Like Enantiomers by Molecular Dynamics, Cofactor Interaction Analysis, and Site-Directed Mutagenesis [J].

Pochetti, Giorgio ;

Mitro, Nico ;

Lavecchia, Antonio ;

Gilardi, Federica ;

Besker, Neva ;

Scotti, Elena ;

Aschi, Massimiliano ;

Re, Nazzareno ;

Fracchiolla, Giuseppe ;

Laghezza, Antonio ;

Tortorella, Paolo ;

Montanari, Roberta ;

Novellino, Ettore ;

Mazza, Fernando ;

Crestani, Maurizio ;

Loiodice, Fulvio .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (11) :4354-4366

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