Publications by authors named "Greta Klejborowska"

12 Publications

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Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives.

Bioorg Med Chem 2021 02 11;32:116014. Epub 2021 Jan 11.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong β-tubulin binding energies, lower than -8.70 kcal/mol, while the binding energy calculated for colchicine is -8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
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http://dx.doi.org/10.1016/j.bmc.2021.116014DOI Listing
February 2021

Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand.

Front Chem 2020 21;8:108. Epub 2020 Feb 21.

PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy.

The cardinal role of microtubules in cell mitosis makes them interesting drug targets for many pharmacological treatments, including those against cancer. Moreover, different expression patterns between cell types for several tubulin isotypes represent a great opportunity to improve the selectivity and specificity of the employed drugs and to design novel compounds with higher activity only on cells of interest. In this context, tubulin isotype βIII represents an excellent target for anti-tumoral therapies since it is overexpressed in most cancer cells and correlated with drug resistance. Colchicine is a well-known antimitotic agent, which is able to bind the tubulin dimer and to halt the mitotic process. However, it shows high toxicity also on normal cells and it is not specific for isotype βIII. In this context, the search for colchicine derivatives is a matter of great importance in cancer research. In this study, homology modeling techniques, molecular docking, and molecular dynamics simulations have been employed to characterize the interaction between 55 new promising colchicine derivatives and tubulin isotype βIII. These compounds were screened and ranked based on their binding affinity and conformational stability in the colchicine binding site of tubulin βIII. Results from this study point the attention on an amide of 4-chlorine thiocolchicine. This colchicine-derivative is characterized by a unique mode of interaction with tubulin, compared to all other compounds considered, which is primarily characterized by the involvement of the α-T5 loop, a key player in the colchicine binding site. Information provided by the present study may be particularly important in the rational design of colchicine-derivatives targeting drug resistant cancer phenotypes.
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http://dx.doi.org/10.3389/fchem.2020.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047339PMC
February 2020

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study.

J Biochem Mol Toxicol 2020 Jun 5;34(6):e22487. Epub 2020 Mar 5.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC  = 8.6 nM) towards primary ALL cells in cell viability assays (IC range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC range of 0.1 to 10.3 nM) or MC (IC range of 2.3-9.1 nM) compared to COL (IC of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.
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http://dx.doi.org/10.1002/jbt.22487DOI Listing
June 2020

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

Bioorg Chem 2020 04 13;97:103664. Epub 2020 Feb 13.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
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http://dx.doi.org/10.1016/j.bioorg.2020.103664DOI Listing
April 2020

Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents.

Bioorg Med Chem 2019 12 8;27(23):115144. Epub 2019 Oct 8.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5-9 against primary ALL-5 (IC = 5.3-14 nM), 5, 7-9 against A549 (IC = 10 nM), 5, 7-9 against MCF-7 (IC = 11 nM), 5-9 against LoVo (IC = 7-12 nM), and 5, 7-9 against LoVo/DX (IC = 48-87 nM). These IC values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.
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http://dx.doi.org/10.1016/j.bmc.2019.115144DOI Listing
December 2019

Synthesis, antiproliferative activity, and molecular docking studies of 4-chlorothiocolchicine analogues.

Chem Biol Drug Des 2020 01 20;95(1):182-191. Epub 2019 Sep 20.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland.

Colchicine is a therapeutic agent currently used in therapies of many diseases. It also shows antimitotic effects, and its high cytotoxic activity against different cancer cell lines has been demonstrated many times. To overcome the limitations of colchicine use in anticancer therapy, we synthesized a series of novel triple-modified 4-chloro-7-carbamatethiocolchicines. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. Additionally, their mode of binding to β-tubulin was evaluated in silico. The majority of triple-modified colchicine derivatives exhibited significantly higher cytotoxicity than colchicine, doxorubicin, and cisplatin against tested cancerous cell lines with much higher selectivity index values for four of them.
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http://dx.doi.org/10.1111/cbdd.13618DOI Listing
January 2020

Antiproliferative activity of ester derivatives of monensin A at the C-1 and C-26 positions.

Chem Biol Drug Des 2019 10 21;94(4):1859-1864. Epub 2019 Jul 21.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland.

Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity, including anticancer activity. A series of structurally diverse monensin esters including its C-1 esters (1-9), C-26-O-acetylated derivatives (10-15), and lactone (16) was synthesized and for the first time evaluated for their antiproliferative activity against four human cancer cell lines with different drug-sensitivity level. All of the MON derivatives exhibited in vitro antiproliferative activity against cancer cells at micromolar concentrations. The majority of the compounds was able to overcome the drug resistance of LoVo/DX and MES-SA/DX5 cell lines. The most active compounds proved to be MON C-26-O-acetylated derivatives (10-15) which exhibited very good resistance index and high selectivity index.
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http://dx.doi.org/10.1111/cbdd.13581DOI Listing
October 2019

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

Cells 2018 Nov 19;7(11). Epub 2018 Nov 19.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.

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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http://dx.doi.org/10.3390/cells7110216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262455PMC
November 2018

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

Cells 2018 Nov 1;7(11). Epub 2018 Nov 1.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.

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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http://dx.doi.org/10.3390/cells7110192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262536PMC
November 2018

One-pot synthesis and antiproliferative activity of novel double-modified derivatives of the polyether ionophore monensin A.

Chem Biol Drug Des 2018 08 18;92(2):1537-1546. Epub 2018 May 18.

Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland.

Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity. New MON derivatives such as double-modified ester-carbonates and double-modified amide-carbonates were obtained by a new and efficient one-pot synthesis with triphosgene as the activating reagent and the respective alcohol or amine. All new derivatives were tested for their antiproliferative activity against two drug-sensitive (MES-SA, LoVo) and two drug-resistant (MES-SA/DX5, LoVo/DX) cancer cell lines, and were also studied for their antimicrobial activity against different Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. For the first time, the activity of MON and its derivatives against MES-SA and MES-SA/DX5 were evaluated.
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http://dx.doi.org/10.1111/cbdd.13320DOI Listing
August 2018

Anti-proliferative activity of Monensin and its tertiary amide derivatives.

Bioorg Med Chem Lett 2015 Oct 28;25(20):4539-43. Epub 2015 Aug 28.

Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.

New tertiary amide derivatives of polyether ionophore Monensin A (MON) were synthesised and their anti-proliferative activity against cancer cell lines was studied. Very high activity (IC50=0.09 μM) and selectivity (SI=232) of MON against human biphenotypic myelomonocytic leukemia cell line (MV4-11) was demonstrated. The MON derivatives obtained exhibit interesting anti-proliferative activity, high selectivity index and also are able to break the drug-resistance of cancer cell line.
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http://dx.doi.org/10.1016/j.bmcl.2015.08.067DOI Listing
October 2015

Synthesis and Antiproliferative Activity of Silybin Conjugates with Salinomycin and Monensin.

Chem Biol Drug Des 2015 Dec 22;86(6):1378-86. Epub 2015 Jul 22.

Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznań, Poland.

Aiming at development of multitarget drugs for the anticancer treatment, new silybin (SIL) conjugates with salinomycin (SAL) and monensin (MON) were synthesized, in mild esterification conditions, and their antiproliferative activity was studied. The conjugates obtained exhibit anticancer activity against HepG2, LoVo and LoVo/DX cancer cell lines. Moreover, MON-SIL conjugate exhibits higher anticancer potential and better selectivity than the corresponding SAL-SIL conjugate.
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http://dx.doi.org/10.1111/cbdd.12602DOI Listing
December 2015
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