Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F Magnetic Resonance ex vivo

Bartusik, Dorota; Tomanek, Bogusław; Lattová, Erika; Perreault, Hélène; Tuszyński, Jack A.; Fallone, B. G.

doi:10.1016/j.bioorg.2009.10.002

Cited by 15 publications

(9 citation statements)

References 18 publications

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“…Ring B appears to be responsible for the irreversible nature of colchicine binding to tubulin, although it may also contribute to its toxic effects [ 11 , 17 ]. Therefore, currently much interest has focused on structural modification of 1 in the hope of improving its anticancer activity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Majcher

Klejborowska

Moshari

et al. 2018

Cells

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Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

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Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Majcher

Klejborowska

Moshari

et al. 2018

Cells

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“…Additionally, diverse structure-activity relationship studies have been performed to elucidate the structural features required for tubulin binding. Substitution of methoxyl group in the C-10 position by a thiomethyl group increases molecular stability and thiocolchicine binds to tubulin more rapidly than colchicine itself [ 16 , 17 , 18 , 19 , 20 , 21 ]. In 2011 Hiromitsu Takayama’s research group [ 22 ] published results of their studies on C-4 halogen substituted colchicine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents

Majcher

Klejborowska

Kaik

et al. 2018

Cells

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Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.

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“…Cell viability was determined from the loss of 19 F signal to determine the efficacy of the different emulsions . Similar approaches have been used to investigate the effect of thiocolchicine derivatives in T‐lymphoblastoid cells and the effect of delta‐tocopherol on MCF7 cells . While cell perfusion 19 F MRS studies are limited, multiple in vivo applications have been described to study drug pharmacokinetics and metabolism using fluorinated compounds …”

Section: Insights Into Intact Cancer Cell Metabolism Using Cell Perfumentioning

confidence: 99%

MRI and MRS of intact perfused cancer cell metabolism, invasion, and stromal cell interactions

et al. 2019

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Because of the spatial and temporal heterogeneities of cancers, technologies to investigate cancer cells and the consequences of their interactions with abnormal physiological environments, such as hypoxia and acidic extracellular pH, with stromal cells, and with the extracellular matrix, under controlled conditions, are valuable to gain insights into the functioning of cancers. These insights can lead to an understanding of why cancers invade and metastasize, and identify effective treatment strategies. Here we have provided an overview of the applications of MRI/MRS/ MRSI to investigate intact perfused cancer cells, their metabolism and invasion, and their interactions with stromal cells and the extracellular matrix. KEYWORDS hypoxia, intact cancer cells, invasion, metabolism, perfusion, stromal cells | INTRODUCTIONCancers are complex systems with spatial and temporal heterogeneities of physiological environments, types and distribution of stromal and immune cells, and extracellular matrix (ECM) structure and composition. Understanding the response of cancer cells to environmental stimuli such as hypoxia and acidic extracellular pH that are frequently observed in tumors, and identifying the role of interactions of cancer cells with stromal and immune cells in promoting aggressive phenotypic characteristics are difficult in vivo, because of these complexities of cancers and their microenvironments. Yet these insights are critical to designing effective treatments for cancer, an achievement that still remains beyond our grasp. In efforts to "deconstruct" the tumor and its environments, cell perfusion systems that allow the interrogation of intact multilayered cells or spheroids under carefully controlled conditions are valuable.Perfusion systems or bioreactors provide a biologically compatible environment to allow cell or organ growth under controlled conditions that can be used in applications for tissue engineering, drug discovery, cell expansion, and hybridoma-based antibody production. 1-3 Applications of noninvasive imaging to such systems could provide temporal and spatial information, but these have been relatively limited because, other than microscopy, the configurations of most imaging systems are not easily adapted to the requirements of cell perfusion. Vertical bore high-field

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Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F Magnetic Resonance ex vivo

Cited by 15 publications

References 18 publications

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents

MRI and MRS of intact perfused cancer cell metabolism, invasion, and stromal cell interactions

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