Loss of expression or functional activity of cell

Loss of expression or functional activity of cell adhesion is intricately related to advanced stages of tumour progression and invasiveness. Martin-Belmonte and Perez-Moreno recently mentioned that the deregulation of adhesion can alter tumourgenesis in the early stage. We have shown for the first time that melanoma cell lung metastasis was reduced in 12/15-LOX KO mice. Co-injection of 12(S)-HETE could increase B16F10 cells lung metastasis in vivo and the adhesion of B16F10 cell to pulmonary epithelia cell surface derived from 12/15-LOX null mice. Furthermore, 12(S)-HETE activated ERK and FAK signalling pathways, thereby upregulated the adhesion and metastatic potential of melanoma cells (Fig. 8). The levels of 12(S)-HETE in the host organ may affect the metastatic capability of melanoma cells. Therefore, 12/15-LOX is a potential therapeutic target for developing drugs to inhibit the progression of melanoma.
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Acknowledgement
Introduction Arachidonic pten pathway (AA) is biologically transformed into a variety of inflammatory mediators through two metabolic pathways, cyclooxygenase and lipoxygenase. Cyclooxygenases are responsible for the production of Prostaglandins (PGs), thromboxanes (TXA2) and prostacyclin (PGI2) while lipoxygenases produce leukotrienes (LTs) and also catalyse the oxidation of lipoproteins (LDL, HDL) to atherogenic forms [1], [2]. Cyclooxygenase isozymes are classed into a constitutive COX-1, induced COX-2 and COX-3 that still remain under investigation [3], [4]. All the above-mentioned mediators are highly expressed in many inflammatory diseases, allergic reaction [5], [6], [7] and neo-angiogenesis [8], [9]. The traditional non-steroidal anti-inflammatory drugs (NAISDs) such as aspirin or even the potent indomethacin exert their anti-inflammatory effect through rough inhibition of both COX-1 and 2. Reasonably, their action is associated with gastric bleeding due inhibition of constitutive COX-1. Moreover, selective COX-2 [10], [11] inhibitors pronounced as Coxibs including celecoxib I (celebrex™) [12] (Fig. 1), rofecoxib (vioxx™) or valdecoxib (bextra™) greatly inhibited the induced COX-2, but their administration is associated with myocardial thrombotic event and this is the reason of rofecoxib and valdecoxib withdrawal from the pharmaceutical market. Coxibs block the cyclooxygenase pathway, therefore metabolism of AA shunted to LOX pathway resulted in increasing the incidence of the unfavourable cardiovascular thrombotic event. According to the above findings, the development of new anti-inflammatory agent with a dual COX-2∖LOX inhibition [13] activity, will introduce an effective cardio-safe drug with no ulcerogenic property. Celebrex is being a lead, due its high anti-inflammatory activity with a minimum gastrointestinal side effect. It has been belonged to a vicinal diaryl stelbene like structure with a pyrazole central ring and a sulfonamide (SO2NH2) at p-position of one of aryl groups. Also exploring many selective COX∖LOX inhibitors such as darbufelone II and CI-987 (III) [14], [15], [16] (Fig. 1), stated that they all have a thiazole moiety. So the aim of this research was directed to the synthesis of new celecoxib analogues on two designs (IV and V). The first design IV has three criteria that one of its diaryl was replaced with a thiazolyl moiety in order to maintain their COX-2∖15-LOX inhibitory activities. Additional modification is adding or removing of CF3 in position −3 of pyrazoles to investigate their essentiality for activity beside to keep both COX-2 inhibitory pharmacophores (SO2NH2 or SO2CH3) as illustrated in Fig. 1. Another design of compounds V which has three modifications. 1-one of aryl is replaced with the thiazole one. 2- keeping sulphonyl groups and 3- an electron rich group (OCH3) was inserted as noticed in drabufelone II in order to maintain synergistic dual COX-2∖15-LOX inhibitory activities. Herein, two new designs of highly effective drug hybrid (celecoxib/darbufelone) that might encourage the higher effectiveness of resulted compounds as anti-inflammatory agents with high safety profiles. Also, The dual inhibition of COX-2/15- LOX would decrease the cardiovascular adverse side effect. Accordingly and to a continuation of previous work [17], [18], [19], [20], we synthesized and evaluate anti-inflammatory activity of the new targeted compounds. Moreover, in vitro COX-1/2 and 15-LOX inhibitory assays were done. Finally, the way of different pyrazole cyclization was discussed and proved by 2D NMR. These 2 D results has been converted the research to be a unique one, hence, many works of literature [21] prove their structures using theoretical computational studies without practical findings.