Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.
Reactions of 2,2‐dimethylaziridine with benzohydroximoyl chlorides [ArC(Cl)NOH] give aziridinylbenzaldoximes 1. It has been found that the aziridine ring in these compounds undergoes ring opening in hydrogen chloride‐dioxane solution to give (Z)‐N‐hydroxy‐N′‐(2‐chloro‐2‐methylpropyl)benzenecarboximidamides [ArC(NHCH2CR1R2Cl)NOH, 4]. Treatment of 1 with hydrochloric acid followed by neutralization with aqueous sodium hydroxide gave 6,6‐dimethyl‐3‐aryl‐1,2,4‐oxadiazines 2. Reaction of 4 with sodium hydride in dioxane gave 5‐isopropyl‐3‐aryl‐4,5‐dihydro‐1,2,4‐oxadiazoles 5. Reaction of the 4,5‐dihydro‐1,2,4‐oxadiazoles 5 with N‐chlorosuccinimide gave the heteroaromatic 1,2,4‐oxadiazoles 6. It is suggested that reactions of 4 with sodium hydride in dioxane solution involve the conjugate base of 4 which undergoes a 1,2‐hydride shift that is concerted with loss of chloride ion. In aqueous sodium hydroxide solution it is suggested that the conjugate base of 4 undergoes ionization of the chlorine atom followed by nucleophilic attack by the oximate anion.
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