In this paper we described synthesis biological evaluation a

In this paper, we described synthesis, biological evaluation and docking study of 3-aroyl-1-(4-sulfamoylphenyl)thiourea derivatives 4a–o as 15-lipoxygenase inhibitors.
Results and discussion
Conclusion We designed and synthesized a novel of thiourea derivatives containing phenylsulfonamide moiety as 15-LOX inhibitors. Most synthesized compounds showed potent activity with IC50 values less than 25 μM. Among them, the 3-methylbenzoyl derivative 4c was the most potent compound (IC50 value of 1.8 μM), being 10-fold more potent than quercetin. Interestingly, compound 4c also showed the highest antioxidant activity, as determined by FRAP assay. The viability assay of the selected compound 4c against oxidative stress-induced cell death in differentiated PC12 SB 415286 mg revealed that compound 4c significantly protected neurons against cell death in low concentrations. The inhibitors of 15-LOX, such as compound 4c prototype maybe useful for preventing and treating inflammatory diseases such as asthma, psoriasis, osteoarthritis, rheumatoid arthritis, and atherosclerosis. Particularly, the ability of compound 4c to prevent oxidative stress-induced cell death in neurons revealed that it may be applicable to neuroprotection in a variety of neurodegenerative diseases such as stroke where oxidative stress is a major cause of injury. Future studies of this novel neuroprotective inhibitor of 15-LOX, including investigation of their ADMET properties and in vivo efficacy are required to demonstrate the usefulness of the agent to combat neurodegenerative diseases.
Experimental Melting points were taken on a Kofler hot stage apparatus and are uncorrected. 1H- and 13C NMR spectra were recorded on Bruker FT-400 using TMS as an internal standard. The IR spectra were obtained on a Nicolet Magna FTIR 550 spectrometer (KBr disks). Mass spectra were recorded with an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. The elemental analysis was performed with an Elementar Analysensystem GmbH VarioEL CHNS mode.
Acknowledgments This research was supported by grant from the Research Council of Tehran University of Medical Sciences and Iran National Science Foundation (INSF).
Introduction Metastasis is the leading cause of cancer-related death. Metastasis is a very complex cascade of events such as tumour growth, invasion and angiogenesis. The metastatic process is dependent on cross-talk between tumour cells and the adjacent microenvironment. Cell adhesion plays an important role in all stages of cancer metastasis. Arachidonic acid (AA) is a polyunsaturated fatty acid that is present in the phospholipids. Free arachidonic acid can be metabolised by two key enzymes: cyclooxygenase (COX) and lipoxygenase (LOX). Numerous clinical and pharmacologic studies have shown that COX-2 expression and its downstream products, such as prostaglandins are attributed to inflammation-associated cancers such as lung, colon, bladder and prostate cancer. On the other hand, LOXs are a group of closely related non-haeme iron-containing dioxygenases and are classified depending on their site of oxygen insertion on AA into 5-, 8-, 12- and 15-LOXs. Recent studies show a functional role of LOXs and their metabolite derivatives in carcinogenesis. However, the role of LOX isoforms in the pathology of human cancers remains unknown. The major product of AA via the 12/15-LOX (encoded by the ALOX15 gene) is hydroxyeicosatetraenoic acid (HETE). HETEs can stimulate various signalling molecules such as Src, lipid kinase phosphoinositide 3-kinase (PI3K), Akt, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and c-Jun N-terminal protein kinase-1 (JNK1), leading to the activation of transcriptional factors including activating transcriptional factor 2 (ATF2), activator protein 1 (AP1), early growth response factor (Egr1) and signal transducer and transcription factors (STATs).9, 10, 11, 12, 13 Furthermore, 12(S)-HETE has been shown to promote melanoma cell spreading on the matrix protein fibronectin and the increase of tyrosine phosphorylation of focal adhesion kinase (FAK) is involved in the enhancement of focal adhesion. 12(S)-HETE has been reported to play a key role in mediating several steps of the process of hematogenous metastasis and tumour cell adhesion. 12(S)-HETE induces the expression of integrins and other cell adhesion molecules.16, 17, 18 Moreover, high concentrations of 12(S)-HETE have been found in highly metastatic murine melanoma cell lines as compared with low metastatic potential cell lines.19, 20 We are the first to examine the role of host 12/15-LOX on the lung metastasis of melanoma cells.