Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

Francesca Gado; Rebecca Ferrisi; Sarah Di Somma; Fabiana Napolitano; Kawthar A. Mohamed; Lesley A. Stevenson; Simona Rapposelli; Giuseppe Saccomanni; Giuseppe Portella; Roger G. Pertwee; Robert B. Laprairie; Anna Maria Malfitano; Clementina Manera

doi:10.3390/molecules27093019

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

Francesca Gado, Rebecca Ferrisi, Sarah Di Somma, Fabiana Napolitano, Kawthar A. Mohamed, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Giuseppe Portella, Roger G. Pertwee, Robert B. Laprairie, Anna Maria Malfitano, Clementina Manera

Medicine

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

5 Citations (Scopus)

Abstract

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.

Original language	English
Article number	3019
Journal	Molecules
Volume	27
Issue number	9
DOIs	https://doi.org/10.3390/molecules27093019
Publication status	Published - May 1 2022

Bibliographical note

Funding Information:
Funding: This study was supported by MIUR (PRIN 2017, Grant 2017SA5837) and the University of Pisa (Progetti di Ricerca di Ateneo”–Project no. PRA_2020_58). S.D.S was supported by a FIRC-AIRC fellowship (N.24259). RBL and KAM are supported by a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant; an NSERC Graduate Scholarship to KAM; and a Canadian Institutes of Health Research (CIHR)-GlaxoSmithKline (GSK) partnership grant (2017014).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

PubMed: MeSH publication types

Journal Article

UN SDGs

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

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10.3390/molecules27093019

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Gado, F., Ferrisi, R., Di Somma, S., Napolitano, F., Mohamed, K. A., Stevenson, L. A., Rapposelli, S., Saccomanni, G., Portella, G., Pertwee, R. G., Laprairie, R. B., Malfitano, A. M., & Manera, C. (2022). Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells. Molecules, 27(9), Article 3019. https://doi.org/10.3390/molecules27093019

Gado, F, Ferrisi, R, Di Somma, S, Napolitano, F, Mohamed, KA, Stevenson, LA, Rapposelli, S, Saccomanni, G, Portella, G, Pertwee, RG, Laprairie, RB, Malfitano, AM & Manera, C 2022, 'Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells', Molecules, vol. 27, no. 9, 3019. https://doi.org/10.3390/molecules27093019

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title = "Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells",

abstract = "1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.",

author = "Francesca Gado and Rebecca Ferrisi and {Di Somma}, Sarah and Fabiana Napolitano and Mohamed, {Kawthar A.} and Stevenson, {Lesley A.} and Simona Rapposelli and Giuseppe Saccomanni and Giuseppe Portella and Pertwee, {Roger G.} and Laprairie, {Robert B.} and Malfitano, {Anna Maria} and Clementina Manera",

note = "Funding Information: Funding: This study was supported by MIUR (PRIN 2017, Grant 2017SA5837) and the University of Pisa (Progetti di Ricerca di Ateneo”–Project no. PRA_2020_58). S.D.S was supported by a FIRC-AIRC fellowship (N.24259). RBL and KAM are supported by a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant; an NSERC Graduate Scholarship to KAM; and a Canadian Institutes of Health Research (CIHR)-GlaxoSmithKline (GSK) partnership grant (2017014). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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T1 - Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists

T2 - Biological Evaluation against Neuroblastoma Cancer Cells

AU - Gado, Francesca

AU - Ferrisi, Rebecca

AU - Di Somma, Sarah

AU - Napolitano, Fabiana

AU - Mohamed, Kawthar A.

AU - Stevenson, Lesley A.

AU - Rapposelli, Simona

AU - Saccomanni, Giuseppe

AU - Portella, Giuseppe

AU - Pertwee, Roger G.

AU - Laprairie, Robert B.

AU - Malfitano, Anna Maria

AU - Manera, Clementina

N1 - Funding Information: Funding: This study was supported by MIUR (PRIN 2017, Grant 2017SA5837) and the University of Pisa (Progetti di Ricerca di Ateneo”–Project no. PRA_2020_58). S.D.S was supported by a FIRC-AIRC fellowship (N.24259). RBL and KAM are supported by a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant; an NSERC Graduate Scholarship to KAM; and a Canadian Institutes of Health Research (CIHR)-GlaxoSmithKline (GSK) partnership grant (2017014). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/5/1

Y1 - 2022/5/1

N2 - 1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.

AB - 1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.

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DO - 10.3390/molecules27093019

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SN - 1420-3049

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JO - Molecules

JF - Molecules

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ER -

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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