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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., (© 2021 The Author(s). Published by BRI.)

Context: Various studies have shown that the leaf extracts of Spondias mombin Linn (Anacardiaceae) possess pharmacological properties such as antioxidant and antiviral effects. However, no biological activity from its essential oil has been reported in literature., Objective: To analyse the chemical constituents, cytotoxic activity and antioxidant capability of the essential oils from fresh and dried leaves of S. mombin., Materials and Methods: Hydrodistillation using Clevenger-type apparatus was employed to obtain the essential oil. Oil analysis was performed using an HP 6890 Gas Chromatograph coupled with an HP 5973 Mass Selective Detector. The cytotoxicity bioassay was carried out using the brine shrimp lethality test (10,000-0.01 μg/mL). Additionally, the reactive oxygen species scavenging potential of the two S. mombin oils (1000-200 μg/mL) were investigated using a hydroxyl radical scavenging and ferric iron reducing system., Results: Chemical analysis of essential oils from S. mombin revealed the presence of 41 compounds, with predominance of monoterpenoids, sesquiterpenoids and non-terpenoids derivatives. In both fractions, the principal component was β-caryophellene (27.9-30.9%), followed by γ-cadinene (9.7-12.3%). There was an increase in the oxygenated monoterpenoid contents and a concomitant decrease in the amounts of sesquiterpenoids hydrocarbons observed on drying the leaves. The oil obtained from the fresh leaves was more active than that obtained from dried leaves, with LC 50 values (from the brine shrimp lethality assay) of 0.01 and 4.78 μg/mL, respectively. The two oils (from fresh and dried leaves) at 1.0 mg/mL scavenged hydroxyl radical by 83% and 99.8%, respectively. Moreover, they reduced ferric ion significantly and compared favourably with vitamin C., Conclusions: Essential oil derived from the leaves of S. mombin could hold promise for future application in the treatment of cancer-related diseases.