Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: Synthesis and antitumor activity in peritoneal mesothelioma experimental models

Anna Carbone, Marzia Pennati, Barbara Parrino, Alessia Lopergolo, Paola Barraja, Alessandra Montalbano, Virginia Spanò, Stefania Sbarra, Valentina Doldi, Michelandrea De Cesare, Girolamo Cirrincione, Patrizia Diana, Nadia Zaffaroni

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Abstract

In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3- thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol- 4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H- indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr34- phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group.

Original languageEnglish
Pages (from-to)7060-7072
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number17
DOIs
Publication statusPublished - Sep 12 2013

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Mesothelioma
Theoretical Models
CDC2 Protein Kinase
Caspases
Paclitaxel
Tumor Burden
Heterografts
Cell Proliferation
Malignant Mesothelioma
pyrrolo(2, 3-b)pyridine
Proteins
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues : Synthesis and antitumor activity in peritoneal mesothelioma experimental models. / Carbone, Anna; Pennati, Marzia; Parrino, Barbara; Lopergolo, Alessia; Barraja, Paola; Montalbano, Alessandra; Spanò, Virginia; Sbarra, Stefania; Doldi, Valentina; De Cesare, Michelandrea; Cirrincione, Girolamo; Diana, Patrizia; Zaffaroni, Nadia.

In: Journal of Medicinal Chemistry, Vol. 56, No. 17, 12.09.2013, p. 7060-7072.

Research output: Contribution to journalArticle

Carbone, A, Pennati, M, Parrino, B, Lopergolo, A, Barraja, P, Montalbano, A, Spanò, V, Sbarra, S, Doldi, V, De Cesare, M, Cirrincione, G, Diana, P & Zaffaroni, N 2013, 'Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: Synthesis and antitumor activity in peritoneal mesothelioma experimental models', Journal of Medicinal Chemistry, vol. 56, no. 17, pp. 7060-7072. https://doi.org/10.1021/jm400842x
Carbone, Anna ; Pennati, Marzia ; Parrino, Barbara ; Lopergolo, Alessia ; Barraja, Paola ; Montalbano, Alessandra ; Spanò, Virginia ; Sbarra, Stefania ; Doldi, Valentina ; De Cesare, Michelandrea ; Cirrincione, Girolamo ; Diana, Patrizia ; Zaffaroni, Nadia. / Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues : Synthesis and antitumor activity in peritoneal mesothelioma experimental models. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 17. pp. 7060-7072.
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abstract = "In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3- thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol- 4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H- indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr34- phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75{\%}) at well-tolerated doses, and two complete responses were observed in each treatment group.",
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AU - Parrino, Barbara

AU - Lopergolo, Alessia

AU - Barraja, Paola

AU - Montalbano, Alessandra

AU - Spanò, Virginia

AU - Sbarra, Stefania

AU - Doldi, Valentina

AU - De Cesare, Michelandrea

AU - Cirrincione, Girolamo

AU - Diana, Patrizia

AU - Zaffaroni, Nadia

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N2 - In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3- thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol- 4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H- indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr34- phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group.

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