From Dioxin to Drug Lead—The Development of 2,3,7,8-Tetrachlorophenothiazine
| Autor: | Christopher M. Schneider, Kristian W. Fried, Apurba Datta, Karl-Werner Schramm, Antonius Kettrup, Paul F. Terranova, Dieter Lenoir, Douglas R. Powell, Claudia Corsten, Karl K. Rozman, Naima Chahbane, Gunda I. Georg |
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| Rok vydání: | 2007 |
| Předmět: |
Drug
Polychlorinated Dibenzodioxins Chlorpromazine Stereochemistry media_common.quotation_subject Guinea Pigs Stimulation Pharmacology Dioxins Biochemistry Rats Sprague-Dawley chemistry.chemical_compound Immune system Phenothiazines Cell Line Tumor Phenothiazine Drug Discovery Cytochrome P-450 CYP1A1 Animals Potency heterocyclic compounds General Pharmacology Toxicology and Pharmaceutics Enzyme inducer Carcinogen media_common biology Organic Chemistry In vitro Rats chemistry Drug Design Enzyme Induction biology.protein Molecular Medicine Female |
| Zdroj: | ChemMedChem. 2:890-897 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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