Publications by authors named "Ewa Maj"

37 Publications

Synthesis and antiproliferative screening of novel doubly modified colchicines containing urea, thiourea and guanidine moieties.

Bioorg Med Chem Lett 2021 Sep 8;47:128197. Epub 2021 Jun 8.

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

A new series of 10-demethoxy-10-methylaminocolchicines bearing urea, thiourea or aguanidine moieties at position C7 has been designed, synthesized and evaluated for in vitro anticancer activity against different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX). The majority of the new derivatives were active in the nanomolar range and were characterized by lower IC values than cisplatin or doxorubicin. Two ureas (4 and 8) and thioureas (19 and 25) were found to be good antiproliferative agents (low IC values and high SI) and could prove to be promising candidates for further research in the field of anticancer drugs based on the colchicine skeleton.
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http://dx.doi.org/10.1016/j.bmcl.2021.128197DOI Listing
September 2021

Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191.

Int J Mol Sci 2021 02 26;22(5). Epub 2021 Feb 26.

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

Plant polyphenols and vitamins D exhibit chemopreventive and therapeutic anticancer effects. We first evaluated the biological effects of the plant polyphenol resveratrol (RESV) and vitamin D active metabolite PRI-2191 on lung cancer cells having different genetic backgrounds. RESV and PRI-2191 showed divergent responses depending on the genetic profile of cells. Antiproliferative activity of PRI-2191 was noticeable in EGFRmut cells, while RESV showed the highest antiproliferative and caspase-3-inducing activity in KRASmut cells. RESV upregulated p53 expression in wtp53 cells, while downregulated it in mutp53 cells with simultaneous upregulation of p21 expression in both cases. The effect of PRI-2191 on the induction of CYP24A1 expression was enhanced by RESV in two KRASmut cell lines. The effect of RESV combined with PRI-2191 on cytokine production was pronounced and modulated. RESV cooperated with PRI-2191 in regulating the expression of IL-8 in EGFRmut cells, while OPN in KRASmut cells and PD-L1 in both cell subtypes. We hypothesize that the differences in response to RESV and PRI-2191 between EGFRmut and KRASmut cell lines result from the differences in epigenetic modifications since both cell subtypes are associated with the divergent smoking history that can induce epigenetic alterations.
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http://dx.doi.org/10.3390/ijms22052354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956761PMC
February 2021

An insight into the anticancer potential of carbamates and thiocarbamates of 10-demethoxy-10-methylaminocolchicine.

Eur J Med Chem 2021 Apr 10;215:113282. Epub 2021 Feb 10.

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

Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer cell lines. Additionally, their mode of action has been evaluated as colchicine binding site inhibitors, using molecular docking studies. Most of the tested compounds showed greater cytotoxicity (IC in a low nanomolar range) and were characterized by a higher selectivity index than standard chemotherapeutics such as cisplatin and doxorubicin as well as unmodified colchicine. Their pharmacological use in cancer therapy could possibly be accomplished with lower dosages and result in less acute toxicity problems than in the case of colchicine. In addition, we present a QSAR model for predicting the antiproliferative activity of doubly modified derivatives for two tumour cell lines.
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http://dx.doi.org/10.1016/j.ejmech.2021.113282DOI Listing
April 2021

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

Photoinduced Skeletal Rearrangement of -Substituted Colchicine Derivatives.

J Org Chem 2021 Aug 22;86(16):11029-11039. Epub 2020 Dec 22.

Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.

Colchicine is an active pharmaceutical ingredient widely used for treating gout, pericarditis, and familial Mediterranean fever with high antimitotic activity. The photoisomerization of colchicine deactivates its anti-inflammatory and antimitotic properties. However, despite numerous reports on colchicine derivatives, their photostability has not been investigated in detail. This report reveals the effects of UV-induced rearrangement on the structure and reports the biological activity of new -substituted colchicine derivatives.
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http://dx.doi.org/10.1021/acs.joc.0c02507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383305PMC
August 2021

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking.

Molecules 2020 Aug 2;25(15). Epub 2020 Aug 2.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.

Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications at C7 (carbon-nitrogen single bond) and C10 (methylamino group) positions. All the obtained compounds have been tested in vitro to determine their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. The majority of obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin and cisplatin against the tested cancerous cell lines. Additionally, most of the presented derivatives were able to overcome the resistance of LoVo/DX cells. Additionally, their mode of binding to β-tubulin was evaluated Molecular docking studies showed that apart from the initial amides and , compound , which had the best antiproliferative activity (IC = 0.1-1.6 nM), stood out also in terms of its predicted binding energy and probably binds best into the active site of βI-tubulin isotype.
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http://dx.doi.org/10.3390/molecules25153540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435877PMC
August 2020

Synthesis and Anticancer Activity of Dimeric Polyether Ionophores.

Biomolecules 2020 07 12;10(7). Epub 2020 Jul 12.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.

Polyether ionophores represent a group of natural lipid-soluble biomolecules with a broad spectrum of bioactivity, ranging from antibacterial to anticancer activity. Three seem to be particularly interesting in this context, namely lasalocid acid, monensin, and salinomycin, as they are able to selectively target cancer cells of various origin including cancer stem cells. Due to their potent biological activity and abundant availability, some research groups around the world have successfully followed semi-synthetic approaches to generate original derivatives of ionophores. However, a definitely less explored avenue is the synthesis and functional evaluation of their multivalent structures. Thus, in this paper, we describe the synthetic access to a series of original homo- and heterodimers of polyether ionophores, in which (i) two salinomycin molecules are joined through triazole linkers, or (ii) salinomycin is combined with lasalocid acid, monensin, or betulinic acid partners to form 'mixed' dimeric structures. Of note, all 11 products were tested in vitro for their antiproliferative activity against a panel of six cancer cell lines including the doxorubicin resistant colon adenocarcinoma LoVo/DX cell line; five dimers (-, - and ) were identified to be more potent than the reference agents (i.e., both parent compound(s) and commonly used cytostatic drugs) in selective targeting of various types of cancer. Dimers and were also found to effectively overcome the resistance of the LoVo/DX cancer cell line.
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http://dx.doi.org/10.3390/biom10071039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408349PMC
July 2020

Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents.

Molecules 2020 Apr 14;25(8). Epub 2020 Apr 14.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. 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, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.
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http://dx.doi.org/10.3390/molecules25081789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221574PMC
April 2020

Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine.

Molecules 2020 Mar 5;25(5). Epub 2020 Mar 5.

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

Colchicine, a pseudoalkaloid isolated from , has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, ) and 1-demethylthiocolchicine (), a series of 12 colchicine derivatives including 5 novel esters (- and -) and 4 carbonates (- and -) were synthesized. The antiproliferative activity assay, together with evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate , hemihydrate and monohydrate .
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http://dx.doi.org/10.3390/molecules25051180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179419PMC
March 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

Differential response of lung cancer cell lines to vitamin D derivatives depending on EGFR, KRAS, p53 mutation status and VDR polymorphism.

J Steroid Biochem Mol Biol 2019 10 18;193:105431. Epub 2019 Jul 18.

Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wroclaw, Poland.

Vitamin D reveals antiproliferative activity against many types of cancer cells. Calcitriol (1,25D3), the most active form of vitamin D3, acts mainly through the vitamin D receptor, regulating the expression of target genes. Cells with reasonable expression of VDR are considered to be sensitive to antiproliferative activity of 1,25D3. However, a few alleles of the VDR gene are correlated with higher or lower response to 1,25D3 treatment. The goal of our study was to establish if cells differing in EGFR, KRAS, p53 mutation status and VDR polymorphism were sensitive to antiproliferative activity of selected vitamin D derivatives (VDDs). In our search for the lead VDD against human lung cancer cells, we selected, for this study, low calcemic analogs of active forms of vitamin D2 and D3 that had previously shown anticancer potential. The selected cell lines revealed differential response to VDDs. The highest proliferation inhibition was observed for EGFR mutant cells while a weaker response was observed for KRAS and/or p53 mutant cells. 24,24-Dihomo-1,25D3 (PRI-1890) showed the highest activity on the VDD-sensitive cell lines (A549, HCC827, NCI-H1299, and NCI-H1703). Therefore, PRI-1890 was selected as the lead VDD for further structure optimization. None of the VDDs used in this study showed antiproliferative activity against A-427 and Calu-3. VDR polymorphisms correlated inversely with sensitivity to the antiproliferative activity of VDDs since we observed less transcriptionally active form of VDR in HCC827 cells sensitive to VDD, while more transcriptionally active form was observed in NCI-H358 cells that were stimulated by VDDs to proliferate. Lack of KRAS and p53 mutations in HCC827 cells may be, therefore, responsible for the higher antiproliferative activity of VDDs, while the presence of KRAS and/or p53 mutations in other cell lines might prevent antiproliferative activity even though the VDDs were transcriptionally active as assessed on increased CYP24A1 expression. VDR gene polymorphism is not directly responsible for the sensitivity of tested cells to VDDs.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105431DOI Listing
October 2019

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

Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes.

Bioorg Chem 2018 12 12;81:553-566. Epub 2018 Sep 12.

Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. Electronic address:

A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4-14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4-8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC values = 0.009-0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.
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http://dx.doi.org/10.1016/j.bioorg.2018.09.004DOI Listing
December 2018

Biological activity of doubly modified salinomycin analogs - Evaluation in vitro and ex vivo.

Eur J Med Chem 2018 Aug 10;156:510-523. Epub 2018 Jul 10.

Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00, Lund, Sweden. Electronic address:

The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double-modified derivative (3a) in a time-dependent manner. The present findings indicate that double-modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.021DOI Listing
August 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

Vitamin D derivatives potentiate the anticancer and anti-angiogenic activity of tyrosine kinase inhibitors in combination with cytostatic drugs in an A549 non-small cell lung cancer model.

Int J Oncol 2018 Feb 15;52(2):337-366. Epub 2017 Dec 15.

Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland.

Numerous in vitro and in vivo studies have demonstrated that calcitriol [1,25(OH)2D3] and different vitamin D analogs possess antineoplastic activity, regulating proliferation, differentiation and apoptosis, as well as angiogenesis. Vitamin D compounds have been shown to exert synergistic effects when used in combination with different agents used in anticancer therapies in different cancer models. The aim of this study was to evaluate the mechanisms of the cooperation of the vitamin D compounds [1,24(OH)2D3 (PRI‑2191) and 1,25(OH)2D3] with tyrosine kinase inhibitors (imatinib and sunitinib) together with cytostatics (cisplatin and docetaxel) in an A549 non-small cell lung cancer model. The cytotoxic effects of the test compounds used in different combinations were evaluated on A549 lung cancer cells, as well as on human lung microvascular endothelial cells (HLMECs). The effects of such combinations on the cell cycle and cell death were also determined. In addition, changes in the expression of proteins involved in cell cycle regulation, angiogenesis and the action of vitamin D were analyzed. Moreover, the effects of 1,24(OH)2D3 on the anticancer activity of sunitinib and sunitinib in combination with docetaxel were examined in an A549 lung cancer model in vivo. Experiments aiming at evaluating the cytotoxicity of the combinations of the test agents revealed that imatinib and sunitinib together with cisplatin or docetaxel exerted potent anti-proliferative effects in vitro on A549 lung cancer cells and in HLMECs; however, 1,24(OH)2D3 and 1,25(OH)2D3 enhanced the cytotoxic effects only in the endothelial cells. Among the test agents, sunitinib and cisplatin decreased the secretion of vascular endothelial growth factor (VEGF)‑A from the A549 lung cancer cells. The decrease in the VEGF‑A level following incubation with cisplatin correlated with a higher p53 protein expression, while no such correlation was observed following treatment of the A549 cells with sunitinib. Sunitinib together with docetaxel and 1,24(OH)2D3 exhibited a more potent anticancer activity in the A549 lung cancer model compared to double combinations and to treatment with the compounds alone. The observed anticancer activity may be the result of the influence of the test agents on the process of tumor angiogenesis, for example, through the downregulation of VEGF‑A expression in tumor and also on the induction of cell death inside the tumor.
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http://dx.doi.org/10.3892/ijo.2017.4228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741374PMC
February 2018

Antiangiogenic cancer treatment: The great discovery and greater complexity (Review).

Int J Oncol 2016 Nov 26;49(5):1773-1784. Epub 2016 Sep 26.

Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland.

The discovery of tumor angiogenesis opened a new path in fighting cancer. The approval of different antiangiogenic agents, most targeting vascular endothelial growth factor (VEGF) signaling, has either increased the effectiveness of standard chemotherapy or even replaced it by offering better patient outcomes. However, an increasing number of preclinical and clinical observations have shown that the process of angiogenesis is far from clearly understood. Apart from targeting the VEGF pathway, novel strategies aim to influence other molecular factors that are involved in tumor angiogenesis. In addition, naturally occurring compounds seem to offer additional agents for influencing angiogenesis. The first concept of antiangiogenic therapy aimed to destroy tumor vessels, while it turned out that, paradoxically, antiangiogenic drugs normalized vasculature and as a result offered an improvement in chemotherapeutic delivery. In order to design an effective treatment schedule, methods for detecting the time window of normalization and biomarkers predicting patient response are needed. The initial idea that antiangiogenic therapy would be resistance-free failed to materialize and currently we still face the obstacle of resistance to antiangiogenic therapy.
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http://dx.doi.org/10.3892/ijo.2016.3709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063425PMC
November 2016

Differences in Antiproliferative Activity Between Salinomycin-AZT Conjugates Obtained via 'Click' and Esterification Reactions.

Med Chem 2017 ;13(2):127-136

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

Background: Pharmacophore hybridization by bioconjugation, in which two bioactive moieties are covalently linked, is one of the current strategies in drug discovery for the development of new compounds with improved affinity and efficacy relative to those of the parent molecules. Prompted by the idea that cancer cells may be effectively killed by 3'-azido-3'-deoxythymidine (AZT) and salinomycin (SAL) individually, we synthesized hybrids of these compounds. The development of this type of derivatives, which can easily penetrate the lipid-rich cell membranes and then undergo hydrolysis inside the cancer cells, is an important research area.

Methods: Efficient methods for the synthesis of two new conjugates are presented. The first method is based on the 'click' chemistry and involves the copper(I) catalysed 1,3-dipolar Huisgen cycloaddition reaction. In the second method AZT as well as SAL are connected by the ester bond under mild reaction conditions. The in vitro anti-proliferative activity of both conjugates against several drugsensitive and drug-resistant cancer cell lines as well as toxicity against normal murine embryonic fibroblasts are also determined.

Results: Our studies clearly showed that the hybrid obtained via esterification reaction (SAL-OAZT) seems to be attractive in the fight against neoplastic diseases because it helps to overcome a strong drug-resistance of the cancer cell lines examined at low micromolar concentrations. The anticancer activity of this hybrid is also connected with high selectivity indexes (low toxicity) against normal cells.On the other hand, the 'click' conjugate (SAL-AZT) is practically inactive against the drug-resistant cancer cell lines tested and weakly active against the drug-sensitive ones. Also no synergistic effect has been found between SAL and AZT against eight cancer cell lines studied.

Conclusion: All of our findings support a strategy to decrease the doxorubicin concentration in combination with SAL-O-AZT hybrid in order to reduce the toxicity of this drug, as recently demonstrated for SAL. The advantages of the SAL-O-AZT conjugate over SAL are better RI and SI parameters at similar IC50values.
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http://dx.doi.org/10.2174/1573406412666160823165522DOI Listing
August 2017

Controlled levels of canonical Wnt signaling are required for neural crest migration.

Dev Biol 2016 09 21;417(1):77-90. Epub 2016 Jun 21.

Department of Biology, Molecular Embryology, Philipps-Universität Marburg, Karl-von-Frisch-Str. 8, 35043 Marburg, Germany. Electronic address:

Canonical Wnt signaling plays a dominant role in the development of the neural crest (NC), a highly migratory cell population that generates a vast array of cell types. Canonical Wnt signaling is required for NC induction as well as differentiation, however its role in NC migration remains largely unknown. Analyzing nuclear localization of β-catenin as readout for canonical Wnt activity, we detect nuclear β-catenin in premigratory but not migratory Xenopus NC cells suggesting that canonical Wnt activity has to decrease to basal levels to enable NC migration. To define a possible function of canonical Wnt signaling in Xenopus NC migration, canonical Wnt signaling was modulated at different time points after NC induction. This was accomplished using either chemical modulators affecting β-catenin stability or inducible glucocorticoid fusion constructs of Lef/Tcf transcription factors. In vivo analysis of NC migration by whole mount in situ hybridization demonstrates that ectopic activation of canonical Wnt signaling inhibits cranial NC migration. Further, NC transplantation experiments confirm that this effect is tissue-autonomous. In addition, live-cell imaging in combination with biophysical data analysis of explanted NC cells confirms the in vivo findings and demonstrates that modulation of canonical Wnt signaling affects the ability of NC cells to perform single cell migration. Thus, our data support the hypothesis that canonical Wnt signaling needs to be tightly controlled to enable migration of NC cells.
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http://dx.doi.org/10.1016/j.ydbio.2016.06.022DOI Listing
September 2016

Synthesis, antiproliferative activity and molecular docking of Colchicine derivatives.

Bioorg Chem 2016 Feb 12;64:103-12. Epub 2016 Jan 12.

Institut für Medizinische Physik und Biophysik Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany.

In order to create more potent anticancer agents, a series of five structurally different derivatives of Colchicine have been synthesised. These compounds were characterised spectroscopically and structurally and their antiproliferative activity against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX) was evaluated. Additionally the activity of the studied compounds was calculated using computational methods involving molecular docking of the Colchicine derivatives to β-tubulin. The experimental and computational results are in very good agreement indicating that the antimitotic activity of Colchicine derivatives can be readily predicted using computational modeling methods.
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http://dx.doi.org/10.1016/j.bioorg.2016.01.002DOI Listing
February 2016

Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model.

Int J Mol Sci 2015 Nov 13;16(11):27191-207. Epub 2015 Nov 13.

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

In previous papers, we presented data on studies on the anticancer activity of the vitamin D₃ analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins.
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http://dx.doi.org/10.3390/ijms161126016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661874PMC
November 2015

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 new bioconjugates of Salinomycin with amino acid esters.

Bioorg Med Chem Lett 2015 Sep 2;25(17):3511-4. Epub 2015 Jul 2.

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

New Salinomycin (SAL) bioconjugates with amino acid methyl esters were obtained and their antiproliferative activity against cancer cell lines including drug-resistant ones was studied. New compounds exhibit antiproliferative activity towards leukemia and doxorubicin-resistant colon adenocarcinoma cell line and are more effective and less toxic than the commonly currently used anticancer drugs.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.086DOI Listing
September 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

Synthesis and biological activity of salinomycin conjugates with floxuridine.

Eur J Med Chem 2015 Mar 27;93:33-41. Epub 2015 Jan 27.

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

As part of our program to develop anticancer agents, we have synthesized new compounds, which are conjugates between well-known anticancer drug, floxuridine and salinomycin which is able to selectivity kill cancer stem cells. The conjugates were obtained in two ways i.e. by copper(I) catalysed click Huisgen cycloaddition reaction performed between 3'-azido-2',3'-dideoxy-5-fluorouridine and salinomycin propargyl amide, and by the ester synthesis starting from salinomycin and floxuridine under mild condition. The compounds obtained were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity against seven human cancer cell lines as well as antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). The conjugate obtained by esterification reaction showed a significantly higher antiproliferative activity against the drug-resistant cancer cells and lower toxicity than those of salinomycin and floxuridine towards normal cells, as well as standard anticancer drugs, such as cisplatin and doxorubicin. The conjugate compound revealed also moderate activity against MRSA and MRSE bacterial strains. Very high activity of floxuridine and 5-fluorouracil against MRSA and MRSE has been also observed.
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http://dx.doi.org/10.1016/j.ejmech.2015.01.045DOI Listing
March 2015

Synthesis, antiproliferative and antibacterial evaluation of C-ring modified colchicine analogues.

Eur J Med Chem 2015 Jan 22;90:296-301. Epub 2014 Nov 22.

Institut für Medizinische Physik und Biophysik Charité, Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany.

A series of 10 amine derivatives of colchicine have been obtained with high yields by modification at C(10)-OCH3 position of C-ring and characterized by spectroscopic methods. In vitro cytotoxicity has been evaluated against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX), as well as antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). From among the compounds tested the most active is colchicine derivative 2h with bis(2-methoxyethyl)amine substituent which is active in nanomolar to submicromolar concentrations and is several times more cytotoxic than cisplatin and doxorubicin. This compound is also effective against the methicillin-resistant Staphylococci strains.
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http://dx.doi.org/10.1016/j.ejmech.2014.11.037DOI Listing
January 2015
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