New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation

Antonio Coluccia; Sara Passacantilli; Valeria Famiglini; Manuela Sabatino; Alexandros Patsilinakos; Rino Ragno; Carmela Mazzoccoli; Lorenza Sisinni; Alato Okuno; Osamu Takikawa; Romano Silvestri; Giuseppe La Regina

doi:10.1021/acs.jmedchem.6b00718

New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation

Antonio Coluccia, Sara Passacantilli, Valeria Famiglini, Manuela Sabatino, Alexandros Patsilinakos, Rino Ragno, Carmela Mazzoccoli, Lorenza Sisinni, Alato Okuno, Osamu Takikawa, Romano Silvestri, Giuseppe La Regina

IRCCS Centro di Riferimento Oncologico della Basilicata (CROB)

Research output: Contribution to journal › Article › peer-review

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC₅₀ value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.

Original language	English
Pages (from-to)	9760-9773
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	21
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00718
Publication status	Published - Nov 10 2016

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Coluccia, A., Passacantilli, S., Famiglini, V., Sabatino, M., Patsilinakos, A., Ragno, R., Mazzoccoli, C., Sisinni, L., Okuno, A., Takikawa, O., Silvestri, R., & La Regina, G. (2016). New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation. Journal of Medicinal Chemistry, 59(21), 9760-9773. https://doi.org/10.1021/acs.jmedchem.6b00718

New Inhibitors of Indoleamine 2,3-Dioxygenase 1 : Molecular Modeling Studies, Synthesis, and Biological Evaluation. / Coluccia, Antonio; Passacantilli, Sara; Famiglini, Valeria; Sabatino, Manuela; Patsilinakos, Alexandros; Ragno, Rino; Mazzoccoli, Carmela; Sisinni, Lorenza; Okuno, Alato; Takikawa, Osamu; Silvestri, Romano; La Regina, Giuseppe.

In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 10.11.2016, p. 9760-9773.

Research output: Contribution to journal › Article › peer-review

Coluccia, A, Passacantilli, S, Famiglini, V, Sabatino, M, Patsilinakos, A, Ragno, R, Mazzoccoli, C, Sisinni, L, Okuno, A, Takikawa, O, Silvestri, R & La Regina, G 2016, 'New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation', Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9760-9773. https://doi.org/10.1021/acs.jmedchem.6b00718

Coluccia, Antonio ; Passacantilli, Sara ; Famiglini, Valeria ; Sabatino, Manuela ; Patsilinakos, Alexandros ; Ragno, Rino ; Mazzoccoli, Carmela ; Sisinni, Lorenza ; Okuno, Alato ; Takikawa, Osamu ; Silvestri, Romano ; La Regina, Giuseppe. / New Inhibitors of Indoleamine 2,3-Dioxygenase 1 : Molecular Modeling Studies, Synthesis, and Biological Evaluation. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 21. pp. 9760-9773.

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abstract = "Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC50 value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.",

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AU - Sabatino, Manuela

AU - Patsilinakos, Alexandros

AU - Ragno, Rino

AU - Mazzoccoli, Carmela

AU - Sisinni, Lorenza

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AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC50 value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.

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New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation

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