IMR Press / FBL / Volume 26 / Issue 10 / DOI: 10.52586/4985
Open Access Article
Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells
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1 Department of Chemistry, University of Hull, HU6 7RX Hull, UK
2 Biomedical Section, University of Hull, HU6 7RX Hull, UK
3 Division of Cancer-Hull York Medical School, University of Hull, HU6 7RX Hull, UK
Front. Biosci. (Landmark Ed) 2021, 26(10), 752–764;
Submitted: 22 July 2021 | Revised: 22 September 2021 | Accepted: 23 September 2021 | Published: 30 October 2021
(This article belongs to the Special Issue New Insight into Extracellular Vesicles in Human Diseases)
Copyright: © 2021 The Author(s). Published by BRI.
This is an open access article under the CC BY 4.0 license (

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)-D-alanine (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 TF-mediated tumour growth without detrimental outcomes on normal vascular cells.

Tissue factor
Cancer cell
Synthetic inhibitor
Fig. 1.
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