RESUMEN
Modification of fumagillin was conducted to develop MetAP-2 inhibitors with desirable pharmacological properties. Replacement of the C4 side chain by benzyloxime preserves the inhibitory activity against MetAP-2 enzyme. Fumagillin analogues containing the C4 benzyloxime moiety were found to be very sensitive to the nature of the C6 substituent on the inhibition activity of HUVEC proliferation. This lack of correlation between MetAP-2 and HUVEC activities might be due to the cellular metabolism of the compounds by epoxide hydrolase, which is present in the cell. Compound (E)-3d, containing ethylpiperazinyl carbamate at C6 position, exhibited antiangiogenic effects similar to TNP-470 on matrigel plug assay and rat corneal micropocket assay.
Asunto(s)
Inhibidores de la Angiogénesis/antagonistas & inhibidores , Ácidos Grasos Insaturados/química , Sesquiterpenos/química , Inhibidores de la Angiogénesis/metabolismo , Animales , Línea Celular , Ciclohexanos , Ácidos Grasos Insaturados/farmacología , Humanos , Ratones , O-(Cloroacetilcarbamoil) Fumagilol , Ratas , Sesquiterpenos/farmacologíaRESUMEN
A series of fumagillin analogues targeted at understanding tolerability of MetAP2 toward substitution at C4 and C6 were synthesized. Initially, the C6 side chain was maintained as cinnamoyl ester and C4 was modified. It was concluded that replacing the natural C4 of fumagillin with a benzyl oxime at C4 resulted in moderate loss of activity toward binding to MetAP2. Placement of a primary or secondary carbamate at C6 did not improve the potency of compounds toward inhibition of MetAP2. However, the inhibitory activity against MetAP2 was gained back by placing polar groups such as piperazinyl carbamate at C6. Small alkyl substituents on the amine of piperazinyl carbamate were well tolerated.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/farmacología , Inhibidores de la Angiogénesis/química , Ciclohexanos , Ácidos Grasos Insaturados/química , Espectroscopía de Resonancia Magnética , Sesquiterpenos , Relación Estructura-ActividadRESUMEN
Platelet-derived growth factor B-chain (PDGF-B)- and transforming growth factor beta (TGF-beta)-mediated accumulation of extracellular matrix proteins contributes to many progressive renal diseases. In vivo, specific antagonism of either PDGF-B or TGF-beta in experimental mesangioproliferative glomerulonephritis resulted in an almost complete inhibition of matrix protein accumulation, which suggests an interaction between signaling pathways of these two growth factors. Because nothing is known on the nature of this possible interaction, PDGF-B was antagonized in the rat anti-Thy 1.1 model of glomerulonephritis by use of specific aptamers and its effects on the TGF-beta system were investigated. Antagonism of PDGF-B led to a significant reduction of glomerular matrix accumulation compared with scrambled aptamer-treated nephritic controls. PDGF-B antagonism had no effect on the overexpression of glomerular TGF-beta mRNA, TGF-beta protein, or the expression of TGF-beta receptor type I and II mRNA. By immunohistology, it was possible to detect overexpression of the cytoplasmic TGF-beta signaling molecules Smad2 (agonistic) and Smad7 (antagonistic) in glomeruli of nephritic control rats which peaked on day 7 after disease induction, i.e., the peak of mesangial cell proliferation in this model. However, immunohistology and Western blot analysis again revealed no difference in the glomerular expression of both Smad proteins between PDGF-B antagonized and nonantagonized nephritic animals. In addition, no difference in the glomerular expression of phosphorylated Smad2 (P-Smad2) was detected between the differently treated nephritic groups. These observations suggest that the effects of PDGF-B antagonism are independent of TGF-beta in mesangioproliferative glomerulonephritides.