HSB-13

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-- J.R.R. Tolkien The Children of Hurin
- HSB-13 -

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Observations:

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

New Compound Could Protect Brain Cells, Fight Neurodegenerative Diseases
December 8, 2010 10:09 AM
Tiffany Kaiser
"Additional research needs to be done, but these compounds have the potential for stopping or slowing the relentless loss of brain cells in diseases such as Alzheimer's and Parkinson's," said D'Mello. "The protective effect that they display in tissue culture and animal models of neurodegenerative disease provides strong evidence of their promise as drugs to treat neurodegenerative disorders."
http://www.dailytech.com/New+Compound+Could+Protect+Brain+Cells+Fight+Neurodegenerative+Diseases/article20345c.htm

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

Identification of 1,4-Benzoxazin-3-ones in Maize Extracts by Gas-Liquid Chromatography and Mass Spectrometry
Plant Physiol. (1979) 63, 9-13

ABSTRACT
Gas-liquid chromatography-mass spectrometry (GLC-MS) has been used for the separation, detection, and identification of 1,4-benzoxazin-3-ones (hydroxamic acids and lactams) and benzoxazolinones found in maize (Zea mays L.) extracts. Compounds of interest were partitioned into ethyl acetate from aqueous maize seedling extracts. For analysis by GLC-MS, trimethylsilyl derivatives were prepared, chromatographed on a column of 3% OV-1, and detected in the mass spectrometer. Mass spectra were obtained for all peaks present in extracts of four maize lnes. A data comparison system was developed for relating unidentified spectra to the spectra of the reference compounds. Based on spectral comparisons, three hydroxamic acids (2,4-dihydroxy-2H-1, 4-benzoxazin-3(4H)-one; 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one; and 2,4-dihydroxy-7,8-dimethoxy-2H-1,4-benzoxazin-3(4H)-one), three lactams (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one; 2,7-ihydroxy-2H-I,4-benzoxazin-3(4H)-one; and 2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), one benzoxazolinone (6-methoxybenzoxazolinone), and two organic acids (malic and aconitic) were identified in the extracts. In addition, one other hydroxamic acid and one other related compound were tentatively identified based on mass spectral evidence.
http://www.plantphysiol.org/cgi/reprint/63/1/9.pdf
http://www.ncbi.nlm.nih.gov/pubmed/16660700

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