Publications by authors named "Joanna Wietrzyk"

223 Publications

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

Bioorg Med Chem Lett 2021 Jun 8:128197. 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
June 2021

Synthesis and Antiproliferative Activity of Triazoles Based on 2-Azabicycloalkanes.

Materials (Basel) 2021 Apr 18;14(8). Epub 2021 Apr 18.

Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.

A library of 21 novel chiral 1,2,3-triazole-based 2-azabicycloalkane conjugates was designed and synthesized using the copper(I)-catalyzed click reaction. The obtained hybrids were assessed for their antiproliferative potency against three selected human cancer cell lines: Hs294T (melanoma), MIA PaCa-2 (pancreas tumor) and NCI-H1581 (lung tumor). The majority of the synthesized compounds demonstrated moderate to potent activity, and some of them appeared more selective than cisplatin, with selectivity index exceeding 9.
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http://dx.doi.org/10.3390/ma14082039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072719PMC
April 2021

Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models.

Int J Mol Sci 2021 Mar 9;22(5). Epub 2021 Mar 9.

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

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)D analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.
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http://dx.doi.org/10.3390/ijms22052781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967212PMC
March 2021

Effect of the dichloro-substitution on antiproliferative activity of phthalimide-thiazole derivatives. Rational design, synthesis, elastase, caspase 3/7, and EGFR tyrosine kinase activity and molecular modeling study.

Bioorg Chem 2021 May 10;110:104819. Epub 2021 Mar 10.

Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland. Electronic address:

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC values in the range of 5.56-16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC values in the range of 6.69-10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC values about 32 μM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.
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http://dx.doi.org/10.1016/j.bioorg.2021.104819DOI Listing
May 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 Feb 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 of novel phytol-derived γ-butyrolactones and evaluation of their biological activity.

Sci Rep 2021 Feb 19;11(1):4262. Epub 2021 Feb 19.

Central Laboratory of Instrumental Analysis, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland.

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Products were obtained in good yields (19-96%) and their structures were fully characterized by spectroscopic data (NMR, HRMS). Four synthesized δ-halo-γ-lactones (4-7) are new and have not been previously described in the literature. In the choice test phytol (1) appeared deterrent to M. persicae, whereas modifications of its structure did not cause the avoidance of the treated leaves by the aphids. In contrast, aphids were attracted to the leaves treated with the new trans-δ-chloro-γ-lactone (6). Electrical Penetration Graph (EPG) technique applied to explore the aphid probing and feeding activity revealed that neither phytol nor lactone 6 affected aphid probing and the consumption of phloem sap, which means that both phytol and the lactone 6 might have acted as postingestive modifiers of aphid behavior. The results of in vitro antitumor assays showed that obtained phytol derivatives exhibit cytotoxic activity against studied cancer cell lines (leukemia, lung and colon carcinoma and its doxorubicin resistant subline). Halolactones 4-6 were identified as the compounds, which arrest cell cycle of leukemia cells mainly in G2/M and S phases.
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http://dx.doi.org/10.1038/s41598-021-83736-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896091PMC
February 2021

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

Bioorg Med Chem 2021 Feb 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

Synthesis and Anticancer Evaluation of Novel Derivatives of Isoxazolo[4,5-][1,2,4]triazepine Derivatives and Potential Inhibitors of Protein Kinase C.

ACS Omega 2021 Jan 24;6(1):119-134. Epub 2020 Dec 24.

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

In the present study, using Thorpe's reaction with Gewald's modification, 4-acetylamino-5-acetyl or 5-benzoyl 3-carboxamide compounds or were obtained. From these compounds, two series of compounds (, , and and , , and ) were obtained with 98% hydrazine. Compounds , , , and were then reacted with the appropriate aldehydes to afford a series of new isoxazole derivatives (, , and ) and the main compounds, and , were isoxazolo[4,5-][1,2,4]triazepine derivatives. The anticarcinogenic activities of selected compounds were tested on six lines of cancer cells, and their activities were compared with the relevant concentrations of the anticarcinogenic drugs cisplatin and doxorubicin in IITD PAN. Several compounds were tested on 60 lines of cancer cells by the NCI (Bethesda, MD, USA). The cyclization of compound into derivative was also carried out. Compound showed extremely high antitumor activity.
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http://dx.doi.org/10.1021/acsomega.0c03801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807470PMC
January 2021

Photoinduced Skeletal Rearrangement of -Substituted Colchicine Derivatives.

J Org Chem 2020 Dec 22. 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
December 2020

N-Methylated Analogs of hIAPP Fragments 18-22, 23-27, 33-37 Inhibit Aggregation of the Amyloidogenic Core of the Hormone.

Chem Biodivers 2021 Jan 17;18(1):e2000842. Epub 2020 Dec 17.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.

Amylin (hIAPP) aggregation leads to the formation of insoluble deposits and is one of the factors in the development of type II diabetes. The aim of this research was to find N-methylated analogs of the aggregating amylin fragments 18-22, 23-27, and 33-37, which would not themselves be susceptible to aggregation and would inhibit the aggregation of the amyloidogenic cores of the hormone. None of the analogs of fragment 18-22 containing one or two N-methylated amino acid residues showed any tendency to aggregate. Only the peptide H-F(N-Me)GA(N-Me) IL-OH (6) derived from the 23-27 hIAPP hot spot did not form fibrous structures. All analogs of the 33-37 amylin fragment were characterized by the ability to form aggregates, despite the presence of N-methylated amino acids in their structures. N-Methylated peptides 1-5 demonstrated inhibitory properties against the aggregation of fragment 18-22. Aggregation of the amyloidogenic core of 23-27 was significantly inhibited by N-methylated peptides 1-3 derived from the (18-22) H-HSSNN-OH fragment and by the H-F(N-Me)GA(N-Me)IL-OH (6) fragment derived from the 23-27 amylin hot spot. Fragment (33-37) H-GSNTY-NH was found to be inhibited in the presence of N-methylated peptides 1-3 derived from the 18-22 fragment and by the double methylated peptide H-F(N-Me)GA(N-Me)IL-OH (6). Research on the possibility of using N-methylated analogs of amyloidogenic amylin cores as inhibitors of hormone aggregation is ongoing, with a focus on finding the minimum concentration of N-methylated peptides capable of inhibiting the aggregation of hIAPP hot spots.
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http://dx.doi.org/10.1002/cbdv.202000842DOI Listing
January 2021

Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity.

Pharmaceuticals (Basel) 2020 Nov 28;13(12). Epub 2020 Nov 28.

Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, 211A Borowska Street, 50-556 Wrocław, Poland.

A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with KPtCl and characterized by elemental analysis, ESI MS spectrometry, H NMR, Pt NMR, IR and far IR spectroscopy. Thermal isomerization of -dichloridobis(1-methyl-4-nitropyrazole)platinum(II) to -dichloridobis(1-methyl-4-nitropyrazole)platinum(II) has been presented, and the structure of the compound has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method. The complex showed better antiproliferative activity than cisplatin for all the tested cancer cell lines. Additionally, -dichloridobis(1-methyl-5-nitropyrazole)platinum(II) has featured a lower IC value than reference cisplatin against MCF-7 cell line. To gain additional information that may facilitate the explanation of the mode of action of tested compounds cellular platinum uptake, stability in L-glutathione solution, influence on cell cycle progression of HL-60 cells and ability to apoptosis induction were determined for compounds and .
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http://dx.doi.org/10.3390/ph13120433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768359PMC
November 2020

Calcitriol in the Presence of Conditioned Media from Metastatic Breast Cancer Cells Enhances Ex Vivo Polarization of M2 Alternative Murine Bone Marrow-Derived Macrophages.

Cancers (Basel) 2020 Nov 23;12(11). Epub 2020 Nov 23.

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

In this study, we differentiated murine bone marrow-derived macrophages (BMDMs) into M0, M1, and M2 in the presence or absence of calcitriol. Real-time PCR analysis of gene expression, FACS analysis of surface markers, and chemokine/cytokine production assays were performed. In addition, the effect of the conditioned media (CM) from murine breast cancer 4T1 (metastatic) and 67NR (non-metastatic) and Eph4-Ev (normal) cells with and without calcitriol on the polarization of M1/M2 cells was determined. We found that calcitriol enhanced the differentiation of M2 macrophages, which was manifested by increased expression of and mRNA and CD36, Arg, and CCL2 in M2 BMDMs and by decreased expression of and mRNA and IL-1, IL-6, OPN, and iNOS in M1 BMDMs. 4T1 CM showed a higher effect on the gene and protein expression in macrophages than 67NR and Eph4-Ev, with the greatest effect observed on M2 macrophages which increased their differentiation and properties characteristic of alternative macrophages. Moreover, M2 macrophages differentiated with calcitriol-stimulated migration of 4T1 and 67NR cells through fibronectin and collagen type IV, respectively. Overall, our results indicated that vitamin D supplementation may not always be beneficial, especially in relation to cancers causing excessive, pathological activation of the immune system.
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http://dx.doi.org/10.3390/cancers12113485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700498PMC
November 2020

Vitamin D Metabolite Profile in Cholecalciferol- or Calcitriol-Supplemented Healthy and Mammary Gland Tumor-Bearing Mice.

Nutrients 2020 Nov 6;12(11). Epub 2020 Nov 6.

Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw, Poland.

To analyze if the prometastatic activity of calcitriol (active vitamin D metabolite), which was previously observed in a 4T1 breast cancer model, is also found in other breast cancers, and to assess the impact of various schemes of vitamin D supply, we used 4T1 and E0771 mouse metastatic and 67NR nonmetastatic cells in this study. BALB/c and C57BL/6 healthy and tumor-bearing mice were exposed to a control (1000 IU), low- (100 IU), and high- (5000 IU) vitamin D diets. Additionally, from day 7 of tumor transplantation, the 1000 and 100 IU groups were gavaged with calcitriol (+cal). After 8 weeks of feeding, plasma levels of 25(OH)D, 24,25(OH)D, and 3-epi-25(OH)D were significantly lower in calcitriol-treated and vitamin D-deficient groups than in the control, whereas the levels of all metabolites were increased in the 5000 IU group. The ratio of 25(OH)D:24,25(OH)D was increased in both calcitriol-treated groups, whereas the ratio of 25(OH)D:3-epi-25(OH)D was increased only in the 100 IU group but decreased in the 5000 IU group. In contrast to E0771, 4T1 lung metastasis was accelerated in all vitamin D-supplemented mice, as well as in the deficient group with an increased inflammatory response. 67NR tumor growth was transiently inhibited in the 1000 IU+cal group, but single metastases were observed in the 5000 and 100 IU groups. Based on the results, we conclude that various schemes of vitamin D supply and vitamin D deficiency led to similar metabolite profiles irrespective of the mice strain and tumor burden. However, depending on the type of breast cancer, different effects on tumor growth and metastasis were noticed.
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http://dx.doi.org/10.3390/nu12113416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695033PMC
November 2020

Biaryl Sulfonamides Based on the 2-Azabicycloalkane Skeleton-Synthesis and Antiproliferative Activity.

Materials (Basel) 2020 Nov 6;13(21). Epub 2020 Nov 6.

Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okólna St. 2, 50-422 Wrocław, Poland.

In a search for new, selective antitumor agents, we prepared a series of sulfonamides built on bicyclic scaffolds of 2-azabicyclo(2.2.1)heptane and 2-azabicyclo(3.2.1)octane. To this end, -Diels-Alder cycloadducts were converted into amines bearing 2-azanorbornane or a bridged azepane skeleton; their treatment with sulfonyl chlorides containing biaryl moieties led to the title compounds. The study of antiproliferative activity of the new agents showed that some of them inhibited the growth of chosen cell lines with the IC values comparable with cisplatin, and some derivatives were found considerably less toxic for nonmalignant cells.
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http://dx.doi.org/10.3390/ma13215010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664408PMC
November 2020

Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells.

Cancers (Basel) 2020 Oct 2;12(10). Epub 2020 Oct 2.

Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland.

Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer-endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.
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http://dx.doi.org/10.3390/cancers12102850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601413PMC
October 2020

Heterogeneity of telomerase reverse transcriptase mutation and expression, telomerase activity and telomere length across human cancer cell lines cultured in vitro.

Exp Cell Res 2020 11 21;396(1):112298. Epub 2020 Sep 21.

Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland. Electronic address:

Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.
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http://dx.doi.org/10.1016/j.yexcr.2020.112298DOI Listing
November 2020

Differential Impact of Calcitriol and Its Analogs on Tumor Stroma in Young and Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Cancer.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

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

(1) Background: Vitamin D compounds (VDC) are extensively studied in the field of anticancer properties, including breast cancer. Previously, we showed that calcitriol and its analogs (PRI-2191 and PRI-2205) stimulate metastasis in 4T1 murine mammary gland cancer models in young mice, whereas the reverse effect was observed in aged ovariectomized (OVX) mice; (2) Methods: We determined the phenotype of monocytes/macrophages using FACS and examined the expression of selected genes and proteins by Real-Time PCR and ELISA; (3) Results: Activities of VDC are accompanied by an increase in the percentage of Ly6C anti-inflammatory monocytes in the spleen of young and a decrease in aged OVX mice. Treatment of young mice with VDC resulted in an increase of CCL2 plasma and tumor concentration and Arg1 in tumor. In later stage of tumor progression the expression of genes related to metastasis in lung tissue was decreased or increased, in old OVX or young mice, respectively; (4) Conclusions: Pro- or anti-metastatic effects of calcitriol and its analogs in young or aged OVX mice, respectively, can be attributed to the differences in the effects of VDC on the tumor microenvironment, as a consequence of differences in the immunity status of young and aged mice.
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http://dx.doi.org/10.3390/ijms21176359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503326PMC
September 2020

New Human Islet Amyloid Polypeptide Fragments Susceptible to Aggregation.

Chem Biodivers 2020 Sep 8;17(9):e2000501. Epub 2020 Sep 8.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, Lodz, 90-924, Poland.

Human Islet Amyloid Polypeptide (hIAPP) plays a key role in the pathogenesis of type II diabetes. The aim of this research was to search for new amyloidogenic fragments of hIAPP. An initial attempt to predict the amyloidogenic cores of polypeptides/proteins using five different computer programs did not provide conclusive results. Therefore, we synthesized hIAPP fragments covering the entire hormone. The fragments were assessed for their aggregation ability, using recommended methods to search for the amyloidogenic fragments of the polypeptides/proteins. It was found that fragments (18-22) H-HSSNN-OH and (33-37) H-GSNTY-NH aggregate and form stable amyloid-like structures. Both of these fragments have a much higher antiproliferative activity relative to the RIN-5F cell compared to the (23-27) H-FGAIL-OH fragment widely regarded as the amyloidogenic core of amylin. The analog of (33-37) H-GSNTY-NH containing a free carboxy group on the C-terminal amino acid (H-GSNTY-OH) does not have amyloidogenic properties and can therefore be considered as a potential inhibitor of amylin aggregation. Research on the use of non-aggregating amylin fragments as potential hormone aggregation inhibitors is ongoing.
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http://dx.doi.org/10.1002/cbdv.202000501DOI Listing
September 2020

Ruthenium(II) and Iridium(III) Complexes as Tested Materials for New Anticancer Agents.

Materials (Basel) 2020 Aug 7;13(16). Epub 2020 Aug 7.

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

The oncological use of cisplatin is hindered by its severe side effects and a very important resistance problem. To overcome these problems, scientists have attempted to design new generation transition-metal anticancer complexes. In this study, we present new complexes, ruthenium(II) [(η--cymene)RuCl(pyCO)]PF (), iridium(III) [(η-Cp)IrCl(pyCO)]PF (), and NH[IrCl(pyCO)]·HO (), based on di-2-pyridylketone (pyCO). The prepared complexes were characterized by FTIR, H, C, N NMR, UV-Vis, PL and elemental analysis techniques. The single-crystal X-ray structure analysis and comparative data revealed pseudo-octahedral half-sandwich and complexes and octahedral tetrachloroiridate(III) with a rare chelating κN,O coordination mode of pyCO. The compounds were tested in vitro against three cancer cell lines-colorectal adenoma (LoVo), myelomonocytic leukaemia (MV-4-11), breast adenocarcinoma (MCF-7), and normal fibroblasts (BALB/3T3). The most promising results were obtained for iridium(III) complex against MV-4-11 (IC = 35.8 ± 13.9 µg/mL) without a toxic effect against normal BALB/3T3, which pointed towards its selectivity as a potential anticancer agent. Extensive research into their mode of binding with DNA confirmed for and complexes non-classical binding modes, while the 3D circular dichroism (CD) experiment (ΔT) suggested that induced the probable formation of covalent bonds with DNA. In addition, the obtained iridium complexes induce ROS, which, in synergy with hydrolysis promoting DNA bonding, may lead to cancer cell death.
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http://dx.doi.org/10.3390/ma13163491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475896PMC
August 2020

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

Octahydroquinoxalin-2(1)-One-Based Aminophosphonic Acids and Their Derivatives-Biological Activity Towards Cancer Cells.

Materials (Basel) 2020 May 22;13(10). Epub 2020 May 22.

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

In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1,6)-3-oxo-2,5-diazabicyclo[4.4.0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction.
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http://dx.doi.org/10.3390/ma13102393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287629PMC
May 2020

The halogenation of natural flavonoids, baicalein and chrysin, enhances their affinity to human protein kinase CK2.

IUBMB Life 2020 06 4;72(6):1250-1261. Epub 2020 May 4.

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

A series of halogenated derivatives of natural flavonoids: baicalein and chrysin were designed and investigated as possible ligands for the catalytic subunit of tumor-associated human kinase CK2. Thermal shift assay method, in silico modeling, and high-performance liquid chromatography-derived hydrophobicity together with IC values determined in biochemical assay were used to explain the ligand affinity to the catalytic subunit of human protein kinase CK2. Obtained results revealed that substitution of baicalein and chrysin with halogen atom increases their binding affinity to hCK2α, and for 8-chlorochrysin the observed effect is even stronger than for the reference CK2 inhibitor-4,5,6,7-tetrabromo-1H-benzotriazole. The cytotoxic activities of the baicalein and chrysin derivatives in the in vitro model have been evaluated for MV4-11 (human biphenotypic B myelomonocytic leukemia), A549 (human lung adenocarcinoma), LoVo (human colon cancer), and MCF-7 (human breast cancer) as well as on the nontumorigenic human breast epithelial MCF-10A cell lines. Among the baicalein derivatives, the strongest cytotoxic effect was observed for 8-bromobaicalein, which exhibited the highest activity against breast cancer cell line MCF-7 (IC 10 ± 3 μM). In the chrysin series, the strongest cytotoxic effect was observed for unsubstituted chrysin, which exhibited the highest activity against leukemic cell line MV4-11 (IC 10 ± 4 μM).
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http://dx.doi.org/10.1002/iub.2298DOI Listing
June 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

Divergent Effect of Tacalcitol (PRI-2191) on Th17 Cells in 4T1 Tumor Bearing Young and Old Ovariectomized Mice.

Aging Dis 2020 Apr 9;11(2):241-253. Epub 2020 Mar 9.

1Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.

Vitamin D and its analogs are known for their role in the development of breast cancer and in immunomodulation. Our previous studies have shown the pro-metastatic effect of calcitriol and tacalcitol (PRI-2191) in young mice bearing 4T1 breast cancer and the anti-metastatic effect in aged ovariectomized (OVX) mice. Therefore, the aim of our work was to characterize Th17 cell population in young and aged OVX mice bearing 4T1 tumors treated with calcitriol and PRI-2191. The expression of genes typical for Th17 cells was examined in splenocytes, as well as splenocytes differentiated with IL-6 and TGF-β to Th17 cells (iTh17). Expression of genes encoding vitamin D receptor () and osteopontin () as well as the secretion of IL-17A were evaluated in iTh17 cells. PRI-2191 treatment increased the expression of and transcription factors, , and in iTh17 cells from young mice. In aged OVX mice this effect was not observed. Increased expression was observed in the case of and genes in iTh17 cells from young mice treated with PRI-2191. What is more, in young mice treated with PRI-2191 the secretion of IL-17A to the culture media by iTh17 cells was increased, whereas in aged OVX mice a significant decrease was noted. Increased expression of in young mice treated with PRI-2191 may enhance the differentiation of Th17 cells.
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http://dx.doi.org/10.14336/AD.2019.0618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069462PMC
April 2020

Three-Component Reaction of Diamines with Triethyl Orthoformate and Diethyl Phosphite and Anti-Proliferative and Antiosteoporotic Activities of the Products.

Molecules 2020 Mar 20;25(6). Epub 2020 Mar 20.

Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.

A three-component reaction between diamines (diaminobenzenes, diaminocyclohexanes, and piperazines), triethyl orthoformate, and diethyl phosphite was studied in some detail. In the case of 1,3- and 1,4-diamines and piperazines, products of the substitution of two amino moieties-the corresponding tetraphosphonic acids-were obtained. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This is most likely the result of the formation of hydrogen bonding between the phosphonate oxygen and a hydrogen of the adjacent amino group, which caused a decrease in the reactivity of the amino group. Most of the obtained compounds inhibited the proliferation of RAW 264.7 macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells, with 1, trans-7, and 16 showing broad nonspecific activity, which makes these compounds especially interesting in the context of anti-osteolytic treatment and the blocking of interactions and mutual activation of osteoclasts and tumor metastatic cells. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid, which were used as controls. However, studies of sheep with induced osteoporosis carried out with compound trans-7 did not support this assumption.
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http://dx.doi.org/10.3390/molecules25061424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144383PMC
March 2020

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors.

Cancers (Basel) 2020 Mar 7;12(3). Epub 2020 Mar 7.

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

Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor.
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http://dx.doi.org/10.3390/cancers12030623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139568PMC
March 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