RESUMEN
Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of iron overload diseases, for example, thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the drug's iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed' iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.
Asunto(s)
Quelantes del Hierro/química , Hierro/química , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure-activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials.
Asunto(s)
Química Farmacéutica/métodos , Dihidropiridinas/química , Quelantes del Hierro/química , Hierro/química , Tiazoles/química , Animales , Diseño de Fármacos , Transporte de Electrón , Ferritinas/química , Homeostasis , Humanos , Quelantes del Hierro/farmacología , Sobrecarga de Hierro/tratamiento farmacológico , Ligandos , Oxidación-Reducción , Primates , Ratas , Ratas Sprague-Dawley , Sideróforos/química , Relación Estructura-Actividad , Transferrina/químicaRESUMEN
Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. The iron-clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron-clearing properties.
Asunto(s)
Dihidropiridinas/farmacología , Quelantes del Hierro/farmacología , Tiazoles/farmacología , Administración Oral , Animales , Cebus , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Dihidropiridinas/química , Dihidropiridinas/metabolismo , Dihidropiridinas/toxicidad , Éteres/química , Éteres/metabolismo , Éteres/farmacología , Éteres/toxicidad , Compuestos Férricos/química , Compuestos Férricos/metabolismo , Hidroxilación , Quelantes del Hierro/química , Quelantes del Hierro/metabolismo , Quelantes del Hierro/toxicidad , Sobrecarga de Hierro/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiopatología , Ligandos , Masculino , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/metabolismo , Tiazoles/toxicidadRESUMEN
The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE(primate)/ICE(rodent), are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.
Asunto(s)
Dihidropiridinas/efectos adversos , Dihidropiridinas/farmacocinética , Quelantes del Hierro/efectos adversos , Quelantes del Hierro/farmacocinética , Hierro/metabolismo , Riñón/efectos de los fármacos , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Animales , Cebus , Moléculas de Adhesión Celular/orina , Dihidropiridinas/química , Heces/química , Hierro/orina , Quelantes del Hierro/química , Riñón/metabolismo , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Tiazoles/químicaRESUMEN
(S)-2-(2,4-Dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (2) was abandoned in clinical trials as an iron chelator for the treatment of iron overload disease because of its nephrotoxicity. However, subsequent investigations revealed that replacing the 4'-(HO) of 2 with a 3,6,9-trioxadecyloxy group, ligand 4, increased iron clearing efficiency (ICE) and ameliorated the renal toxicity of 2. This compelled a closer look at additional polyether analogues, the subject of this work. The 3,6,9,12-tetraoxatridecyloxy analogue of 4, chelator 5, an oil, had twice the ICE in rodents of 4, although its ICE in primates was reduced relative to 4. The corresponding 3,6-dioxaheptyloxy analogue of 2, 6 (a crystalline solid), had high ICEs in both the rodent and primate models. It significantly decorporated hepatic, renal, and cardiac iron, with no obvious histopathologies. These findings suggest that polyether chain length has a profound effect on ICE, tissue iron decorporation, and ligand physiochemical properties.
Asunto(s)
Fenómenos Químicos , Dihidropiridinas/química , Dihidropiridinas/farmacología , Éteres/química , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Hierro/aislamiento & purificación , Tiazoles/química , Tiazoles/farmacología , Animales , Conductos Biliares/metabolismo , Cebus , Cristalografía por Rayos X , Dihidropiridinas/metabolismo , Dihidropiridinas/toxicidad , Diseño de Fármacos , Éter/química , Humanos , Hierro/metabolismo , Quelantes del Hierro/metabolismo , Quelantes del Hierro/toxicidad , Sobrecarga de Hierro/metabolismo , Riñón/efectos de los fármacos , Ligandos , Masculino , Octanoles/química , Ratas , Tiazoles/metabolismo , Tiazoles/toxicidad , Agua/químicaRESUMEN
A new target strategy in the development of bacterial vaccines, the induction of antibodies to microbial outer membrane ferrisiderophore complexes, is explored. A vibriobactin (VIB) analogue, with a thiol tether, 1-(2,3-dihydroxybenzoyl)-5,9-bis[[(4S,5R)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-5-methyl-4-oxazolyl]carbonyl]-14-(3-mercaptopropanoyl)-1,5,9,14-tetraazatetradecane, was synthesized and linked to ovalbumin (OVA) and bovine serum albumin (BSA). The antigenicity of the VIB microbial iron chelator conjugates and their iron complexes was evaluated. When mice were immunized with the resulting OVA-VIB conjugate, a selective and unequivocal antigenic response to the VIB hapten was observed; IgG monoclonal antibodies specific to the vibriobactin fragment of the BSA and OVA conjugates were isolated. The results are consistent with the idea that the isolated adducts of siderophores covalently linked to their bacterial outer membrane receptors represent a credible target for vaccine development.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Anticuerpos Monoclonales/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas Bacterianas/inmunología , Catecoles/inmunología , Oxazoles/inmunología , Sideróforos/inmunología , Vibrio cholerae/inmunología , Animales , Anticuerpos Monoclonales/química , Reacciones Antígeno-Anticuerpo , Proteínas de la Membrana Bacteriana Externa/química , Vacunas Bacterianas/química , Sitios de Unión , Catecoles/química , Bovinos , Femenino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Ovalbúmina/química , Ovalbúmina/inmunología , Oxazoles/química , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/inmunología , Sideróforos/químicaRESUMEN
The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?
Asunto(s)
Dihidropiridinas/administración & dosificación , Dihidropiridinas/síntesis química , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/síntesis química , Sobrecarga de Hierro/metabolismo , Enfermedades Renales/inducido químicamente , Tiazoles/administración & dosificación , Tiazoles/síntesis química , Administración Oral , Animales , Cebus , Dihidropiridinas/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Hierro/metabolismo , Quelantes del Hierro/química , Sobrecarga de Hierro/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ligandos , Lípidos/química , Masculino , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Tiazoles/química , Agua/químicaRESUMEN
A series of iron-clearing efficiencies (ICEs), ferrokinetics, and toxicity studies for ( S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (deferitrin, 1), ( S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid ( 2), and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid ( 3) are reported. The ICEs in rodents are shown to be dose-dependent and saturable for ligands 2 and 3 and superior to 1. Both polyether analogues in subcutaneous (sc) versus oral (po) administration in rodents and primates demonstrated excellent bioavailability. Finally, in a series of toxicity studies of ligands 1- 3, the dosing regimen was shown to have a profound effect in animals treated with ligand 1. When ligand 1 was given at doses of 237 micromol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 micromol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.
Asunto(s)
Dihidropiridinas/síntesis química , Dihidropiridinas/farmacología , Diseño de Fármacos , Éter/química , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Sistema Biliar/efectos de los fármacos , Sistema Biliar/metabolismo , Cercopithecus , Dihidropiridinas/química , Hierro/metabolismo , Quelantes del Hierro/síntesis química , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Riñón/efectos de los fármacos , Cinética , Masculino , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
A series of iron chelators, three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (DADFT) and three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (DADMDFT) analogues are synthesized and assessed for their lipophilicity (log Papp), iron-clearing efficiency (ICE) in rodents and iron-loaded primates (Cebus apella), toxicity in rodents, and organ distribution in rodents. The results lead to a number of generalizations useful in chelator design strategies. In rodents, while log Papp is a good predictor of a chelator's ICE, chelator liver concentration is a better tool. In primates, log Papp is a good predictor of ICE, but only when comparing structurally very similar chelators. There is a profound difference in toxicity between the DADMDFT and DADFT series: DADMDFTs are less toxic. Within the DADFT family of ligands, the more lipophilic ligands are generally more toxic. Lipophilicity can have a profound effect on ligand organ distribution, and ligands can thus be targeted to organs compromised in iron overload disease, for example, the heart.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Quelantes del Hierro/síntesis química , Tiazoles/síntesis química , Animales , Bilis/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Cebus , Dihidropiridinas/síntesis química , Dihidropiridinas/química , Dihidropiridinas/farmacología , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Complejo Hierro-Dextran/sangre , Complejo Hierro-Dextran/farmacocinética , Complejo Hierro-Dextran/orina , Riñón/metabolismo , Hígado/metabolismo , Masculino , Miocardio/metabolismo , Especificidad de Órganos , Páncreas/metabolismo , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Distribución TisularRESUMEN
Previous studies revealed that within a family of ligands the more lipophilic chelators have better iron-clearing efficiency. The larger the log P(app) value of the compound, the better the iron-clearing efficiency. What is also clear from the data is that although the relative effects of log P(app) changes are essentially the same through different families, there are differences in absolute value between families. However, there also exists a second, albeit somewhat more disturbing, relationship. In all sets of ligands, the most lipophilic chelator is always the most toxic. The current study focuses on designing ligands that balance the lipophilicity/toxicity problem while iron-clearing efficiency is maintained. Earlier studies with (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(CH(3)O)-DADFT, 6] indicated that this methyl ether was a ligand with excellent iron-clearing efficiency in both rodents and primates; however, it was too toxic. On the basis of this finding, a less lipophilic, more water-soluble ligand than 6 was assembled, (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE, 11], a polyether analogue, along with its ethyl and isopropyl esters. The parent polyether and its isopropyl and ethyl esters were all shown to be highly efficient iron chelators in both rodents and primates. A comparison of 11 in rodents with the desferrithiocin analogue (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT, 1] revealed the polyether to be more tolerable, achieving higher concentrations in the liver and significantly lower concentrations in the kidney. The lower renal drug levels are in keeping with the profound difference in the architectural changes seen in the kidney of rodents given 1 versus those treated with 11.
Asunto(s)
Ácidos/química , Ácidos Carboxílicos/química , Éteres/química , Éteres/toxicidad , Riñón/efectos de los fármacos , Tiazoles/química , Animales , Quelantes/química , Diseño de Fármacos , Éteres/síntesis química , Éteres/farmacocinética , Haplorrinos , Hierro/química , Masculino , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/química , Poliaminas/química , Espermina/análogos & derivados , Espermina/administración & dosificación , Espermina/química , Tiazoles/administración & dosificación , Tiazoles/química , Animales , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Electricidad , Ésteres/administración & dosificación , Ésteres/química , Ésteres/farmacocinética , Quelantes del Hierro/farmacocinética , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Espermidina/química , Espermidina/farmacocinética , Espermina/farmacocinética , Relación Estructura-Actividad , Tiazoles/farmacocinéticaRESUMEN
Exploitation of the polyamine backbone as a vector for intracellular transport of various pharmacophores has focused largely on fixing the cargo molecule to one of the nitrogens in the linear chain. This communication describes the assembly of a model aminopolyamine analogue, 6-amino-N(1),N(12)-diethylspermine, and its biological properties. This amino polyamine presents an additional site of attachment for cargo molecules, reduces cell growth, and achieves cellular concentrations that are higher than those of N(1),N(12)-diethylspermine.
Asunto(s)
Antineoplásicos/síntesis química , Espermina/análogos & derivados , Espermina/síntesis química , Acetiltransferasas/metabolismo , Adenosilmetionina Descarboxilasa/metabolismo , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Transporte Biológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ornitina Descarboxilasa/metabolismo , Espermina/farmacocinética , Espermina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Altering the lipophilicity (log P(app)) of desferrithiocin analogues can change the organ distribution of the chelators and lead to enhanced iron clearance. For example, alkylation of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] and its analogues to more lipophilic compounds, such as (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(CH3O)-DADFT], provides ligands that achieved between a 3- and 8-fold increase in chelator concentrations in the heart, liver, and pancreas (the organs most at risk in iron-overload disease) of treated rodents. The 4'-O-methylated compounds are demethylated to their hydroxylated counterparts in rodents; furthermore, this O-demethylation takes place in both rodent and human liver microsomes. The relationship between chelator lipophilicity and iron-clearing efficacy in the iron-overloaded Cebus apella primate is further underscored by a comparison of the iron-clearing efficiency of (S)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT] and its 3'-(CH3O) counterpart. Finally, these DFT analogues are shown to be both inhibitors of the iron-mediated oxidation of ascorbate as well as effective radical scavengers.
Asunto(s)
Catecoles/síntesis química , Dihidropiridinas/síntesis química , Quelantes del Hierro/síntesis química , Hierro/farmacocinética , Tiazoles/síntesis química , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacocinética , Ácido Ascórbico/química , Catecoles/química , Catecoles/farmacocinética , Cebus , Dihidropiridinas/química , Dihidropiridinas/farmacocinética , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacocinética , Humanos , Técnicas In Vitro , Hierro/química , Quelantes del Hierro/química , Quelantes del Hierro/farmacocinética , Hígado/metabolismo , Masculino , Miocardio/metabolismo , Oxidación-Reducción , Páncreas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Distribución TisularRESUMEN
The current study demonstrates unequivocally that polyamines can serve as vectors for the intracellular delivery of the bidentate chelator 1,2-dimethyl-3-hydroxypyridin-4-one (L1). The polyamine-hydroxypyridinone conjugate 1-(12-amino-4,9-diazadodecyl)-2-methyl-3-hydroxy-4(1H)-pyridinone is assembled from spermine and 3-O-benzylmaltol. The conjugate is shown to form a 3:1 complex with Fe(III) and to be taken up by the polyamine transporter 1900-fold against a concentration gradient. The K(i) of the conjugate is 3.7 microM vs spermidine for the polyamine transporter. The conjugate is also at least 230 times more active in suppressing the growth of L1210 murine leukemia cells than is the parent ligand, decreases the activities of the polyamine biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase, and upregulates spermidine-spermine N (1)-acetyltransferase. However, the effect on native polyamine pools is a moderate one. These findings are in keeping with the idea that polyamines can also serve as efficient vectors for the intracellular delivery of other iron chelators.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Férricos/química , Quelantes del Hierro/química , Poliaminas/metabolismo , Piridonas/síntesis química , Espermina/síntesis química , Acetiltransferasas/biosíntesis , Adenosilmetionina Descarboxilasa/metabolismo , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Unión Competitiva , Transporte Biológico Activo , Proteínas Portadoras/metabolismo , División Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Leucemia L1210 , Ratones , Ornitina Descarboxilasa/metabolismo , Piridonas/metabolismo , Piridonas/farmacología , Espermina/análogos & derivados , Espermina/metabolismo , Espermina/farmacología , Regulación hacia ArribaRESUMEN
For patients who require lifelong blood transfusions, there is no efficient means, unless chelation therapy is employed, for elimination of excess iron. Alternatives to desferrioxamine, the currently accepted treatment for transfusional iron overload, are being investigated. The current article focuses on an enantiomeric pair of analogs of desferrithiocin, (+)-(S)- and (-)-(R)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (4'-hydroxydesazadesferrithiocin). The crystal structure corroborated the absolute configuration of the two compounds, (+) and (-) for the (S)- and (R)-enantiomers, respectively. Job's plots established the tridentate nature of both analogs and circular dichroism spectra confirmed the ligands' antipodal relationship. (+)-(S)-4'-Hydroxydesazadesferrithiocin is a more efficient deferration agent than is the (-)-(R)-enantiomer in a Cebus apella model of iron overload. Pharmacokinetic analyses and IC(50) measurements in L1210 murine leukemia cells were undertaken in an effort to account for the contrast in efficacy between the two enantiomers. Some differences exist in the plasma pharmacokinetic parameters between the two analogs. However, a more plausible explanation may be the apparent differences in transport across the cell membrane; the IC(50) value in L1210 cells of the (+)-(S)-enantiomer was at least 5-fold lower than that of the (-)-(R)-compound.
Asunto(s)
Dihidropiridinas/química , Quelantes del Hierro/química , Tiazoles/química , Animales , Cebus , Cristalografía por Rayos X , Dihidropiridinas/farmacocinética , Dihidropiridinas/orina , Heces/química , Humanos , Ratones , Estereoisomerismo , Tiazoles/farmacocinética , Tiazoles/orinaRESUMEN
The impact of altering the octanol-water partition properties (log P) of analogues of desazadesferrithiocin, (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid, on the ligands' iron clearing properties is described. Increasing chelator lipophilicity can both substantially augment iron clearing efficiency in Cebus apella primates as well as alter the mode of iron excretion, favoring fecal over urinary output. The complications of iron overload are often associated with the metal's interaction with hydrogen peroxide, generating hydroxyl radicals (Fenton chemistry) and, ultimately, other related deleterious species. In fact, some iron chelators actually promote this chemistry. All of the compounds synthesized and tested in the current study are shown to be both inhibitors of the iron-mediated oxidation of ascorbate, thus removing the metal from the Fenton cycle, and effective radical scavengers.
Asunto(s)
Depuradores de Radicales Libres/síntesis química , Quelantes del Hierro/síntesis química , Piridinas/síntesis química , Tiazoles/síntesis química , 1-Octanol , Animales , Ácido Ascórbico/química , Cebus , Heces/química , Depuradores de Radicales Libres/farmacocinética , Depuradores de Radicales Libres/farmacología , Hierro/química , Hierro/metabolismo , Quelantes del Hierro/farmacocinética , Quelantes del Hierro/farmacología , Sobrecarga de Hierro/metabolismo , Ligandos , Oxidación-Reducción , Piridinas/farmacocinética , Piridinas/farmacología , Solubilidad , Solventes , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Orina/química , AguaRESUMEN
Traditional thinking has been that hexacoordinate Fe(III) ligands are more effective at preventing iron's interactions with reactive oxygen species, most particularly the Fe(II)-mediated reduction of hydrogen peroxide to the hydroxyl radical (i.e., Fenton chemistry), than are ligands of lower denticity. Thus, a hexacoordinate derivative of the well-characterized tricoordinate ligand (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid [4'-(HO)-DADMDFT], (S,S)-1,11-bis[5-(4-carboxy-4,5-dihydrothiazol-2-yl)-2,4-dihydroxyphenyl]-4,8-dioxaundecane, was designed with the aid of a molecular modeling program and synthesized. Evaluations both in vitro and in vivo were carried out to determine whether there is any advantage, at the level of prevention of Fenton chemistry, radical trapping, or iron clearance, to constructing a desferrithiocin-based hexacoordinate analogue. The hexacoordinate analogue was more effective at preventing the iron-mediated oxidation of ascorbate at low ligand/metal ratios than was its tricoordinate parent and can function as an excellent radical scavenger. At equivalent iron binding doses in the bile duct cannulated rodent, oral administration of the tricoordinate ligand was 3-fold more effective than was po administration of the hexacoordinate derivative. However, sc administration of the hexacoordinate derivative resulted in an efficiency that was 3 times greater than that of the tricoordinate chelator. Unfortunately, the rodent findings were not substantiated in the primates. The hexacoordinate ligand was only about one-half as efficient as its tricoordinate parent when administered sc. Owing to these results, po dosing was not attempted. Thus, there appears to be no overall advantage to coupling two molecules of 4'-(HO)-DADMDFT to afford a hexacoordinate derivative.
Asunto(s)
Dihidropiridinas/química , Quelantes del Hierro/química , Resorcinoles/química , Tiazoles/química , Animales , Ácido Ascórbico/química , Bilis/química , Cebus , Dihidropiridinas/síntesis química , Heces/química , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Hierro/metabolismo , Hierro/orina , Quelantes del Hierro/síntesis química , Quelantes del Hierro/farmacología , Ligandos , Oxidación-Reducción , Resorcinoles/síntesis química , Resorcinoles/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
Desferrithiocin, a natural product iron chelator (siderophore), offers an excellent platform from which to construct orally active iron chelators which have a good therapeutic window. A systematic structure-activity study on desferrithiocin identified the structural fragments necessary for the compound's oral iron-clearing activity. There are strict requirements regarding the distance between the ligating centers; they cannot be altered without loss of efficacy. The thiazoline ring must remain intact. Benz-fusions, which were designed to improve the ligands' tissue residence time and possibly iron-clearing efficiency, are ineffective. The maintenance of an (S)-configured C-4 carbon is optimal in the design of desferrithiocin-based iron chelators. With this information in hand, alteration of the redox potential of the aromatic ring was initiated. Introduction of a hydroxy in the 4'-position of at least three different desazadesferrithiocin analogues resulted in moderate to small changes in iron clearing efficacy yet dramatic reductions in the toxicity of the compounds were observed. Although the toxicity studies of these desferrithiocin analogues are continuing, it is clear that it is possible to alter a siderophore in such a way as to ameliorate its toxicity profile while maintaining its iron-clearing properties.