New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Giuseppe La Regina; Ruoli Bai; Antonio Coluccia; Valentina Naccarato; Valeria Famiglini; Marianna Nalli; Domiziana Masci; Annalisa Verrico; Paola Rovella; Carmela Mazzoccoli; Eleonora Da Pozzo; Chiara Cavallini; Claudia Martini; Maria Cristina Martini; Stefania Vultaggio; Giulio Dondio; Mario Varasi; Ciro Mercurio; Ernest Hamel; Patrizia Lavia; Romano Silvestri

doi:10.1016/j.ejmech.2018.04.042

New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valentina Naccarato, Valeria Famiglini, Marianna Nalli, Domiziana Masci, Annalisa Verrico, Paola Rovella, Carmela Mazzoccoli, Eleonora Da Pozzo, Chiara Cavallini, Claudia Martini, Maria Cristina Martini, Stefania Vultaggio, Giulio Dondio, Mario Varasi, Ciro Mercurio, Ernest Hamel, Patrizia LaviaRomano Silvestri^*

^*Corresponding author

Research output: Contribution to journal › Article

Abstract

We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

Original language	English
Pages (from-to)	283-297
Number of pages	15
Journal	European Journal of Medicinal Chemistry
Volume	152
DOIs	https://doi.org/10.1016/j.ejmech.2018.04.042
Publication status	Published - 2018

Keywords

Antineoplastic Agents
Cancer cell
Cell Proliferation
Cell Survival
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Indole
Indoles
Inhibitor
Microtubule
Molecular Structure
Polymerization
Structure-Activity Relationship
Tubulin
Tubulin Modulators
Tumor Cells, Cultured

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2018.04.042

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La Regina, G., Bai, R., Coluccia, A., Naccarato, V., Famiglini, V., Nalli, M., Masci, D., Verrico, A., Rovella, P., Mazzoccoli, C., Da Pozzo, E., Cavallini, C., Martini, C., Martini, M. C., Vultaggio, S., Dondio, G., Varasi, M., Mercurio, C., Hamel, E., ... Silvestri, R. (2018). New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors. European Journal of Medicinal Chemistry, 152, 283-297. https://doi.org/10.1016/j.ejmech.2018.04.042

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title = "New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors",

abstract = "We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.",

keywords = "Antineoplastic Agents, Cancer cell, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indole, Indoles, Inhibitor, Microtubule, Molecular Structure, Polymerization, Structure-Activity Relationship, Tubulin, Tubulin Modulators, Tumor Cells, Cultured, Antineoplastic Agents, Cancer cell, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indole, Indoles, Inhibitor, Microtubule, Molecular Structure, Polymerization, Structure-Activity Relationship, Tubulin, Tubulin Modulators, Tumor Cells, Cultured",

author = "{La Regina}, Giuseppe and Ruoli Bai and Antonio Coluccia and Valentina Naccarato and Valeria Famiglini and Marianna Nalli and Domiziana Masci and Annalisa Verrico and Paola Rovella and Carmela Mazzoccoli and {Da Pozzo}, Eleonora and Chiara Cavallini and Claudia Martini and Martini, {Maria Cristina} and Stefania Vultaggio and Giulio Dondio and Mario Varasi and Ciro Mercurio and Ernest Hamel and Patrizia Lavia and Romano Silvestri",

year = "2018",

doi = "10.1016/j.ejmech.2018.04.042",

language = "English",

volume = "152",

pages = "283--297",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

La Regina, G, Bai, R, Coluccia, A, Naccarato, V, Famiglini, V, Nalli, M, Masci, D, Verrico, A, Rovella, P, Mazzoccoli, C, Da Pozzo, E, Cavallini, C, Martini, C, Martini, MC, Vultaggio, S, Dondio, G, Varasi, M, Mercurio, C, Hamel, E, Lavia, P & Silvestri, R 2018, 'New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors', European Journal of Medicinal Chemistry, vol. 152, pp. 283-297. https://doi.org/10.1016/j.ejmech.2018.04.042

TY - JOUR

T1 - New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

AU - La Regina, Giuseppe

AU - Bai, Ruoli

AU - Coluccia, Antonio

AU - Naccarato, Valentina

AU - Famiglini, Valeria

AU - Nalli, Marianna

AU - Masci, Domiziana

AU - Verrico, Annalisa

AU - Rovella, Paola

AU - Mazzoccoli, Carmela

AU - Da Pozzo, Eleonora

AU - Cavallini, Chiara

AU - Martini, Claudia

AU - Martini, Maria Cristina

AU - Vultaggio, Stefania

AU - Dondio, Giulio

AU - Varasi, Mario

AU - Mercurio, Ciro

AU - Hamel, Ernest

AU - Lavia, Patrizia

AU - Silvestri, Romano

PY - 2018

Y1 - 2018

N2 - We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

AB - We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

KW - Antineoplastic Agents

KW - Cancer cell

KW - Cell Proliferation

KW - Cell Survival

KW - Dose-Response Relationship, Drug

KW - Drug Screening Assays, Antitumor

KW - Humans

KW - Indole

KW - Indoles

KW - Inhibitor

KW - Microtubule

KW - Molecular Structure

KW - Polymerization

KW - Structure-Activity Relationship

KW - Tubulin

KW - Tubulin Modulators

KW - Tumor Cells, Cultured

KW - Antineoplastic Agents

KW - Cancer cell

KW - Cell Proliferation

KW - Cell Survival

KW - Dose-Response Relationship, Drug

KW - Drug Screening Assays, Antitumor

KW - Humans

KW - Indole

KW - Indoles

KW - Inhibitor

KW - Microtubule

KW - Molecular Structure

KW - Polymerization

KW - Structure-Activity Relationship

KW - Tubulin

KW - Tubulin Modulators

KW - Tumor Cells, Cultured

UR - http://hdl.handle.net/10807/195403

UR - https://www.sciencedirect.com/science/article/pii/s0223523418303763

U2 - 10.1016/j.ejmech.2018.04.042

DO - 10.1016/j.ejmech.2018.04.042

M3 - Article

SN - 0223-5234

VL - 152

SP - 283

EP - 297

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Abstract

Keywords

UN SDGs

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