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Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells

Adeniran, Oluremi I; Mohammad, Mohammad A; Featherby, Sophie; Maraveyas, Anthony; Boa, Andrew N.; Ettelaie, Camille

Authors

Oluremi I Adeniran

Mohammad A Mohammad

Sophie Featherby

Anthony Maraveyas

Camille Ettelaie



Abstract

Introduction: The restriction of prolyl-protein cis/trans isomerase 1 (Pin1) activity has been shown to prevent the release of tissue factor (TF) leading to the accumulation of the latter protein within the cell. This study tested the ability of novel small molecules to inhibit Pin1, suppress TF activity and release, and induce cellular apoptosis. Methods: Four compounds were designed and synthesised based on modification of 5-(p-methoxyphenyl)-2-methylfuran-3-carbonyl amide and the outcome on MDA-MB-231 and primary cells examined. These compounds contained 3-(2-naphthyl)-Dalanine (4a), D-tryptophan (4b), D-phenylalanine (4c), and D-tyrosine (4d) at the amino-termini. Results: Treatment of cells with compound 4b and 4d reduced the cell-surface TF activity after 60 min on MDA-MB-231 cells. Incubation with compound 4d also reduced TF antigen on the cell surface and its incorporation into microvesicles, while compounds 4a and 4b significantly increased TF release. None of the four compounds significantly altered the total amount of TF antigen or TF mRNA expression. Compound 4b and 4d also suppressed the binding of Pin1 to TF-cytoplasmic domain peptide. However, compound 4d reduced while compound 4b increased the Pin1 isomerase activity. Finally, treatment with compound 4b and 4d reduced the cell numbers, increased nuclear localisation of p53, Bax protein and bax mRNA expression and induced cellular apoptosis in MDA-MB-231 but not primary endothelial cells. Conclusions: In conclusion, we have identified small molecules to regulate the function of TF within cells. Two of these compounds may prove to be beneficial in moderating TF function specifically and restrain TFmediated tumour growth without detrimental outcomes on normal vascular cells.

Citation

Adeniran, O. I., Mohammad, M. A., Adeniran, O. I., Mohammad, M. A., Featherby, S., Maraveyas, A., …Ettelaie, C. (2021). Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells. Frontiers in Bioscience-Landmark, 26(10), 752-764. https://doi.org/10.52586/4985

Journal Article Type Article
Acceptance Date Sep 23, 2021
Online Publication Date Oct 30, 2021
Publication Date Oct 30, 2021
Deposit Date Nov 19, 2021
Publicly Available Date Nov 22, 2021
Journal Frontiers in Bioscience - Landmark
Print ISSN 1093-9946
Electronic ISSN 2768-6698
Peer Reviewed Peer Reviewed
Volume 26
Issue 10
Pages 752-764
DOI https://doi.org/10.52586/4985
Keywords Tissue factor; Pin1; Cancer cell; p53; Bax; Synthetic inhibitor
Public URL https://hull-repository.worktribe.com/output/3883774

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