From dioxin to drug lead--the development of 2,3,7,8-tetrachlorophenothiazine.
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.
Fried
Kristian W
KW
Dept. of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66212, USA.
Schneider
Christopher M
CM
Schramm
Karl-Werner
KW
Datta
Apurba
A
Chahbane
Naima
N
Corsten
Claudia
C
Powell
Douglas R
DR
Lenoir
Dieter
D
Kettrup
Antonius
A
Terranova
Paul
P
Georg
Gunda I
GI
Rozman
Karl K
KK
D000818:Animals; D045744:Cell Line, Tumor; D002746:Chlorpromazine / Q000737:chemistry; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004147:Dioxins / Q000737:chemistry; D015195:Drug Design; D004790:Enzyme Induction; D005260:Female; D006168:Guinea Pigs; D010640:Phenothiazines / Q000009:adverse effects / Q000138:chemical synthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
C531157:2,3,7,8-tetrachlorophenothiazine; D004147:Dioxins; D010640:Phenothiazines; D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; C020887:dibenzo(1,4)dioxin; D002746:Chlorpromazine