char = S;code = 83
char = y;code = 121
char = n;code = 110
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = l;code = 108
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char = i;code = 105
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char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
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char = c;code = 99
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = s;code = 115
char = t;code = 116
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char = d;code = 100
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
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char = t;code = 116
char = i;code = 105
char = p;code = 112
char = r;code = 114
char = o;code = 111
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char = i;code = 105
char = f;code = 102
char = e;code = 101
char = r;code = 114
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char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
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char = b;code = 98
char = u;code = 117
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char = i;code = 105
char = n;code = 110
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char = a;code = 97
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char = g;code = 103
char = e;code = 101
char = t;code = 116
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char = n;code = 110
char = g;code = 103
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char = a;code = 97
char = z;code = 122
char = e;code = 101
char = t;code = 116
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char = d;code = 100
char = i;code = 105
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char = 2;code = 50
char = -;code = 45
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = .;code = 46
result sql = Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones.
Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones.
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char = ;code = 32
char = t;code = 116
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char = e;code = 101
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result sql = 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.

Publication: Bioorg. Med. Chem. 2011 Apr 1 ;19(7)::2306-25. :doi: 10.1016/j.bmc.2011.02.022.
Publication Date: 2011 Apr 1
Study Author(s): O'Boyle, Niamh M;Greene, Lisa M;Bergin, Orla;Fichet, Jean-Baptiste;McCabe, Thomas;Lloyd, David G;Zisterer, Daniela M;Meegan, Mary J;
Institution: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland. [email protected]
Shortcut link to this study:
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.
PMID: 21397510

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