Biological evaluation of new diarylpentanoid analogues for antitumor activity

Authors

  • E. Castro UNIPRO – Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal https://orcid.org/0000-0002-2135-0929
  • J. Moreira Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cru-zeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal
  • P. M. A. Silva UNIPRO – Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal; TOXRUN – Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
  • L. Saraiva LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universi-dade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
  • M. Pinto Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cru-zeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal
  • Hassan Bousbaa UNIPRO – Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal https://orcid.org/0000-0002-4006-5779
  • H. Cidade Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cru-zeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal

DOI:

https://doi.org/10.48797/sl.2023.26

Keywords:

Poster

Abstract

Background: Cancer is associated with high mortality rates and its incidence worldwide is increasing significantly [1]. Several therapeutic strategies have been used in cancer therapy such as microtu-bule-targeting agents [2]. However, these drugs are highly toxic and are associated with high tumor resistance, making their long-term use unfeasible [3,4]. Therefore, new small molecules that can overcome the disadvantages associated with the drugs currently in use in the clinic are needed. We previously reported the in vitro growth inhibitory effect of the diarylpentanoid BP-M345 on human cancer cells, as well as its cellular mechanism of action [5]. Here, BP-M345 analogues have been syn-thetized in a goal to improve the antimitotic/antitumor efficacy of the original BP-M345. Objective: The present study aimed to characterize BP-M345 analogues regarding their cytotoxic activity and mechanism of action, focusing on their potential as antimitotic agent. Methods: A sulforhodamine B assay was used to determine the GI50 of BP-M345 analogues in different cancer cell lines. To evaluate the antimitotic activity, the mitotic index was determined. In addition, lung cancer cells were exposed to compounds, A sulforhodamine B assay was used to determine the GI50 of BP-M345 analogues in different cancer cell lines. To evaluate the antimitotic activity, the mitotic index was determined. In addition, lung cancer cells were exposed to compounds, for twenty-four or forty- eight hours, and the consequence on spindle morphology, cellular proliferation and cell death were evaluated using the following assays: immunofluorescence, colony-formation assay, and flow cytometry, respectively. Time-lapse microscopy imaging was also performed to follow in real time the cell fate of the compound-treated cells. Results: BP-M345 analogues showed potent growth inhibition activity on cancer cells and exhibited a potent antimitotic activity. Mechanistically, BP-M345 analogues induced perturbation of the mitotic spindles through microtubule instability. Consequently, treated cells exhibit defects in chromosome congression during mitosis, which induced a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by apoptosis. Conclusions: BP-M345 analogues have been shown to be highly potent antimitotic agents, more effective than the original BP-M345 leading to massive cancer cell death.

References

1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics. CA Cancer J Clin 2023, 73, 17-48.

2. Wood, K.W.; Cornwell, W.D.; Jackson, J.R. Past and future of the mitotic spindle as an oncology target. Curr Opin Pharmacol 2001, 1, 370.377.

3. Novais, P.; Silva, P.M.A.; Amorim, I.; Bousbaa, H. Second-generation antimitotics in cancer clinical trials. Pharmaceutics 2021, 13, 1011.

4. Henriques, A.C.; Ribeiro, D.; Pedrosa, J.; Sarmento, B.; Silva, P.M.; Bousbaa, H. Mitosis inhibitors in an-ticancer therapy: When blocking the exit becomes a solution. Cancer Lett 2019, 440:64-81.

5. Novais, P.; Silva, P.; Moreira, J.; Palmeira, A.; Amorim, I.; Pinto, M.; Bousbaa, H. BP-M345, a new di-arylpentanoid with promising antimitotic activity. Molecules 2021, 26, 7139.

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Published

2023-04-21

How to Cite

Castro, E., Moreira, J., Silva, P. M. A., Saraiva , L., Pinto, M., Bousbaa, H., & Cidade, H. (2023). Biological evaluation of new diarylpentanoid analogues for antitumor activity. Scientific Letters, 1(Sup 1). https://doi.org/10.48797/sl.2023.26

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