RESUMEN

The number of Open Access (OA) research articles is trending upward. This research aims to understand the correlations between different OA types and the impact of OA research articles evaluated based on the citation numbers. To avoid bias caused by the publication year, we chose to use COVID-19 studies in different fields to take advantage of this topic's quick turnaround of data. We analyzed the bibliometrics data and citation numbers (excluding self-citations) of around 42,000 English language articles published in 2020 related to COVID-19. We evaluated different types of OA categories such as Gold, Bronze, and Hybrid articles separately. Results show that amongst all OA categories, Hybrid/Green and Bronze/Green OA articles had significant citation advantages. Green OA articles returned more citations than articles with the other OA status. Gold OA articles have no citation advantages compared to non-OA articles. Gold/Green OA articles had the highest self-citation rates, followed by Non-OA articles. The results of the study can be used in understanding different OA categories and the reasons for OA choices. Certain strategies can be made accordingly to improve the awareness of OA in different fields and help OA publishers to improve the OA services.

RESUMEN

The COVID-19 pandemic created a global health crisis that impacted the supply of personal protective equipment and created a shortage of much-needed face shields and masks for essential workers. During this time, a community of manufacturers, academic institutes, and hobbyists came together and tried to address the supply shortage by providing 3D-printed face shields and masks. Although the Secretary of U.S. Department of Human and Health Services and the Food and Drug Administration relaxed some of the liability and product regulations regarding 3D-printed medical supplies during the pandemic, the safety of 3D-printed face shields and masks is still a concern. In this Review, we have highlighted some of the safety concerns related to printing materials, design consideration, waste generation and disposal, intellectual property and manufacturing regulations, and the sanitization of 3D-printed personal protective equipment.

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-Actividad

RESUMEN

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/química

RESUMEN

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/toxicidad

RESUMEN

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/química

RESUMEN

The synthesis of the Rhodococcus erythropolis siderophores heterobactins A and B, and the structurally related Nocardia heterobactin, is described. Two approaches for the assembly of these asymmetric ligand donor chelators are explored. In the first approach, a scheme predicated on the biosynthesis of the Paracoccus denitrificans siderophore, parabactin, is employed. In this approach, the central donor synthon is added last. In the second scheme, the central donor and the terminal 2,3-dihydroxybenzoyl fragment are first fixed to the ligand's D-ornithine backbone. This is followed by condensation with the cyclic ornithine hydroxamate glycine segment. The schemes offer a flexible approach to other heterobactins. Job's plots suggest that heterobactin A and Nocardia heterobactin form 1:1 ligand/metal complexes, while heterobactin B forms a 3:2 ligand/metal complex.

RESUMEN

Extracts from the root bark of Calotropis gigantea were subjected to bioactivity-guided fractionation using growth inhibitory effects against Entamoeba histolytica. The n-hexane soluble portion of the chloroform extract showed in vitro antiamoebic activity against the HK-9 strain of Entamoeba histolytica. Chromatographic separation of the chloroform extract afforded the known compound, procesterol, which showed activity against E. histolytica.

Asunto(s)

Calotropis/química , Entamoeba histolytica/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Esteroides/farmacología , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacología , Estructura Molecular , Corteza de la Planta/química , Raíces de Plantas/química , Esteroides/química

RESUMEN

(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/química

RESUMEN

Iron chelators have been shown to control the growth of cancer cells in culture by sequestering exogenous iron in the media. Thus, the ligands prevent cellular access to the metal. However, because transferrin provides iron to tumor cells in animals, chelators have not been effective antitumor agents. Polyamine chelator conjugates in which the polyamine vectored ligands into cells were far more active than the free chelators themselves. However, the free ligands were not released from the vector once in the cell. The current study focuses on the synthesis and preliminary evaluation of a polyamine chelator conjugate capable of releasing the free ligand intracellularly via a nonspecific esterase.

RESUMEN

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/química

Asunto(s)

Amebicidas/química , Amebicidas/farmacología , Amebiasis/tratamiento farmacológico , Amebicidas/síntesis química , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/aislamiento & purificación , Humanos , Hidrocarburos/síntesis química , Hidrocarburos/química , Hidrocarburos/aislamiento & purificación , Metales/química , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/aislamiento & purificación

RESUMEN

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/química

RESUMEN

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/química

RESUMEN

The impact of introducing a 3,6,9-trioxadecyloxyl group at various positions of the desazadesferrithiocin (DADFT) aromatic ring on iron clearance and organ distribution is described. Three DADFT polyethers are evaluated: (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE, 3], (S)-4,5-dihydro-2-[2-hydroxy-5-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-5'-(HO)-DADFT-PE, 6], and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE, 9]. The iron-clearing efficiency (ICE) in rodents and primates is shown to be very sensitive to which positional isomer is evaluated, as is the organ distribution in rodents. The polyethers had uniformly higher ICEs than their corresponding parent ligands in rodents, consistent with in vivo ligand-serum albumin binding studies. Ligand 9 is the most active polyether analogue in rodents and is also very effective in primates, suggesting a higher index of success in humans. In addition, this analogue is also shown to clear more iron in the urine of the primates than many of the other chelators. If this trend were also observed in patients, it would facilitate iron-balance studies in a clinical setting.

Asunto(s)

Dihidropiridinas/farmacocinética , Hierro/farmacocinética , Tiazoles/farmacocinética , Animales , Cebus , Dihidropiridinas/química , Quelantes del Hierro/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Tiazoles/química , Distribución Tisular

RESUMEN

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 Tisular

RESUMEN

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-Actividad

RESUMEN

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/farmacocinética

RESUMEN

Reaction between [Pd(DMSO)(2)Cl(2)] (DMSO=dimethylsulfoxide) and N(4)-substituted thiosemicarbazones derived from 5-nitrothiophene-2-carboxaldehyde (L) afforded the complexes [Pd(L)Cl(2)]. These new complexes have been characterized by elemental analyses and spectroscopic studies. Spectroscopic studies reveal that thionic sulfur and azomethine nitrogen atom of thiosemicarbazones are coordinated to metal ion. The testing of the anti-amoebic activity of these complexes against the protozoan parasite Entamoeba histolytica suggests that compound 9, 10, and 11 might be endowed with important anti-amoebic properties since they showed less IC(50) values than metronidazole. Moreover, compound 11 displays notable amoebicidal activity than metronidazole (IC(50) values of 0.79 microM vs 1.93 microM, respectively).

Asunto(s)

Aldehídos/química , Amebicidas/síntesis química , Compuestos Organometálicos/síntesis química , Paladio/química , Compuestos de Sulfhidrilo/química , Amebicidas/farmacología , Animales , Entamoeba histolytica/efectos de los fármacos , Concentración 50 Inhibidora , Compuestos Organometálicos/farmacología , Análisis Espectral , Relación Estructura-Actividad , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología

RESUMEN

Synthesis of new Palladium(II) and Ruthenium(II) complexes of the type, [Pd(L)Cl(2)] and [Ru(eta(4)-C(8)H(12))(L)Cl(2)] [where, L = thiosemicarbazones derived from 5-nitrothiophene-2-carboxaldehyde and cycloalkylaminothiocarbonyl hydrazines] have been isolated by the reaction of [Pd(DMSO)(2)Cl(2)] and [Ru(eta(4)-C(8)H(12))(CH(3)CN)(2)Cl(2)] with 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones. The spectral data revealed that the thiosemicarbazones act as bidentate ligands, making use of thionic sulphur and the azomethine nitrogen atom for coordination to the central metal ion. Microdilution method was used for the assessment of antiamoebic activity of all the compounds against HK-9 strain of Entamoeba histolytica. Among all the thiosemicarbazones, 5-NT-4-BPTSCN (3) showed significant antiamoebic activity (IC(50) - 2.56 microM). Enhancement of antiamoebic activity resulted by introducing palladium and ruthenium metals in the thiosemicarbazone moiety. All the Pd(II) and Ru(II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones were found more active then their respective ligands. The complexes 1a-4a, 1b and 3b showed antiamoebic activity.

Asunto(s)

Amebicidas , Compuestos Organometálicos , Paladio/química , Rutenio/química , Tiosemicarbazonas , Amebicidas/síntesis química , Amebicidas/química , Amebicidas/farmacología , Animales , Entamoeba histolytica/efectos de los fármacos , Concentración 50 Inhibidora , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Pruebas de Sensibilidad Parasitaria , Análisis Espectral/métodos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología