Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships

Research output: Contribution to journalArticlepeer-review

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Pyrazole-Based Acid Ceramidase Inhibitors : Design, Synthesis, and Structure-Activity Relationships. / Diamanti, Eleonora; Bottegoni, Giovanni; Goldoni, Luca; Realini, Natalia; Pagliuca, Chiara; Bertozzi, Fabio; Piomelli, Daniele; Pizzirani, Daniela.

In: Synthesis (Germany), Vol. 48, No. 17, 01.09.2016, p. 2739-2756.

Research output: Contribution to journalArticlepeer-review

Harvard

Diamanti, E, Bottegoni, G, Goldoni, L, Realini, N, Pagliuca, C, Bertozzi, F, Piomelli, D & Pizzirani, D 2016, 'Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships', Synthesis (Germany), vol. 48, no. 17, pp. 2739-2756. https://doi.org/10.1055/s-0035-1561456

APA

Diamanti, E., Bottegoni, G., Goldoni, L., Realini, N., Pagliuca, C., Bertozzi, F., Piomelli, D., & Pizzirani, D. (2016). Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships. Synthesis (Germany), 48(17), 2739-2756. https://doi.org/10.1055/s-0035-1561456

Vancouver

Author

Diamanti, Eleonora ; Bottegoni, Giovanni ; Goldoni, Luca ; Realini, Natalia ; Pagliuca, Chiara ; Bertozzi, Fabio ; Piomelli, Daniele ; Pizzirani, Daniela. / Pyrazole-Based Acid Ceramidase Inhibitors : Design, Synthesis, and Structure-Activity Relationships. In: Synthesis (Germany). 2016 ; Vol. 48, No. 17. pp. 2739-2756.

Bibtex

@article{18a527b9650a4d86a5864b5a43ffc9e3,
title = "Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships",
abstract = "Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.",
keywords = "acid ceramidase, atomic property field (APF), ceramides, melanoma, regioisomers, structure-activity relationship (SAR)",
author = "Eleonora Diamanti and Giovanni Bottegoni and Luca Goldoni and Natalia Realini and Chiara Pagliuca and Fabio Bertozzi and Daniele Piomelli and Daniela Pizzirani",
year = "2016",
month = sep,
day = "1",
doi = "10.1055/s-0035-1561456",
language = "English",
volume = "48",
pages = "2739--2756",
journal = "Synthesis: journal of synthetic organic chemistry",
issn = "0039-7881",
publisher = "Georg Thieme Verlag",
number = "17",

}

RIS

TY - JOUR

T1 - Pyrazole-Based Acid Ceramidase Inhibitors

T2 - Design, Synthesis, and Structure-Activity Relationships

AU - Diamanti, Eleonora

AU - Bottegoni, Giovanni

AU - Goldoni, Luca

AU - Realini, Natalia

AU - Pagliuca, Chiara

AU - Bertozzi, Fabio

AU - Piomelli, Daniele

AU - Pizzirani, Daniela

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.

AB - Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.

KW - acid ceramidase

KW - atomic property field (APF)

KW - ceramides

KW - melanoma

KW - regioisomers

KW - structure-activity relationship (SAR)

UR - http://www.scopus.com/inward/record.url?scp=84973632294&partnerID=8YFLogxK

U2 - 10.1055/s-0035-1561456

DO - 10.1055/s-0035-1561456

M3 - Article

AN - SCOPUS:84973632294

VL - 48

SP - 2739

EP - 2756

JO - Synthesis: journal of synthetic organic chemistry

JF - Synthesis: journal of synthetic organic chemistry

SN - 0039-7881

IS - 17

ER -