Background: Leukotrienes (LTs) constitute a bioactive group of polyunsaturated fatty acid (PUFA) metabolites molded by the enzymatic activity of lipoxygenase (LO) and have a pivotal role in inflammation and allergy. Evidence is accumulating both by in vitro cell culture experiments and animal tumor model studies in support of the direct involvement of aberrant metabolism of arachidonic acid (ACD) in the development of several types of human cancers such as lung, prostate, pancreatic and colorectal malignancies. Several independent experimental data suggest a correlation between tumoral cells viability and LO gene expression, especially, 5-lipoxygenase (5-LO). Overexpressed 5-LO cells live longer, proliferate faster, invade more effectively through extracellular matrix destruction and activate the anti-apoptotic signaling mechanisms more intensively compared to the normal counterparts. Thus, some groups of lipoxygenase inhibitors may be effective as promising chemopreventive agents. Methods: A structured search of bibliographic databases for peer-reviewed research literature regarding the role of LO in the pathogenesis of cancer was performed. The characteristics of screened papers were summarized and the latest advances focused on the discovery of new LO inhibitors as anticancer agents were discussed. Results: More than 180 papers were included and summarized in this review; the majority was about the newly designed and synthesized 5-LO inhibitors as anti-inflammatory and anticancer agents. The enzyme’s structure, 5-LO pathway, 5-LO inhibitors structure-activity relationships as well as the correlation between these drugs and a number of most prevalent human cancers were described. In most cases, it has been emphasized that dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LO) or dual 5-lipoxygenase/microsomal prostaglandin E synthase-1 (5-LO/mPGES-1) inhibitors possess considerable inhibitory activities against their target enzymes as well as potent antiproliferative effects. Several papers disclosing 5-lipoxygenase activating protein (FLAP) antagonists as a new group of 5-LO activity regulators are also subject to this review. Also, the potential of 12-lipoxygenase (12-LO) and 15-lipoxygenase (15-LO) inhibitors as chemopreventive agents were outlined to expand the scope of new anticancer agents discovery. Some peptides and peptidomimetics with anti-LT activities were described as well. In addition, the cytotoxic effects of lipoxygenase inhibitors and their adverse effects were discussed and some novel series of natural-product-derived inhibitors of LO was also discussed in this review. Conclusion: This review gives insights into the novel lipoxygenase inhibitors with anticancer activity as well as the different molecular pharmacological strategies to inhibit the enzyme effectively. The findings confirm that certain groups of LO inhibitors could act as promising chemopreventive agents.
Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea‐based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide‐based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P2) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P1) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid as the reference standard. Compound 12e with a 4‐methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC50 value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.
: Human carbonic anhydrase (hCA) and cyclooxygenase-2 (COX-2) have been known for a long to be chiefly involved in both the pathogenesis and progression of cancer and cancer chemoresistance. Interestingly, there is emerging evidence that the sulfonamide-type COX-2 selective inhibitors (coxibs) demonstrate inhibitory action against the cancer-related hCA isoforms, confirmed by X-ray crystal structures for celecoxib and valdecoxib complexes with the hCA active site. Consequently, the antineoplastic activity of the sulfonamide coxibs may be justified by the contribution of hCA inhibition to such processes in addition to COX-2 inhibition. Accordingly, these compounds' anti-tumoral activity should be further explored for their possible use in cancer prevention and combination therapy; however, few papers deal with this issue. Beginning with a brief description of the main molecular and catalytic features of both enzymes and their roles in tumor physiology, this review covers a survey of the most recent evidence regarding the molecules targeting one or both of hCA and COX-2, also providing insights into their mechanism of action and efficacy in preventing cancer.
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