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.

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

“…The C-ring at the 3-position of the β-lactam is observed to fill the pocket of tubulin more optimally than in the case of colchicine. This binding orientation differs from that previously observed for a related series of β-lactams, where the aryl ring at the C4-position of the β-lactam filled the space occupied by the C-ring of colchicine [15,16].…”

“…Reported heterocyclic CA-4 analogues include imidazole 8,[9] tetrazole 9 [10] and benzoxepin 10 [11] (Figure 2). The azetidin-2-one (β-lactam) ring [12] is an alternative scaffold for potent non-isomerisable combretastatin analogues (11 -13, Figure 2) [13][14][15][16]. Having previously investigated comprehensive structure-activity relationships of these series with a phenyl-substituted ring at the 3-position of the azetidinone ring, it was of importance to extend the SAR by investigating a range of aryl substituents at the 4-position.…”

Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents

“…The appropriately substituted benzaldehyde (10 mmol) and substituted aniline (10 mmol) were refluxed together in ethanol (50 mL 25 were prepared and characterised as described previously by us. 54.9, 55.7, 60.6, 97.7, 111.3, 117.9, 121.8, 129.3, 135.9, 137.0, 147.4, 153 55.4, 55.6, 60.5, 97.6, 101.2, 106.3, 107.8, 125.3, 130.5, 135.7, 147.5, 148.0, 150.1, 153.4, 158.4 55.7, 60.6, 97.7, 125.5, 129.7, 130.5, 131.6, 132.0, 147.9, 153 55.4, 55.6, 60.5, 97.7, 112.3, 114.7, 125.8, 129.2, 135.9, 147.2, 149.4, 150.8, 153.3, 157 4, 114.3, 118.5, 129.1, 132.6, 137.2, 139.9, 146.8, 153.7, 157 55.7, 60.6, 97.9, 122.9, 125.1, 129.4, 133.6, 136.7, 137.3, 146 55.9, 57.2, 98.1, 122.6, 127.4, 128.4, 129.9, 133.3, 135.4, 151.5, 161 55.6, 55.6, 60.6, 97.7, 108.0, 113.9, 124.8, 128.4, 135.6, 146.8, 147.6, 148.7, 153.5, 159 (s, 1H).…”

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

“…The starting 3-substituted-3-hydroxy butanoic acid ethyl esters (2a-c) were prepared via Reformatsky reaction of ethyl bromoacetate with the appropriate ketones 1a-c following previously reported methods [31][32][33] .…”