Novel cis-restricted β-lactam combretastatin A-4 analogues display anti-vascular and anti-metastatic properties in vitro

Nathwani, Seema-Maria; Hughes, Linda; Greene, Lisa M.; Carr, Miriam; O’Boyle, Niamh M.; McDonnell, Susan; Meegan, Mary J.; Zisterer, Daniela M.

doi:10.3892/or.2012.2181

Cited by 18 publications

(6 citation statements)

References 48 publications

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“…By displacing the ethylene bridge with a 1,4-diaryl-2-azetidinone (β-lactam) ring in the combretastatin structure, cis-trans isomerization was prevented and a group of cis restricted CA-4 derivatives was synthesized by Nathwani et al The effect of synthesized β-lactam compounds on tumor vascularization and its effect on tumor cell migration were investigated. It has been determined that CA-104 and CA-432 β-lactam compounds exhibited their anti-angiogenic effects in MDA-M -231 breast adenocarcinoma cells by decreasing the release of vascular endothelial growth factor [46].…”

Section: Vascular Effectsmentioning

confidence: 99%

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

et al. 2020

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Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

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Section: Vascular Effectsmentioning

confidence: 99%

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

et al. 2020

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“…Small interfering RNA technology demonstrated a role for the RhoA/RhoA-associated kinase signaling pathway in the CA-4-mediated inhibition of T cell migration (Pollock et al, 2014). Other synthetic combretastatatin analogs also demonstrated significant antimetastasis/migration properties (Nathwani et al, 2013;Porcù et al, 2013;Pollock et al, 2014). Importantly, CA-4 demonstrated therapeutic activity in patients with metastatic anaplastic thyroid cancer (Granata et al, 2013).…”

Section: Antimetastasis/migration Agentsmentioning

confidence: 99%

“…As previously discussed, the combretastatins are one of a few groups of anticancer agents that act independently of cancer type and tumor site by targeting the associated vasculature as opposed to the tumor itself and thus bypassing associated problems of resistance due to tumor heterogeneity. However, targeting the tumor vasculature can reduce tumor glucose and oxygen levels Carr et al, 2010;Greene et al, 2010Greene et al, , 2011Greene et al, , 2012Nathwani et al, 2013;O'Boyle et al, 2011 and thus paradoxically create an environment that can trigger prosurvival pathways. In this review, we discuss drug resistance directly and indirectly associated with combretastatin exposure and how they can overcome drug resistance associated with other chemotherapeutics.…”

Section: Cell Survival/resistancementioning

confidence: 99%

Combretastatins: More Than Just Vascular Targeting Agents?

Greene

Meegan

Zisterer

2015

J Pharmacol Exp Ther

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Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs.

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“…These compounds also demonstrated both anti-angiogenic effects in MDA-MB-231 breast adenocarcinoma cells. In addition, we established that these compounds inhibited the migration of MDA-MB-231 cells indicating a potential anti-metastatic function for these compounds [47]. To further our understanding of the antiproliferative activity of these compounds, we wished to investigate the design, synthesis and evaluation of a series of azetidin-2-ones containing a vinyl substituent at C3 of the azetidin-2-one ring, and to explore the effect of this hydrophobic substituent on the biological activity of these compounds in which the cis configuration (Rings A and B) is locked into the azetidin-2-one ring structure.…”

Section: Introductionmentioning

confidence: 99%

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

et al. 2019

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Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

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Novel cis-restricted β-lactam combretastatin A-4 analogues display anti-vascular and anti-metastatic properties in vitro

Cited by 18 publications

References 48 publications

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Combretastatins: More Than Just Vascular Targeting Agents?

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

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