From Dioxin to Drug Lead—The Development of 2,3,7,8‐Tetrachlorophenothiazine

Abstract

Polychlorinated dibenzo-p-dioxins are persistent environmental pollutants. The most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wasting syndrome and is a potent carcinogen and immunosuppressant in the rat at high doses. However, low doses cause opposite effects to some of those observed at higher doses, resulting in chemoprevention, stimulation of the immune system, and longevity in experimental animals. The new TCDD analogue, 2,3,7,8-tetrachlorophenothiazine (TCPT), was developed to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. Its development marked a deviation from the traditional scope of phenothiazine drug design by deriving biological effects from aryl substituents. TCPT was synthesized in three steps. The key ring-closing step was performed utilizing a Buchwald-Hartwig amination to provide TCPT in 37% yield. Its potency to induce CYP1A1 activity over 24 h was 370 times lower than that of TCDD in vitro. The elimination half-life of the parent compound in serum was 5.4 h in the rat and 2.7 h in the guinea pig, compared to 11 and 30 days, respectively, for TCDD. These initial findings clearly differentiate TCPT from TCDD and provide the basis for further studies of its potential as a drug lead.

Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

“…Despite the many reported detrimental effects of TCDD and AhR activation, low levels of AhR activation have been shown to have certain beneficial effects, such as chemoprevention, stimulation of the immune system, and longevity in experimental animals (Kociba et al , 1978; Fried et al , 2007). As Fgf21 is a promising therapeutic candidate to treat metabolic syndrome, AhR activation-induced Fgf21 may contribute to beneficial effects of certain dietary polyphenols and very low doses of TCDD.…”

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide

“…125 These polar solvents have also been found to be advantageous for amination reactions with these ligands in conjunction with microwave heating. 126, 127 …”

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[226] A modified version of these conditions was subsequently employed in an intramolecular reaction by Rozman in the synthesis of chlorinated phenothiazines as models for dioxin-like compounds (Scheme 61). [227] Copper-mediated Ullmann-type conditions usually used for these cyclizations were unsatisfactory in this case due to decomposition of the product under the reaction conditions. Subsequent studies by Skjaerbaek in the course of synthesizing p38 MAP kinase inhibitors have illustrated that under microwave irradiation XPhos can be an even more effective ligand and that the process can be extended to aryl triflates as electrophiles.…”