Specific sequestering agents for the actinides. 21. Synthesis and initial biological testing of octadentate mixed catecholate-hydroxypyridinonate ligands.
The linear octadentate ligand 3,4,3-LIHOPO, which contains four 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) groups, is the most effective agent for in vivo chelation of Pu(IV) yet prepared. However, its clinical potential is limited by acute toxicity of the free ligand (but not Fe3+ complex) at high dosage. The high acidity of HOPO ligands and the much lower acidity of catechol (CAM) ligands suggested that mixed octadentate (CAM-HOPO) ligands containing one or two 1,2-HOPO and three (or two) catechol (CAM) groups might be as effective for Pu removal [fully eight-coordinated Pu(IV) complexes formed at pH > or = 6] and less toxic than 3,4,3-LIHOPO. Treatment of spermine with 3-(2,3-dimethoxybenzoyl)thiazol-idine-2-thione (1) (molar ratio 2:1) gave 1,14-bis(2,3-dimethoxybenzoyl)-1,5,10,14-tetraazatetradecane (2, DiCAM-spermine) in 80% yield. Addition of 2 to a 2-fold excess of the reaction product of 1-hydroxy-2-pyridone-6-carboxylic acid (HOPO-C) and 1,1'-carbonyldiimidazole (CDI) in N,N-dimethylformamide (DMF) and deprotection with BBr3 gave 1,14-bis(2,3-dihydroxybenzoyl)-5,10-bis(1-hydroxy-2-pyridon-6-oyl) -1,5,10,14-tetraaza-tetradecane [3, 3,4,3-LI(diCAM-diHOPO)] in 5% yield. Addition of 2 to an equimolar amount of the reaction product of HOPO-C and CDI in N,N-dimethylacetamide (DMAA), purification of the hexadentate intermediate, subsequent treatment with an equimolar amount of 2,3-dimethoxybenzoyl chloride (DMB), and deprotection with BBr3 gave 1,5,14-tris(2,3-dihydroxybenzoyl)-10-(1-hydroxy-2-pyridon-6-oyl)-1 ,5,10,14- tetraazatetradecane [4, 3,4,3-LI(triCAM-HOPO)] in 5% yield. Ligands were administered to mice [30 mumol kg-1 ip at 1 h or orally at 3 min after iv injection of plutonium(IV)-238 citrate, kill at 24 h]. Plutonium excretion after injection of either CAM-HOPO ligand was 700% of that for 24-h Pu-injected controls, 140% of that for mice given the tetracatecholate analogue 3,4,3-LICAM (significantly more, p < 0.01), but only 80% of that promoted by 3,4,3-LIHOPO (significantly less). Orally administered 3,4,3-LI-(diCAM-diHOPO) promoted significantly more Pu excretion than an equimolar amount of CaNa3DTPA. Potency of the CAM-HOPO ligands for in vivo chelation of Pu(IV) resembled that of structurally hexadentate tris-(hydroxypyridinonate) and tris(sulfocatecholate) ligands and functionally hexadentate tetrakis-(sulfocatecholate) and tetrakis(carboxycatecholate) ligands. The Pu complexes of the CAM-HOPO ligands are to some degree unstable at pH < 7.4, as judged by Pu residues in kidneys in excess of 24-h Pu-injected controls. Synthetic yields were insufficient for chemical investigations or evaluation of acute toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Uhlir
L C
LC
Department of Chemistry, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
Durbin
P W
PW
Jeung
N
N
Raymond
K N
KN
D008671:Actinoid Series Elements / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D011005:Plutonium / Q000378:metabolism* / Q000652:urine; D011728:Pyridones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D008671:Actinoid Series Elements; D002396:Catechols; D002614:Chelating Agents; D011728:Pyridones; C080800:1,14-bis(2,3-dihydroxybenzoyl)-5,10-bis(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14-tetraazatetradecane; C080802:1,5,14-tris(2,3-dihydroxybenzoyl)-10-(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14-tetraazatetradecane; D011005:Plutonium