Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

Abstract

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2′-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

Morin Prevents Ultraviolet-B Radiation-Induced Photocarcinogenesis Through Activating Thrombospondin-1 in the Mouse Skin

“…The inhibition of COX-2 and iNOS expression has been shown to suppress the development of skin tumor [32]. Previous report stated that sulindac, a specific inhibitors for COX-1/COX-2 expression that may reduce prostaglandin production leads to the inhibition of UVB-induced skin cancer [33]. Our results also clearly mentioned that administration of morin significantly inhibited UVB-induced overexpression of COX-2 and iNOS in mouse skin.…”

Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: Implications in drug designing and development

“…Involvement of COX-1, in the pathophysiology of diseases, such as pain, fever, analgesia, neuroinflammation and cancer is based on both preclinical and clinical reports proposing COX-1 as a potential therapeutic target [6]. Thus, involvement of COX-1, rather than COX-2, in carcinogenesis has been demonstrated emphatically in ovarian and breast human cancers [7][8][9].…”

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

“…Potent inhibitors of TXS display a key cationinteraction with the iron atom from heme group present in the enzyme catalytic site. This interaction is well-known in literature [53][54][55] specially for imidazole-or 3-pyridine-based inhibitors 52,56 . Accordingly, our results revealed that the phenyl ring in 3a, 3b and 3h derivatives oriented toward the heme group establish a feasible cation-interaction with the heme iron.…”