Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells
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 act...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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IMR Press
2021-10-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/26/10/10.52586/4985 |
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| author | Oluremi I Adeniran Mohammad A Mohammad Sophie Featherby Anthony Maraveyas Andrew N Boa Camille Ettelaie |
| author_facet | Oluremi I Adeniran Mohammad A Mohammad Sophie Featherby Anthony Maraveyas Andrew N Boa Camille Ettelaie |
| author_sort | Oluremi I Adeniran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T10:50:09Z |
| format | Article |
| id | doaj.art-8fad0060e3134e5a8740b212781a8e9e |
| institution | Directory Open Access Journal |
| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-12-21T10:50:09Z |
| publishDate | 2021-10-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Frontiers in Bioscience-Landmark |
| spelling | doaj.art-8fad0060e3134e5a8740b212781a8e9e2022-12-21T19:06:40ZengIMR PressFrontiers in Bioscience-Landmark2768-67012021-10-01261075276410.52586/4985s2768-6701(21)00059-9Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cellsOluremi I Adeniran0Mohammad A Mohammad1Sophie Featherby2Anthony Maraveyas3Andrew N Boa4Camille Ettelaie5Department of Chemistry, University of Hull, HU6 7RX Hull, UKBiomedical Section, University of Hull, HU6 7RX Hull, UKBiomedical Section, University of Hull, HU6 7RX Hull, UKDivision of Cancer-Hull York Medical School, University of Hull, HU6 7RX Hull, UKDepartment of Chemistry, University of Hull, HU6 7RX Hull, UKBiomedical Section, University of Hull, HU6 7RX Hull, UKIntroduction: 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.https://www.imrpress.com/journal/FBL/26/10/10.52586/4985tissue factorpin1cancer cellp53baxsynthetic inhibitor |
| spellingShingle | Oluremi I Adeniran Mohammad A Mohammad Sophie Featherby Anthony Maraveyas Andrew N Boa Camille Ettelaie Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells Frontiers in Bioscience-Landmark tissue factor pin1 cancer cell p53 bax synthetic inhibitor |
| title | Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| title_full | Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| title_fullStr | Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| title_full_unstemmed | Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| title_short | Synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| title_sort | synthesis and analysis of small molecules to restrain the function of tissue factor within tumour cells |
| topic | tissue factor pin1 cancer cell p53 bax synthetic inhibitor |
| url | https://www.imrpress.com/journal/FBL/26/10/10.52586/4985 |
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