Herein, ring-cleaved (
24
) and truncated (
25
) analogues of an azasugar, 1-deoxynojirimycin (
23
), exhibited inhibitory activity (
K
i
= 4-10 μM) equal to that of the parent compound (
1
,
K
i
= ...14 μM). Based on this structure-activity relationship (SAR), four ring-cleaved (
26a-26c
and
27c
) and three truncated (
28a-28c
) analogues of salacinol (
1
), a potent thiosugar-ring-containing α-glucosidase inhibitor, were synthesised. Bioassay results revealed that all the synthetics were inactive, indicating that the 5-membered thiosugar ring of
1
played an essential role in the potent activities of sulfonium-type inhibitors. The present findings are interesting and important in understanding the function of salacinol, considering that the observed inhibitory activity trend was contrary to the SAR observed in aza-compounds (
23
,
24
, and
25
) in a previous study, which suggested that the cyclic structure did not contribute to their strong inhibitory activity.
In contrast to previous SAR studies of aza-compounds (
23
vs.
24
and
25
), the present study using analogues (
26a26c
,
27c
, and
28a28c
) of salacinol (
1
) revealed an essential role of the thiosugar ring in effectively inhibiting -glucosidase.
We show that salacinol-type α-glucosidase inhibitors are ligand-compatible with the GH 31 family. Salacinol and its 3′-
O
-benzylated analogs inhibit human lysosomal α-glucosidase at submicromolar ...levels. Simple structure-activity relationship studies reveal that the salacinol side-chain stereochemistry significantly influences binding to GH31 α-glucosidases.
Salacinol-type α-glucosidase inhibitors are ligand-compatible with the GH 31 family. Salacinol and its 3′-
O
-benzylated analogs inhibit human lysosomal α-glucosidase at submicromolar levels.
Propargylations of 1,3-diketones using 3-sulfanyl and 3-selanylpropargyl alcohols 1 in MeNO2–H2O gave alkynyl ketones 2a—m, 2o—v and 6,7-dihydro-5H-cyclohexabpyran-5-ones 3k—n. With some bases, the ...useful propargylated 1,3-diketones underwent intramolecular cyclization to give 6,7-dihydro-5H-benzofuran-4-ones 4a—i or 4,5,6,7-tetrahydrobenzofurans 5p, 6p—v.
To investigate the neurotoxic outcome in the rat retina exposed to nitric oxide (NO) released from an NO donor and to evaluate the effects of neurotrophic factors on the survival of NO-damaged ...retinal cells.
An NO releasing compound, N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine (NOC 12), was intravitreously injected into a rat's right eye. The influences of NOC 12 on retinal neurons and the neuroprotective effects of ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) on NOC 12-mediated damage were estimated by counting cells in the ganglion cell layer (GCL) and by measuring the thickness of retinal layers. The exact count of retinal ganglion cells (RGCs) was also confirmed by means of retrograde labeling with a fluorescent tracer.
Morphometric analyses of retinal damage in the NOC 12-exposed eyes demonstrated a significant and dose-dependent decrease in cell density in the GCL and a reduction in thickness of the inner plexiform layer and inner nuclear layer, but not of the outer nuclear layer. TdT-dUTP terminal nick-end labeling of retinal sections after intravitreous injection of NOC 12 demonstrated that NO could trigger apoptotic cell death. The counting of the RGCs labeled with a fluorescent tracer suggested that a decrease in GCL cell density induced by NOC 12 reflects a loss in RGCs. Treatment with CNTF (1 microg) or BDNF (1 microg) before the intravitreous injection of NOC 12 (400 nmol) demonstrated that these trophic factors have protective effects against NO-induced neuronal cell death in the retina.
Exogenous NO induces retinal neurotoxicity, suggesting that NO plays a pathogenic role in degenerative retinal diseases. BDNF and CNTF protect retinal neurons from NO-mediated neurotoxicity.
Propargylations of 1,3-diketones using 3-sulfanyl and 3-selanylpropargyl alcohols 1 in MeNO2-H2O gave alkynyl ketones 2a--m, 2o--v and 6,7-dihydro-5H-cyclohexabpyran-5-ones 3k--n. With some bases, ...the useful propargylated 1,3-diketones underwent intramolecular cyclization to give 6,7-dihydro-5H-benzofuran-4-ones 4a--i or 4,5,6,7-tetrahydrobenzofurans 5p, 6p--v.
We compared the degree of neurotoxic outcome in the retina exposed to three nitric oxide (NO) donors with different half-life of NO release. Intravitreal injection of NO donors resulted in a ...significant decrease in cell density in the ganglion cell layer and thinning of the inner plexiform layer in a half-life time-dependent manner. Concurrent injection of an NO-trapping reagent with an NO donor abolished NO donor-induced retinal damage. (+)-MK-801 also prevented NO-induced retinal damage, indicating that N-methyl- D -aspartate receptors are partly involved in NO-induced neurodegeneration. These results may be relevant to a pathogenic role of NO – glutamate receptor in several ophthalmic disorders.
The present resonant x-ray scattering has been performed on a monoclinically split single domain of NaV(2)O(5). The observation of a critically enhanced contrast between V(4+) and V(5+) ions has led ...us to the unequivocal conclusion of the charge-order pattern of the low-temperature phase of NaV(2)O(5) below T(c) = 35 K. In spite of the possible four types of configuration of the zigzag-type charge-order patterns in the ab plane (A,A',B and B'), the stacking sequence along the c axis is determined as the AAA'A' type by comparison with model calculations.
Selegiline, a therapeutic agent of Parkinson's disease, and its metabolite, desmethylselegiline, were explored for their neuroprotective effects against
N-methyl-
d-aspartate (NMDA)-induced cell ...death in rat retina. Morphometric analysis of the retina revealed that an intravitreal injection of NMDA induced a significant decrease in cell density in the ganglion cell layer and in thickness of the inner plexiform layer, but not of other retinal layers such as the outer nuclear layer. Concurrent intravitreal injection of selegiline with NMDA did not show a significant protective effect, whereas co-injection of desmethylselegiline provided protection from NMDA-induced retinal damage. Parenteral administration (both single and consecutive dosing) of selegiline significantly prevented loss of ganglion cell layer cells. Counting of retinal ganglion cells by fluorescent tracer labeling confirmed that selegiline protected retinal ganglion cells from NMDA toxicity. The selegiline treatment did not produce a significant increase, though it tended to such as effect, in a brain-derived neurotrophic factor (BDNF) level in the retina, when compared with the NMDA-treated control group. These results indicate that parenteral treatment with selegiline rescues inner retinal cells from NMDA-induced neural damage, and that desmethylselegiline may contribute, in part, to the protective activities of selegiline. The neuroprotective effects exerted by selegiline may be attributed partially to a change in the retinal BDNF expression.
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