RESUMEN
A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.
Asunto(s)
Antineoplásicos/síntesis química , Espermina/análogos & derivados , Espermina/síntesis química , Acetiltransferasas/metabolismo , Adenosilmetionina Descarboxilasa/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Concentración 50 Inhibidora , Leucemia L1210 , Ratones , Ornitina Descarboxilasa/metabolismo , Espermina/química , Espermina/farmacología , Relación Estructura-Actividad , Pruebas de Toxicidad Aguda , Células Tumorales CultivadasRESUMEN
The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.
Asunto(s)
Antidiarreicos/síntesis química , Ciclohexilaminas/síntesis química , Espermina/análogos & derivados , Espermina/síntesis química , Administración Oral , Animales , Antidiarreicos/química , Antidiarreicos/farmacología , Antidiarreicos/toxicidad , Aceite de Ricino , Ciclohexilaminas/química , Ciclohexilaminas/farmacología , Ciclohexilaminas/toxicidad , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Perros , Femenino , Dosificación Letal Mediana , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratas , Ratas Sprague-Dawley , Espermina/química , Espermina/farmacología , Relación Estructura-Actividad , Distribución Tisular , Pruebas de Toxicidad AgudaRESUMEN
The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the benz-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.
Asunto(s)
Dihidropiridinas/síntesis química , Quelantes del Hierro/síntesis química , Tiazoles/síntesis química , Animales , Cebus , Dihidropiridinas/farmacología , Hierro/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacologíaRESUMEN
The (S)-desferrithiocin (DFT) skeleton is shown to be a useful pharmacophore on which to design orally effective iron chelators. While the study clearly indicates that formal reduction of the desazadesmethyldesferrithiocin thiazoline to a thiazolidine (6), expansion of the desmethyldesferrithiocin thiazoline to a thiazine (7), or substitution of the thiazoline sulfur of of desazedes-methyldesferrithiocin by an oxygen (8 and 9) lead to a substantial loss of activity, conversion of (S)-desmethyldesferrithiocin (1) to an N-methylhydroxamate (4) or to the hexacoordinate dihydroxamate ligand (5) results in active compounds. This investigation thus demonstrates which structural components of the siderophore are required for iron clearance after oral administration and suggests the use of the desferrithiocin platform as a vector for other chelators.