کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1393111 | 1501182 | 2010 | 15 صفحه PDF | دانلود رایگان |

The synthesis and study of the structure–activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. 12d exerts antimitotic effects through an inhibition of tubulin polymerisation and subsequent G2/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.
Docked pose of β-lactam 12d overlayed with N-deacetyl-N-(2-mercaptoacetyl)colchicine (DAMA-colchicine) in the tubulin binding site.Figure optionsDownload as PowerPoint slide
Journal: European Journal of Medicinal Chemistry - Volume 45, Issue 12, December 2010, Pages 5752–5766