1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells

Sergio Valente, Paolo Mellini, Francesco Spallotta, Vincenzo Carafa, Angela Nebbioso, Lucia Polletta, Ilaria Carnevale, Serena Saladini, Daniela Trisciuoglio, Chiara Gabellini, Maria Tardugno, Clemens Zwergel, Chiara Cencioni, Sandra Atlante, Sébastien Moniot, Clemens Steegborn, Roberta Budriesi, Marco Tafani, Donatella Del Bufalo, Lucia Altucci & 2 others Carlo Gaetano, Antonello Mai

Research output: Contribution to journalArticle

  • 4 Citations

Abstract

Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.

Original languageEnglish
Pages (from-to)1471-1491
Number of pages21
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
DOIs
StatePublished - 25 Feb 2016

Fingerprint

Dihydropyridines
AMP-Activated Protein Kinases
Skin
Neoplasms
Sirtuins
Myoblasts
Metabolic Diseases
Neurodegenerative Diseases
Wound Healing
Water

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells. / Valente, Sergio; Mellini, Paolo; Spallotta, Francesco; Carafa, Vincenzo; Nebbioso, Angela; Polletta, Lucia; Carnevale, Ilaria; Saladini, Serena; Trisciuoglio, Daniela; Gabellini, Chiara; Tardugno, Maria; Zwergel, Clemens; Cencioni, Chiara; Atlante, Sandra; Moniot, Sébastien; Steegborn, Clemens; Budriesi, Roberta; Tafani, Marco; Del Bufalo, Donatella; Altucci, Lucia; Gaetano, Carlo; Mai, Antonello.

In: Journal of Medicinal Chemistry, Vol. 59, No. 4, 25.02.2016, p. 1471-1491.

Research output: Contribution to journalArticle

Valente, S, Mellini, P, Spallotta, F, Carafa, V, Nebbioso, A, Polletta, L, Carnevale, I, Saladini, S, Trisciuoglio, D, Gabellini, C, Tardugno, M, Zwergel, C, Cencioni, C, Atlante, S, Moniot, S, Steegborn, C, Budriesi, R, Tafani, M, Del Bufalo, D, Altucci, L, Gaetano, C & Mai, A 2016, '1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells' Journal of Medicinal Chemistry, vol 59, no. 4, pp. 1471-1491. DOI: 10.1021/acs.jmedchem.5b01117

Valente, Sergio; Mellini, Paolo; Spallotta, Francesco; Carafa, Vincenzo; Nebbioso, Angela; Polletta, Lucia; Carnevale, Ilaria; Saladini, Serena; Trisciuoglio, Daniela; Gabellini, Chiara; Tardugno, Maria; Zwergel, Clemens; Cencioni, Chiara; Atlante, Sandra; Moniot, Sébastien; Steegborn, Clemens; Budriesi, Roberta; Tafani, Marco; Del Bufalo, Donatella; Altucci, Lucia; Gaetano, Carlo; Mai, Antonello / 1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells.

In: Journal of Medicinal Chemistry, Vol. 59, No. 4, 25.02.2016, p. 1471-1491.

Research output: Contribution to journalArticle

@article{e986a14f0ac64d99a9f21b52ce16e081,
title = "1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells",
abstract = "Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.",
author = "Sergio Valente and Paolo Mellini and Francesco Spallotta and Vincenzo Carafa and Angela Nebbioso and Lucia Polletta and Ilaria Carnevale and Serena Saladini and Daniela Trisciuoglio and Chiara Gabellini and Maria Tardugno and Clemens Zwergel and Chiara Cencioni and Sandra Atlante and Sébastien Moniot and Clemens Steegborn and Roberta Budriesi and Marco Tafani and {Del Bufalo}, Donatella and Lucia Altucci and Carlo Gaetano and Antonello Mai",
year = "2016",
month = "2",
doi = "10.1021/acs.jmedchem.5b01117",
volume = "59",
pages = "1471--1491",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - 1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells

AU - Valente,Sergio

AU - Mellini,Paolo

AU - Spallotta,Francesco

AU - Carafa,Vincenzo

AU - Nebbioso,Angela

AU - Polletta,Lucia

AU - Carnevale,Ilaria

AU - Saladini,Serena

AU - Trisciuoglio,Daniela

AU - Gabellini,Chiara

AU - Tardugno,Maria

AU - Zwergel,Clemens

AU - Cencioni,Chiara

AU - Atlante,Sandra

AU - Moniot,Sébastien

AU - Steegborn,Clemens

AU - Budriesi,Roberta

AU - Tafani,Marco

AU - Del Bufalo,Donatella

AU - Altucci,Lucia

AU - Gaetano,Carlo

AU - Mai,Antonello

PY - 2016/2/25

Y1 - 2016/2/25

N2 - Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.

AB - Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=84959335947&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959335947&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b01117

DO - 10.1021/acs.jmedchem.5b01117

M3 - Article

VL - 59

SP - 1471

EP - 1491

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -