HSB-13

[Swarfmaker]

Identification of novel 1,4-benzoxazine compounds that are protective
in tissue culture and in vivo models of neurodegeneration.
J Neurosci Res. 2010 Jul;88(9):1970-84.
Wang L, Ankati H, Akubathini SK, Balderamos M, Storey CA, Patel AV,
Price V, Kretzschmar D, Biehl ER, D'Mello SR.

Department of Molecular and Cell Biology, University of Texas at
Dallas, Richardson, TX, USA.
Abstract

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease, and Huntington's disease and conditions such as ischemic
stroke affect millions of individuals annually and exert an enormous
financial burden on society. A hallmark of these conditions is the
abnormal loss of neurons. Currently, there are no effective strategies
to prevent neuronal death in these pathologies. We report that several
2-arylidine and 2-hetarylidin derivatives of the 1,4-benzoxazines
class of compounds are highly protective in tissue culture models of
neurodegeneration. Results obtained using pharmcalogical inhibitors
indicate that neuroprotection by these compounds does not involve the
Raf-MEK-ERK or PI-3 kinase-Akt signaling pathways nor other survival-
promoting molecules such as protein kinase A (PKA), calcium calmodulin
kinase A (CaMK), and histone deacetylases (HDACs). We tested one of
these compounds, (Z)-6-amino-2-(3',5'-dibromo-4'-
hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one, designated as
HSB-13, in the 3-nitropropionic acid (3-NP)-induced mouse model of
Huntington's disease. HSB-13 reduced striatal degeneration and
improved behavioral performance in mice administered with 3-NP.
Furthermore, HSB-13 was protective in a Drosophila model of amyloid
precursor protein (APP) toxicity. To understand how HSB-13 and other
1,4-benzoxazines protect neurons, we performed kinase profiling
analyses. These analyses showed that HSB-13 inhibits GSK3, p38 MAPK,
and cyclin-dependent kinases (CDKs). In comparison, another compound,
called ASK-2a, that protects cerebellar granule neurons against low-
potassium-induced death inhibits GSK3 and p38 MAPK but not CDKs.
Despite its structural similarity to HSB-13, however, ASK-2a is
incapable of protecting cortical neurons and HT22 cells against
homocysteic acid (HCA)-induced or Abeta toxicity, suggesting that
protection against HCA and Abeta depends on CDK inhibition. Compounds
described in this study represent a novel therapeutic tool in the
treatment of neurodegenerative diseases.

PMID: 20143421 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/20143421


Novel Compounds Show Early Promise in Treatment of Parkinson's,
Huntington's, Alzheimer's

ScienceDaily (Dec. 7, 2010) — Investigators at Southern Methodist
University and The University of Texas at Dallas have discovered a
family of small molecules that shows promise in protecting brain cells
against nerve-degenerative diseases such as Parkinson's, Alzheimer's
and Huntington's, which afflict millions...
http://www.sciencedaily.com/releases/2010/12/101207131737.htm

Of course, one wonders if this chemical is found in any plant or food
product.

[Swarfmaker]

Novel 2-Alkylamino-1,4-benzoxazine Derivatives as Potent
Neuroprotective
Agents: Structure-Activity Relationship Studies
J. Med. Chem. 2005, 48, 1282-1286

Estelle Blattes,† Brian Lockhart,‡ Pierre Lestage,‡ Leslie
Schwendimann,§ Pierre Gressens,§ Maurice-Bernard Fleury,† and Martine
Largeron†,*

UMR 8638 CNRS - Universite´ Rene´ Descartes, Synthe`se et Structure de
Mole´cules d’Inte´reˆt Pharmacologique, Faculte´ des Sciences
Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270
Paris Cedex 06, France, Institut de Recherches Servier, 125 Chemin de
Ronde, 78290 Croissy-sur-Seine, France, and INSERM U 676 and Service
de Neurologie Pe´diatrique, Hoˆpital Robert Debre´, 48 boulevard Se
´rurier, 75019 Paris, France
Received August 25, 2004

2-Alkylamino-substituted-1,4-benzoxazine derivatives, a new class of
potential neuroprotective agents, were synthesized and examined for
their intrinsic cytotoxicity and their capacity to inhibit oxidative
stress-mediated neuronal degeneration in vitro. Through structure-
activity relationship studies, the 3,3-diphenyl-substituted-1,4-
benzoxazine derivative 3l was identified as the optimal candidate,
owing to its potent neuroprotective activity, without the
manifestation of intrinsic cytotoxicity. Accordingly, 3l proved to be
effective in an animal model of excitotoxic lesions in newborn
mice...Oxygen, though essential for aerobic metabolism, can be
converted to toxic metabolites such as superoxide, hydrogen peroxide,
and hydroxyl radicals, collectively known as reactive oxygen species
(ROS). When ROS generation exceeds the capacity of endogenous
enzymatic and nonenzymatic antioxidant defense systems, tissues become
vulnerable to damage, as the result of a widely accepted phenomenon
called oxidative stress.1... Consequently, supplementation with
exogenous antioxidants could represent an important therapeutic
potential to minimize central nervous system damage.4 Hence, there is
considerable interest in the discovery and development of efficient
synthetic antioxidants. In the course of our search for new
neuroprotective agents, we have previously reported the synthesis of
novel 8-alkylamino-substituted-1,4-benzoxazine derivatives 1, as well
as 3-alkylamino-2,4-dihydroxybenzophenones 2 (Chart 1). From their
capacity to inhibit oxidative stress-mediated neuronal degeneration in
vitro, these compounds were found to be potent neuroprotective agents,
with activity close to that of standard R-tocopherol [a form of
vitamin E].5 From the combined results of both intrinsic cytotoxicity
and neuroprotection, substituted 1,4-benzoxazines were identified as
the best candidates for therapeutic potential.
http://www.u676.org/Documents/Blattes-JMedChem-05.pdf
http://www.ncbi.nlm.nih.gov/pubmed/15715499