Phenothiazines as lipid peroxidation inhibitors and cytoprotective agents.
A series of phenothiazines was synthesized and evaluated as in vitro inhibitors of iron-dependent lipid peroxidation. The MIC (minimum tested concentration that gave greater than or equal to 50% inhibition) for 2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanolamine methanesulfonate (6) was 0.26 microM. Whereas methyl substitution at N-10 diminished activity nearly 100-fold, other structural modifications such as varying the amine group, the distance separating the amine substituent from the phenothiazine nucleus, and the linking group had little effect. Compound 6 was more effective than probucol, a known antioxidant, in blocking Cu2+ catalyzed oxidation of low-density lipoprotein (LDL) as measured by competitive scavenger receptor mediated degradation of 125I-labeled acetyl-LDL by mouse peritoneal macrophage cells in vitro. At a concentration of 5 microM, compound 6 also protected primary cultures of rat hippocampal neurons exposed to hydrogen peroxide (50 microM) when assessed 18 h later by fluorescein diacetate and propidium iodide uptake.
Yu
M J
MJ
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
McCowan
J R
JR
Thrasher
K J
KJ
Keith
P T
PT
Luttman
C A
CA
Ho
P P
PP
Towner
R D
RD
Bertsch
B
B
Horng
J S
JS
Um
S L
SL
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D003300:Copper / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010529:Peritoneal Cavity / Q000166:cytology; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D000975:Antioxidants; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; D010640:Phenothiazines; C073191:2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanamine; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron