Polyamine-vectored iron chelators: the role of charge.
The utility of polyamines as vectors for the intracellular transport of iron chelators is further described. Consistent with earlier results with polyamine analogues, these studies underscore the importance of charge in the design of polyamine-vectored chelators. Four polyamine conjugates are synthesized, two of terephthalic acid [N(1)-(4-carboxy)benzoylspermine (7) and its methyl ester (6)] and two of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] [(S)-4,5-dihydro-2-[2-hydroxy-4-(12-amino-5,9-diazadodecyl-oxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (10) and its ethyl ester (9)]. These four molecules were evaluated in murine leukemia L1210 cells for their impact on cell proliferation (48- and 96-h IC(50) values), their ability to compete with spermidine for the polyamine transport apparatus (K(i)), and their intracellular accumulation. The data revealed that when neutral molecules (cargo fragments) were fixed to the polyamine vector, the conjugates competed well with spermidine for transport and were accumulated intracellularly to millimolar levels. However, this was not the case when the cargo fragments were negatively charged. Metabolic studies of the polyamine-vectored (S)-4'-(HO)-DADFTs in rodents indicated that not only did the expected deaminopropylation step occur, but also a surprisingly high level of oxidative deamination at the terminal primary nitrogens took place. Finally, the iron-clearing efficiency of the (S)-4'-(HO)-DADFT conjugates was determined in a bile-duct-cannulated rodent model. Attaching the ligand to a polyamine vector had a profound effect on increasing the iron-clearing efficiency of this chelator relative to its parent drug.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, 32610-0485, USA. bergeron@mc.cop.ufl.edu
Bharti
Neelam
N
Wiegand
Jan
J
McManis
James S
JS
Yao
Hua
H
Prokai
Laszlo
L
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004560:Electricity; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D011073:Polyamines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013095:Spermidine / Q000737:chemistry / Q000493:pharmacokinetics; D013096:Spermine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics
C501761:4,5-dihydro-2-(2-hydroxy-4-(12-amino-5,9-diazadodecyloxy)phenyl)-4-methyl-4-thiazolecarboxylic acid; D002352:Carrier Proteins; D004952:Esters; D007502:Iron Chelating Agents; C501760:N(1)-(4-carboxy)benzoylspermine; D011073:Polyamines; D013844:Thiazoles; D013096:Spermine; D013095:Spermidine