期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 48, 期 20, 页码 6409-6422出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm0502034
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资金
- NIGMS NIH HHS [GM23200] Funding Source: Medline
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 mu M compared to 4.16 mu M for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 mu M. Also, 60 provided significant protection against y-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.
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