SARs of annonaceous acetogenins in rat liver mitochondria.
The Annonaceous acetogenins represent a class of compounds with diverse bioactivities, including promising cytotoxicites. These are due, at least in part, to inhibition of complex I in the oxidative phosphorylation pathway in mitochondria. Fourteen Annonaceous acetogenins were tested in a rat liver mitochondrial oxygen uptake assay to probe additional structure-activity relationships. In this subcellular assay, the activity of non-adjacent bis-THF ring acetogenins depends on the distance between the two THF rings; the activity decreases to that of a mono-THF ring acetogenin if the distance is too long. When one THF ring is replaced with a tetrahydropyran ring, the activity remains comparable. The configuration of the THF ring, in mono ring compounds, seems to be more important than stereochemical differences in the rings of adjacent bis-THF ring compounds. Bullatacin, an adjacent bis-THF ring acetogenin, was used as a standard compound in every run to normalize the data.
Alfonso
D
D
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana, USA.
Johnson
H A
HA
Colman-Saizarbitoria
T
T
Presley
C P
CP
McCabe
G P
GP
McLaughlin
J L
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity*; D005663:Furans / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D007783:Lactones