ABSTRACT
The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10-dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[(2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N, N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl)ethylamino]-O-tosyl-1-++ +butan ol. All of the hydroxylated analogues were active against L1210 cells with 96-h IC(50) values of =2 microM, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues on ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., N(1),N(11)-diethylnorspermine [DENSPM]) at 1 microM; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N(1)-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R, R)-(HO)(2)DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (R, R)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Polyamines/chemical synthesis , Polyamines/pharmacology , Animals , Hydroxylation , Leukemia L1210/pathology , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Tumor Cells, CulturedABSTRACT
A series of (S)-desmethyldesferrithiocin (DMDFT, 1) hydroxamates and a bis-salicyl polyether hydroxamate are evaluated for their iron-clearing properties in rodents; some of these are further assessed in primates. These hydroxamates include (S)-desmethyldesferrithiocin, N-methylhydroxamate (2); (S)-desmethyldesferrithiocin, N-[5-(acetylhydroxyamino)pentyl]hydroxamate (3); desmethyldesferrithiocin, N-benzylhydroxamate (4); (S,S)-N(1), N(8)-bis[4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-thiazoyl]-N(1), N(8)-dihydroxy-3,6-dioxa-1,8-octanediamine (5); and N(1), N(8)-bis(2-hydroxybenzoyl)-N(1),N(8)-dihydroxy-3,6-dioxa-1, 8-octanediamine (6). The ligands are evaluated when given both orally (po) and subcutaneously (sc) in the bile-duct-cannulated rodent model. In iron-overloaded primates, ligands 1-4 are assessed when administered po and sc. The efficiencies of the hydroxamates are shown to vary considerably; giving the compounds sc consistently resulted in greater chelating efficiency in vivo. After oral administration in the primate, compound 3, a pentacoordinate unsymmetrical dihydroxamate, produces iron excretion sufficient to warrant further preclinical evaluation both as a potential orally active iron-chelating agent and as a parenteral iron chelator. The increased iron clearance of several of these ligands when administered sc versus po also underscores the idea that parenteral administration is a reasonable alternative to a less efficient, orally active device which would require large and frequent doses.
Subject(s)
Dihydropyridines/chemistry , Hydroxamic Acids/chemical synthesis , Iron Chelating Agents/chemical synthesis , Thiazoles/chemistry , Thiazoles/chemical synthesis , Administration, Oral , Animals , Cebus , Dihydropyridines/pharmacology , Drug Evaluation, Preclinical , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Injections, Subcutaneous , Iron Chelating Agents/chemistry , Iron Chelating Agents/pharmacology , Iron Chelating Agents/toxicity , Iron Overload/drug therapy , Ligands , Male , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.