Synthesis of Novel Cinnamides and a Bis Cinnamate Bearing 1,2,3-Triazole Functionalities with Antiproliferative and Antimetastatic Activities on Melanoma Cells

The present investigation describes the synthesis of novel cinnamides and a bis cinnamate bearing 1,2,3-triazole functionalities and investigation of their antiproliferative and antimetastatic effects on melanoma cells. The necessity for the development of new chemotherapeutic agents for melanoma treatment motivated this work. Sixteen derivatives were obtained with yields ranging from 23-81% and fully characterized by spectroscopic (¹H and ¹³C nuclear magnetic resonance, infrared) and spectrometric high resolution mass spectrometry (HRMS) techniques. The derivatives were in vitro evaluated against B16-F10 murine melanoma cell line. The most effective compound (a bis cinnamate) (6b) reduced the melanoma cell viability, generated cell cycle arrest, and influenced the metastatic behavior of melanoma cells by decreasing migration, invasion, and colony formation. Based on these findings, it is believed that compound 6b may represent an interesting scaffold to be explored toward the development of new antimelanoma agents.

Keywords:
cinnamides; cinnamates; cinnamic acid; 1,2,3-triazoles; B16-F10 cell line

Authorship

Fabíola S Santos
# These authors contributed equally to this work.

Laboratório de Síntese Orgânica (LABSINTO), Departamento de Química, Universidade Federal de Minas Gerais (UFMG), 31270-901 Belo Horizonte-MG, BrazilUniversidade Federal de Minas Gerais (UFMG)BrazilBelo Horizonte, MG, BrazilLaboratório de Síntese Orgânica (LABSINTO), Departamento de Química, Universidade Federal de Minas Gerais (UFMG), 31270-901 Belo Horizonte-MG, Brazil

Juliana A. do Vale
# These authors contributed equally to this work.

Departamento de Biologia Geral, Universidade Federal de Viçosa (UFV), 36570-900 Viçosa-MG, BrazilUniversidade Federal de Viçosa (UFV)BrazilViçosa, MG, BrazilDepartamento de Biologia Geral, Universidade Federal de Viçosa (UFV), 36570-900 Viçosa-MG, Brazil

Lucas S Santos

Talita B Gontijo

Graziela D. A Lima

Leandro L. de Oliveira

https://orcid.org/0000-0003-4353-7011

Mariana Machado-Neves

Róbson R Teixeira

Departamento de Química, Universidade Federal de Viçosa (UFV), 36570-900 Viçosa-MG, BrazilUniversidade Federal de Viçosa (UFV)BrazilViçosa, MG, BrazilDepartamento de Química, Universidade Federal de Viçosa (UFV), 36570-900 Viçosa-MG, Brazil

https://orcid.org/0000-0003-3181-1108

Rossimiriam P. de Freitas ^**e-mail: rossimiriam@ufmg.br

https://orcid.org/0000-0001-6974-3724

*e-mail: rossimiriam@ufmg.br

#
These authors contributed equally to this work.

Author Contributions

FSS was responsible for investigation, data curation, writing original draft and writing-review and editing; JAV was responsible for investigation, data curation and writing original draft; LSS performed acquisition of data; TBG performed acquisition of data; GDAL was responsible for biological experiments; LLO was responsible for data curation and formal analysis; MMN conducted the biological experiments; RRT was responsible for conceptualization, formal analysis, funding acquisition, writing original draft and supervision; RPF was responsible for planning, project administration, funding acquisition, writing-review and coordination.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (8)

Thumbnail

Scheme 1
Synthesis of cinnamides 3a-3n.

Thumbnail

Scheme 2
Preparation of compounds 6a and 6b.

Thumbnail

Figure 1
Effect of compounds 3a-3n, 6a and 6b on cell viability of melanoma cells. B16-F10 metastatic melanoma was treated with 100.0 µM of each compound for 48 h. Each bar shows the mean of percentage of survival of melanoma cells determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The compounds that showed statistical difference in relation to the control were selected for IC₅₀ evaluation. Data expressed as the mean ± SEM (standard error of the mean). *p < 0.05 and **p < 0.01 versus control (DMSO, dimethyl sulfoxide, 0.4% v/v) by one-way ANOVA and Dunn’s post-hoc test.

Thumbnail

Figure 2
Effect of compounds 3c, 3e, 3f, 3j and 6b on cell viability of non-tumor cell line. Vero fibroblast-like kidney cells were treated with 100.0 µM of each compound derived from cinnamic acid for 48 h. Each bar shows the mean of percentage of survival of Vero cells determined by MTT assay. Data expressed as the mean ± SEM. **p < 0.01 and ***p < 0.001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunn’s post-hoc test.

Thumbnail

Figure 3
Effect of compound 6b on melanoma cell cycle. B16-F10 cells were treated with 12.5, 25.0, and 50.0 µM of compound 6b. Cells treated with DMSO 0.4% v/v were used as control. Cell cycle was evaluated using propidium iodide, followed by cytometry analysis after 48 h of incubation. Data expressed as the mean ± SEM. *p < 0.05, **p < 0.01 and ****p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post-hoc test.

Thumbnail

Figure 4
Effect of compound 6b on migration of B16-F10 melanoma cells in vitro. (a) B16-F10 metastatic melanoma was wounded with a pipette tip and then treated with 12.5, 25.0 and 50.0 μM of 6b compound for 24 h. (b) Photos of the wound were taken at 0 and 24 h after treatment with 50.0 μM of the compound under 100× magnitude microscope. Data expressed as the mean ± SEM. **p < 0.01 versus control (0.04% DMSO) by one-way ANOVA and Dunnett’s post-hoc test.

Thumbnail

Figure 5
Effect of compound 6b on invasion of B16-F10 melanoma cells in vitro. (a) Photomicrography represents the cells invasion through matrigel-coated transwell. (b) The bar graph represents the percentage of invasive cell that was treated with 12.5, 25.0, and 50.0 μM of compound 6b for 60 min. Data expressed as the mean ± SEM. ****p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post hoc test.

Thumbnail

Figure 6
Effect of compound 6b on colony formation of B16-F10 melanoma cells in vitro. (a) Photomicrography showing the formation of B16-F10 colonies after treatment with 12.5, 25.0 and 50.0 μM of the compound 6b. (b) The bar graph represents the percentage of colony formation after 7 days. Data expressed as mean ± SEM. ****p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post-hoc test.

Scheme 1 Synthesis of cinnamides 3a-3n.

Scheme 2 Preparation of compounds 6a and 6b.

Figure 1 Effect of compounds 3a-3n, 6a and 6b on cell viability of melanoma cells. B16-F10 metastatic melanoma was treated with 100.0 µM of each compound for 48 h. Each bar shows the mean of percentage of survival of melanoma cells determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The compounds that showed statistical difference in relation to the control were selected for IC₅₀ evaluation. Data expressed as the mean ± SEM (standard error of the mean). *p < 0.05 and **p < 0.01 versus control (DMSO, dimethyl sulfoxide, 0.4% v/v) by one-way ANOVA and Dunn’s post-hoc test.

Figure 2 Effect of compounds 3c, 3e, 3f, 3j and 6b on cell viability of non-tumor cell line. Vero fibroblast-like kidney cells were treated with 100.0 µM of each compound derived from cinnamic acid for 48 h. Each bar shows the mean of percentage of survival of Vero cells determined by MTT assay. Data expressed as the mean ± SEM. p < 0.01 and p < 0.001 versus* control (DMSO 0.4% v/v) by one-way ANOVA and Dunn’s post-hoc test.

Figure 3 Effect of compound 6b on melanoma cell cycle. B16-F10 cells were treated with 12.5, 25.0, and 50.0 µM of compound 6b. Cells treated with DMSO 0.4% v/v were used as control. Cell cycle was evaluated using propidium iodide, followed by cytometry analysis after 48 h of incubation. Data expressed as the mean ± SEM. *p < 0.05, p < 0.01 and **p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post-hoc test.

Figure 4 Effect of compound 6b on migration of B16-F10 melanoma cells in vitro. (a) B16-F10 metastatic melanoma was wounded with a pipette tip and then treated with 12.5, 25.0 and 50.0 μM of 6b compound for 24 h. (b) Photos of the wound were taken at 0 and 24 h after treatment with 50.0 μM of the compound under 100× magnitude microscope. Data expressed as the mean ± SEM. **p < 0.01 versus control (0.04% DMSO) by one-way ANOVA and Dunnett’s post-hoc test.

Figure 5 Effect of compound 6b on invasion of B16-F10 melanoma cells in vitro. (a) Photomicrography represents the cells invasion through matrigel-coated transwell. (b) The bar graph represents the percentage of invasive cell that was treated with 12.5, 25.0, and 50.0 μM of compound 6b for 60 min. Data expressed as the mean ± SEM. ****p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post hoc test.

Figure 6 Effect of compound 6b on colony formation of B16-F10 melanoma cells in vitro. (a) Photomicrography showing the formation of B16-F10 colonies after treatment with 12.5, 25.0 and 50.0 μM of the compound 6b. (b) The bar graph represents the percentage of colony formation after 7 days. Data expressed as mean ± SEM. ****p < 0.0001 versus control (DMSO 0.4% v/v) by one-way ANOVA and Dunnett’s post-hoc test.

How to cite

copy

Sociedade Brasileira de Química Instituto de Química - UNICAMP, Caixa Postal 6154, 13083-970 Campinas SP - Brazil, Tel./FAX.: +55 19 3521-3151 - São Paulo - SP - Brazil
E-mail: office@jbcs.sbq.org.br

Acompanhe os números deste periódico no seu leitor de RSS

Versão para download de PDF

PDF

Inglês

Versões e tradução automática

Versão original do texto

English

Tradução automática

Google Translator
Microsoft Translator

Como citar

RIS

BIBTEX

Outros formatos de citação e exportação:

SciELO - Scientific Electronic Library Online
Rua Dr. Diogo de Faria, 1087 – 9º andar – Vila Clementino 04037-003 São Paulo/SP - Brasil
E-mail: scielo@scielo.org

Leia a Declaração de Acesso Aberto

Métricas

Synthesis of Novel Cinnamides and a Bis Cinnamate Bearing 1,2,3-Triazole Functionalities with Antiproliferative and Antimetastatic Activities on Melanoma Cells

PlumX

Mensagem

[1] *e-mail: rossimiriam@ufmg.br