The effects of selected bulky substituents on the pulmonary toxicity of 3-furyl ketones in mice.
Preliminary studies examined the toxicity of a series of simple alkyl 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (1), in mice, but little was known about how aromatic or bulky side chains might affect toxicity. Therefore, 3-furylphenyl ketone (2) 3-furylphenethyl ketone (3) and 1-3-furyl-4, 4-dimethylpentan-1-one (4) were synthesized to examine this problem. The 48-h LD50 (i.p.) in Notre Dame Swiss mice for each analog was greater than that of the parent toxicant, perilla ketone (1, 30 +/- 5; 2, 173 +/- 4; 3, 150 +/- 11; 4, 79 +/- 5 mumol/kg). Absorption and distribution of these compounds should be similar based on their lipophilicities. Preliminary evidence suggested that the reduced toxicities of 2, 3 and 4 compared with 1 cannot be explained on the basis of 13C-NMR (electron density) characteristics. Instead, the reduced potency likely is the result of steric hindrance of bioactivation by the bulky side chain substituents and(or) alternative metabolism on the phenyl ring rather than the furan ring of 2 and 3.
Wilson
W C
WC
University of Illinois, Urbana 61801.
Simon
J
J
Garst
J E
JE
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D008168:Lung / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D039821:Monoterpenes; D013729:Terpenes / Q000633:toxicity*; D014118:Toxins, Biological / Q000633:toxicity*
D039821:Monoterpenes; D013729:Terpenes; D014118:Toxins, Biological; C015426:perilla ketone