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Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones.

Abstract：

:A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC(50) values of 7 nM and 10nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC(50)=1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

O'Boyle NM,Greene LM,Bergin O,Fichet JB,McCabe T,Lloyd DG,Zisterer DM,Meegan MJ

doi

10.1016/j.bmc.2011.02.022

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

2306-25

issue

7

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(11)00130-1

journal_volume

19

pub_type

杂志文章

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