4 research outputs found
A Bioactive Resveratrol Trimer from the Stem Bark of the Sri Lankan Endemic Plant <i>Vateria copallifera</i>
A new resveratrol trimer, vateriferol
(<b>1</b>), having four <i>cis</i>-oriented methine
protons and constituting four contiguous stereocenters, was isolated
from the bark extract of <i>Vateria copallifera</i> by bioassay-guided
fractionation using a combination of normal, reversed phase, and size
exclusion column chromatography. The structure was established based
on its spectroscopic data. Vateriferol (<b>1</b>) was evaluated
in vitro for its antioxidant capacity, enzyme inhibitory activity,
growth inhibitory activity on a number of cancer cell lines, neuroprotective
activity, and anti-inflammatory activity. Vateriferol (<b>1</b>) exhibited AChE inhibitory activity (IC<sub>50</sub> 8.4 ±
0.2 μM), ORAC activity (2079 ± 0.20 TE/g), and neuroprotective
activity at 1.5 μM using PC12 cells deprived of oxygen and glucose
and lowered NO levels in lipopolysaccharide-stimulated SIM-A9 microglial
cells at 14.7 and 73.6 μM. Vateriferol (<b>1</b>) exhibited
weak cytotoxic potency (<50% growth inhibition) against the tested
cell lines at 147.2 μM
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted