Structural alterations in desferrioxamine compatible with iron clearance in animals.
The design, synthesis, and biological evaluation of amideless desferrioxamine analogues are described. The design concept is predicated on the idea that a low molecular weight desferrioxamine analogue would represent a better pharmacophore from which to construct an orally effective or more efficient trihydroxamate than the parent chelator. The study demonstrates that (1) the monohydroxamate units of desferrioxamine must be linked to promote iron clearance, (2) the N-propanoyl-N-pentyl fragments of desferrioxamine can be replaced with smaller, e.g., C-5, methylene units without compromising the analogue's iron-clearing properties, and (3) a delicate balance exists between the molecule's iron-clearing efficiency and its lipophilicity.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610.
Liu
Z R
ZR
McManis
J S
JS
Wiegand
J
J
D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003676:Deferoxamine / Q000031:analogs & derivatives*; D007501:Iron / Q000378:metabolism* / Q000652:urine; D008297:Male; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D007501:Iron; D003676:Deferoxamine