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 language | English |
|---|---|
| Pages (from-to) | 7060-7072 |
| Number of pages | 13 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 56 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - Sep 12 2013 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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 journal › Article
}
TY - JOUR
T1 - Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues
T2 - Synthesis and antitumor activity in peritoneal mesothelioma experimental models
AU - Carbone, Anna
AU - Pennati, Marzia
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
PY - 2013/9/12
Y1 - 2013/9/12
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.
AB - 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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U2 - 10.1021/jm400842x
DO - 10.1021/jm400842x
M3 - Article
VL - 56
SP - 7060
EP - 7072
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 17
ER -