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

Greene, T. F.; Wang, Shu; Greene, Lisa M.; Nathwani, Seema M.; Pollock, Jade K.; Malebari, Azizah M.; McCabe, Thomas; Twamley, Brendan; O’Boyle, Niamh M.; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.1021/acs.jmedchem.5b01086

Cited by 57 publications

(28 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, suitably substituted hydroxyl β -lactam has been used in the semisynthesis of a side chain bridged paclitaxel 18 . Importantly, some β -lactam analogues were shown to cause apoptosis in cancer cells through induction of microtubule disorganization and mitotic catastrophe 19 , 20 . Hence, in this study, β -lactam was chosen as a basic skeleton to develop new antitumor agents.…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Liu

et al. 2017

Sci Rep

View full text Add to dashboard Cite

We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

show abstract

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Liu

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Their importance is no longer exclusive due to the extensive clinical use of the b-lactam antibiotics but also because of their potential as intermediates in the synthesis of other types of compounds of biological interest. The antitumour properties of b-lactams have previously been reported 32,[34][35][36] together with inhibitory activity against serine proteases such as prostate-specific antigen (PSA) 37 , and other serine proteases such as tryptase 38 and human leukocyte elastase (HLE) 39 .…”

mentioning

confidence: 99%

Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells

Carr

Knox

Lloyd

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although CA-4P targeting the colchicine binding site was designated with orphan drug status for the treatment of anaplastic thyroid cancer and ovarian cancer by the FDA [ 29 ], two major problems are still encountered during its use as therapeutics: (1) the isomerization to the inactive trans configuration during storage by heat and light [ 30 ]; (2) the undesirable side effects and potent toxicity against normal cells [ 31 ]. Compared to CA-4P , there is no isomerized double bond in compound 11f .…”

Section: Discussionmentioning

confidence: 99%

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors

Liu

Zhao

et al. 2017

Molecules

View full text Add to dashboard Cite

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 μM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 μM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.

show abstract

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

Abstract: Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated leading to the discovery of a number of potent antiproliferative compounds, includingtrans -4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl) 3

Cited by 57 publications

References 49 publications

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors

Contact Info

Product

Resources

About