Abstract
The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and gamma-irradiation. To optimize the protective activity of the previously reported pifithrin-alpha (PFT-alpha, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized. The aromatic analogues of 39 were more protective than 39, while the aromatic analogues of 1 were not active. Compound 19 containing a pyrrolidinyl substituent on the phenyl ring provided potent antiapoptotic activity (EC50 of 1.31 microM compared to 4.16 microM for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 microM. Also, 60 provided significant protection against gamma-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Benzothiazoles
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Dexamethasone / pharmacology
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Gamma Rays
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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In Vitro Techniques
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Lymphocytes / cytology
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Lymphocytes / drug effects*
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Lymphocytes / radiation effects
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Mice
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Mice, Inbred C57BL
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Thymus Gland / cytology
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Toluene / analogs & derivatives*
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Toluene / chemical synthesis
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Toluene / chemistry
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Toluene / pharmacology
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Tumor Suppressor Protein p53 / physiology
Substances
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2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-(4-pyrrolidin-1-ylphenyl)ethanone
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2-(4-pyrrolidin-1-ylphenyl)benzo(d)imidazo(2,1-b)thiazole
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Benzimidazoles
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Benzothiazoles
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Imidazoles
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Pyrrolidines
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Thiazoles
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Tumor Suppressor Protein p53
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Toluene
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Dexamethasone
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pifithrin