Publications by authors named "Michał Antoszczak"

34 Publications

Role of Vitamin E in Selected Malignant Neoplasms in Women.

Nutr Cancer 2021 Jul 19:1-8. Epub 2021 Jul 19.

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

Vitamin E, which is actually a mixture of eight isoforms (four tocopherols and four tocotrienols), is a powerful antioxidant that protects polyunsaturated fatty acids against oxidation and has the ability to break the chain lipid peroxidation, which is used in the treatment of heart disease, atherosclerosis, muscle disorders or infertility among men. Studies in-vitro show that one of the effects of tocopherol is the reduction of cancer stem cell activity which is connected to poor clinical course. In the scientific literature, reports on the participation of vitamin E not only in protection against the mutagenic effects of reactive oxygen species, but also in its anti-angiogenic activity and the ability to inhibit the invasion and metastasis of neoplastic cells are increasingly common. In this context, the role of vitamin E in preventing the neoplastic process and selected malignant neoplasms among women seems to be of particular interest. In this article, we present the results of research on the potential anticancer effects of vitamin E in the fight against breast, cervical, endometrial and ovarian cancer.
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http://dx.doi.org/10.1080/01635581.2021.1952626DOI Listing
July 2021

Evaluation of the anticancer activity of singly and doubly modified analogues of C20-epi-salinomycin.

Eur J Pharmacol 2021 Jul 13;908:174347. Epub 2021 Jul 13.

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

In developed countries, cancer is the second leading cause of death, with colon and prostate cancer belonging to the group of most often diagnosed types of neoplastic diseases. The search for new treatment strategies against these types of cancer is thus of top current interest. In this context, salinomycin (SAL), a naturally occurring polyether ionophore, has been identified recently as a very promising anticancer drug candidate towards several tumour cells. In the present work, a broad library of 24 derivatives of C20-epi-salinomycin (2), including C1 singly, C20 singly and C1/C20 doubly modified analogue structures, was screened to identify compounds with improved activity against colon and prostate cancer cells. Our study demonstrated that the growth inhibitory potency of the parent compound on both primary and metastatic colon cancer cells was similar to that of the semisynthetic products derived from SAL, and simultaneously the SAL analogues showed more potent toxic action on metastatic prostate cancer cells than that of the chemically unmodified ionophore. In contrast to the widely used oncological drug doxorubicin, some of the SAL derivatives demonstrated promising anticancer activity with no toxic effects on non-tumour cells, and with more favourable cytotoxicity than that of a reference agent 5-fluorouracil. Mechanistically, the SAL analogues induced late apoptosis in colon cancer cells and necrosis in prostate cancer cells, as well as reduced secretion of interleukin 6 (IL-6) in these cells.
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http://dx.doi.org/10.1016/j.ejphar.2021.174347DOI Listing
July 2021

Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models.

Biomed Pharmacother 2021 Jun 12;141:111815. Epub 2021 Jun 12.

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.

Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC range of 1.1 ± 0.1-1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44/CD24 stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development.
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http://dx.doi.org/10.1016/j.biopha.2021.111815DOI Listing
June 2021

Ester derivatives of salinomycin efficiently eliminate breast cancer cells via ER-stress-induced apoptosis.

Eur J Pharmacol 2021 Feb 19;893:173824. Epub 2020 Dec 19.

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

The polyether ionophore salinomycin (SAL) has been found to selectively target breast cancer cells, including those with stem-like phenotype. On the other hand, SAL amides and esters obtained through derivatisation of the C1 carboxyl of the ionophore were found to exhibit anticancer properties, whilst reducing potential toxicity issues which often occur during standard chemotherapy. However, the studies on the activity and especially on the mechanisms of action of this class of semi-synthetic products against breast cancer cells are very limited. Therefore, in this work, we confirmed the anti-breast cancer activity of SAL, and further investigated the potential of its selected C1 amide and ester analogs to destroy breast cancer cells, including the highly aggressive triple-negative MDA-MB-231 cells. Importantly, SAL esters were found to be more potent than the native structure and their amide counterparts. Our data revealed that SAL ester derivatives, particularly compounds 5 and 7 (2,2,2-trifluoroethyl and benzotriazole ester of SAL, respectively), increase the level of p-eIF2α (Ser51) and IRE1α proteins. Additionally, an increased level of DNA damage indicators such as γH2AX protein and modified guanine (8-oxoG) was observed. These findings suggest that the apoptosis of MCF-7 and MDA-MB-231 cells induced by the most promising esters derived from SAL may result from the interaction between ER stress and DNA damage response mechanisms.
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http://dx.doi.org/10.1016/j.ejphar.2020.173824DOI Listing
February 2021

Statins: HMG-CoA Reductase Inhibitors as Potential Anticancer Agents against Malignant Neoplasms in Women.

Pharmaceuticals (Basel) 2020 Nov 25;13(12). Epub 2020 Nov 25.

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

Statins, also known as HMG-CoA inhibitors, are a class of bioactive small molecules that efficiently reduce the levels of cholesterol, and therefore are commonly used to manage and prevent various cardiovascular diseases. With respect to their original medical indications, statins are currently in the group of the most prescribed drugs worldwide. Of note is that statins are perceived actually rather as agents that have pleiotropic activities; in addition to their inhibitory activity on the production of endogenous cholesterol. Statins may also affect cell proliferation, angiogenesis and/or migration (metastasis) of different cancer cells, and play a positive role in the chemoprevention of cancer, thus being the excellent candidates to be repurposed in oncology. Particularly intriguing in this context seems to be the promising role of statins on both the incidence and course of common malignant neoplasms in women. In this article, we review and discuss the effect of the use of statins in the treatment of three types of cancer, i.e., breast, endometrial and ovarian cancer, with the highest mortality among gynecological cancers.
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http://dx.doi.org/10.3390/ph13120422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760915PMC
November 2020

Singly and doubly modified analogues of C20-epi-salinomycin: A new group of antiparasitic agents against Trypanosoma brucei.

Eur J Med Chem 2021 Jan 2;209:112900. Epub 2020 Oct 2.

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

Polyether ionophores, with >120 molecules belonging to this group, represent a class of naturally-occurring compounds that exhibit a broad range of pharmacological properties, including promising activity towards a variety of parasites. In this context, salinomycin (SAL) seems to be interesting, as this ionophore has been found to be active against parasites that are responsible for a number of human and animal diseases. On the other hand, less explored is the investigation into the anti-parasitic activity of SAL derivatives. Recently, we identified C1 amides and esters of SAL and its analogue, C20-oxosalinomycin, as promising structures for trypanocidal drug candidates. In search for novel compounds effective against African trypanosomes, the synthetic access to a completely new series of C20-epi-salinomycin (compound 2) analogues is described in this paper. This series includes products obtained via derivatisation of either the C1 carboxyl or the C20 hydroxyl of 2, but also C1/C20 double modified derivatives. The anti-trypanosomal activity as well as the cytotoxic activity of these analogues were evaluated with bloodstream forms of T. brucei and human myeloid HL-60 cells, respectively. It was found that the C20 single modified derivatives 8, 12, and 18 (C20 decanoate, C20 ethyl carbonate, and C20 allophanate of 2, respectively) were the most active compounds in selectively targeting bloodstream-form trypanosomes, with 50% growth inhibition (GI) values of 0.027-0.043 μM and selectivity indices of 165-353. These results indicate that modification at the C20 position of C20-epi-salinomycin 2 can provide semi-synthetic products with enhanced trypanocidal activity that could be of great value for the development of new drugs to treat African trypanosomiasis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112900DOI Listing
January 2021

Antidepressants and Antipsychotic Agents as Repurposable Oncological Drug Candidates.

Curr Med Chem 2021 ;28(11):2137-2174

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

Drug repurposing, also known as drug repositioning/reprofiling, is a relatively new strategy for the identification of alternative uses of well-known therapeutics that are outside the scope of their original medical indications. Such an approach might entail a number of advantages compared to standard de novo drug development, including less time needed to introduce the drug to the market, and lower costs. The group of compounds that could be considered as promising candidates for repurposing in oncology include the central nervous system drugs, especially selected antidepressant and antipsychotic agents. In this article, we provide an overview of some antidepressants (citalopram, fluoxetine, paroxetine, sertraline) and antipsychotics (chlorpromazine, pimozide, thioridazine, trifluoperazine) that have the potential to be repurposed as novel chemotherapeutics in cancer treatment, as they have been found to exhibit preventive and/or therapeutic action in cancer patients. Nevertheless, although drug repurposing seems to be an attractive strategy to search for oncological drugs, we would like to clearly indicate that it should not replace the search for new lead structures, but only complement de novo drug development.
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http://dx.doi.org/10.2174/0929867327666200907141452DOI Listing
May 2021

Role of vitamin D in selected malignant neoplasms.

Nutrition 2020 Nov - Dec;79-80:110964. Epub 2020 Jul 30.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland. Electronic address:

Vitamin D is a fat-soluble essential nutrient that affects multiple biologic functions in the organism through calcitriol and the vitamin D receptor. This review article focuses on the results of studies on the relationship between the level of vitamin D and cancer incidence or mortality, but also on the anticancer properties of vitamin D that support its significant role in the prevention, clinical course, and overall survival rates of selected cancers (colorectal, prostate, breast, ovarian, endometrial, bladder, and malignant melanoma). The mechanisms of vitamin D action involve, among others, polymorphism of vitamin D receptor, cell cycle, caspases, and cancer stem cells. The level of vitamin D has been also demonstrated to serve as a biomarker in some cancers, and high levels of vitamin D can be conducive to successful cancer therapy.
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http://dx.doi.org/10.1016/j.nut.2020.110964DOI Listing
June 2021

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

Antibacterial activity of singly and doubly modified salinomycin derivatives.

Bioorg Med Chem Lett 2020 05 24;30(9):127062. Epub 2020 Feb 24.

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

The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2-3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1-4 µg mL. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic - ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives.
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http://dx.doi.org/10.1016/j.bmcl.2020.127062DOI Listing
May 2020

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives-An In Vitro Study.

Molecules 2020 Jan 26;25(3). Epub 2020 Jan 26.

Radiobiology Lab, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznań, Poland.

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs-5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.
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http://dx.doi.org/10.3390/molecules25030537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037477PMC
January 2020

Old wine in new bottles: Drug repurposing in oncology.

Eur J Pharmacol 2020 Jan 12;866:172784. Epub 2019 Nov 12.

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

Increasing costs, much time consumption and high risk of failure associated with the process of de novo development of new anticancer drugs have prompted the pharmaceutical industry to seek alternative strategies that may facilitate and accelerate the whole process. In particular, the repurposing strategy, known also as repositioning or reprofiling strategy, is a potential source of new treatment options for cancer patients with high unmet medical needs. However, it should be noted that the repurposing strategy, being still a new trend in drug development, should only complement the process of discovering new anticancer drugs, and should not be its alternative. The best repurposable oncological drug candidates are the agents whose original patent protection has already expired, and for which there is a possibility to create a formulation enabling, together with a new therapeutic indication, new patent protection. In this review article we discuss the advantages of the repurposing strategy, and provide an overview of a number of promising candidates, such as artesunate, aspirin, cimetidine, doxycycline, ivermectin, metformin, rapamycin (sirolimus), and thalidomide, that have the potential to be repurposed as anticancer drugs both in cancer prevention and therapy. In addition, we highlight some of the studies regarding the signalling pathways and molecular targets altered by these drugs, and describe the biological mechanisms underlying their anticancer effects.
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http://dx.doi.org/10.1016/j.ejphar.2019.172784DOI Listing
January 2020

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20-oxo Analogues.

ChemMedChem 2020 01 27;15(2):236-246. Epub 2019 Nov 27.

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

The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single- [N,N-dipropyl amide of salinomycin (5 a)] and two novel double-modified analogues [N,N-dipropyl amide of C20-oxosalinomycin (5 b) and piperazine amide of C20-oxosalinomycin (13 b)] were found to be more potent toward the MDA-MB-231 cell line than SAL or its C20-oxo analogue 2. When select analogues were tested against the NCI-60 human tumor cell line panel, 4 a [N,N-diethyl amide of salinomycin] showed particular activity toward the ovarian cancer cell line SK-OV-3. Additionally, both SAL and 2 were found to be potent ex vivo against human ER/PR , Her2 invasive mammary carcinoma, with 2 showing minimal toxicity toward normal epithelial cells. The present findings highlight the therapeutic potential of SAL derivatives for select targeting of different cancer types.
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http://dx.doi.org/10.1002/cmdc.201900593DOI Listing
January 2020

Salinomycin and its derivatives - A new class of multiple-targeted "magic bullets".

Eur J Med Chem 2019 Aug 9;176:208-227. Epub 2019 May 9.

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

The history of drug development clearly shows the scale of painstaking effort leading to a finished product - a highly biologically active agent that would be at the same time no or little toxic to human organism. Moreover, the aim of modern drug discovery can move from "one-molecule one-target" concept to more promising "one-molecule multiple-targets" one, particularly in the context of effective fight against cancer and other complex diseases. Gratifyingly, natural compounds are excellent source of potential drug leads. One of such promising naturally-occurring drug candidates is a polyether ionophore - salinomycin (SAL). This compound should be identified as multi-target agent for two reasons. Firstly, SAL combines a broad spectrum of bioactivity, including antibacterial, antifungal, antiviral, antiparasitic and anticancer activity, with high selectivity of action, proving its significant therapeutic potential. Secondly, the multimodal mechanism of action of SAL has been shown to be related to its interactions with multiple molecular targets and signalling pathways that are synergistic for achieving a therapeutic anticancer effect. On the other hand, according to the Paul Ehrlich's "magic bullet" concept, invariably inspiring the scientists working on design of novel target-selective molecules, a very interesting direction of research is rational chemical modification of SAL. Importantly, many of SAL derivatives have been found to be more promising as chemotherapeutics than the native structure. This concise review article is focused both on the possible role of SAL and its selected analogues in future antimicrobial and/or cancer therapy, and on the potential use of SAL as a new class of multiple-targeted "magic bullet" because of its multimodal mechanism of action.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.031DOI Listing
August 2019

Anti-trypanosomal activity of doubly modified salinomycin derivatives.

Eur J Med Chem 2019 Jul 3;173:90-98. Epub 2019 Apr 3.

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

As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the C1 carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of C1 esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel C1/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of T. brucei and human myeloid HL-60 cells revealed that the single-modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI) values of 0.037 and 0.035 μM, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI values between 0.032 and 0.035 μM but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development.
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http://dx.doi.org/10.1016/j.ejmech.2019.03.061DOI Listing
July 2019

A comprehensive review of salinomycin derivatives as potent anticancer and anti-CSCs agents.

Eur J Med Chem 2019 Mar 16;166:48-64. Epub 2019 Jan 16.

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

Polyether ionophore antibiotics (ionophores) represent a large group of more than 120 lipid-soluble compounds that are widely used in veterinary medicine because of their significant antimicrobial activity. In addition to the industrial use of ionophores, some of them effectively and selectively inhibit properties of different cancer cells and enhance the antitumor effects of chemo- and/or radiotherapy. Salinomycin (SAL) is particularly interesting in this regard as it shows potent activity against various types of cancer cells, including those that display multi-drug resistance, and cancer stem cells. Therefore, a very interesting direction of research is chemical modification of SAL which may lead to obtaining analogs that are characterized by better biological activity and lower toxicity than those of the starting compound. This review article is focused on the possible role of both SAL-based drug delivery systems and SAL derivatives in future cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.034DOI Listing
March 2019

Anti-parasitic activity of polyether ionophores.

Eur J Med Chem 2019 Mar 17;166:32-47. Epub 2019 Jan 17.

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

Despite some progress in recent years, the fight against parasitic diseases still remains a great challenge. Parasitic diseases affect primarily (but not exclusively) the poorest people living in underdeveloped regions of the world. The distribution of parasitoses are linked to tropical and subtropical climate conditions, to population growth and to impoverishment. If not treated, parasitic diseases may lead to serious health problems, and even death. Particularly vulnerable groups include infants and young children, pregnant women and immunocompromised individuals. Polyether ionophore antibiotics (ionophores), traditionally used in veterinary medicine as anti-coccidial feed additives and non-hormonal growth promoters, are of considerable interest, as they have been found to be highly effective agents against various parasites, both in vitro and in vivo. This review summarizes the anti-parasitic effects of the most important polyether ionophores against parasites that are responsible for a number of animal and human parasitic diseases. Recent findings and advances that support the potential of polyether ionophore antibiotics as novel anti-parasitic drug candidates are also presented and discussed.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.035DOI Listing
March 2019

A medicinal chemistry perspective on salinomycin as a potent anticancer and anti-CSCs agent.

Eur J Med Chem 2019 Feb 24;164:366-377. Epub 2018 Dec 24.

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

Tumors are phenotypically heterogeneous and include a small sub-population of cancer cells (2-5% of the tumor mass) with stem-cell like properties. The cancer stem cell hypothesis postulates that the cancer stem cells (CSCs) show the ability to seed the tumor to distant tissues/organs, and their presence results in cancer progression and relapses. Extensive efforts have therefore been directed at new therapy strategies to eliminate not only non-CSCs, but also cancer cells with stem-cell like properties. Importantly, in 2009, the natural ionophore - salinomycin (SAL) was shown to be promising in this respect; SAL selectively and efficiently reduced the proportion of breast CSCs in vitro and in vivo. Since this original report, SAL has been shown to be active against numerous cancer cells and CSCs of different origin, including those that display multi-drug resistance. This concise review article is focused on the possible role of SAL in future cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2018.12.057DOI Listing
February 2019

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

Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro.

Biomed Pharmacother 2018 Mar;99:384-390

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States. Electronic address:

Salinomycin (SAL) and monensin (MON) are polyether ionophore antibiotics commonly used in veterinary medicine. They are known from their anti-cancer activity against various types of cancer cells, including those that display multi-drug resistance as well as cancer stem cells. In order to increase the biological activity profile and reduce toxicity against normal cells, while retaining the activities in the micromolar range, a library of ester and amide derivatives of SAL was synthesized and previously reported. In this paper, we examined the activity of SAL, its ten derivatives, and MON on primary acute lymphoblastic leukemia cells. MON and six SAL derivatives were more potent than SAL in cell viability assays. Further, selected active SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. Moreover, SAL acted synergistically with the Bcl-2 inhibitor ABT-263, whereas 2,2,2-trifluoroethyl ester, the most active analog of SAL, antagonized ABT-263, suggesting possible differences in molecular mechanism.
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http://dx.doi.org/10.1016/j.biopha.2018.01.081DOI Listing
March 2018

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

In vitro activity of salinomycin and monensin derivatives against Trypanosoma brucei.

Parasit Vectors 2016 07 25;9(1):409. Epub 2016 Jul 25.

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

Background: African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells.

Results: Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2-trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50 % growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 μM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250.

Conclusions: The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti-trypanosomal drug development.
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http://dx.doi.org/10.1186/s13071-016-1698-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972190PMC
July 2016

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

Tertiary amides of Salinomycin: A new group of antibacterial agents against Bacillus anthracis and methicillin-resistant Staphylococcus epidermidis.

Bioorg Med Chem Lett 2015 4;25(10):2082-8. Epub 2015 Apr 4.

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

For the first time, a series of tertiary amides of polyether antibiotic-Salinomycin have been obtained and screened for their antibacterial activity against different strains of bacteria, including Bacillus anthracis and clinical methicillin-resistant Staphylococcus epidermidis (MRSE). Moreover, biofilm inhibition of MRSE and genotoxicity tests against Bacillus subtilis have been performed. Our studies show that Salinomycin and its some derivatives are active against tested bacteria and exhibited definitely bacteriostatic, not bactericidal activity.
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http://dx.doi.org/10.1016/j.bmcl.2015.03.085DOI Listing
January 2016

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

Antiproliferative Activity of Polyether Antibiotic--Cinchona Alkaloid Conjugates Obtained via Click Chemistry.

Chem Biol Drug Des 2015 Oct 10;86(4):911-7. Epub 2015 Feb 10.

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

A series of eight new conjugates of salinomycin or monensin and Cinchona alkaloids were obtained by the Cu(I)-catalysed 1,3-dipolar Huisgen cycloaddition (click chemistry) of respective N-propargyl amides of salinomycin or monensin with four different Cinchona alkaloid derived azides. In vitro antiproliferative activity of these conjugates evaluated against three cancer cell lines (LoVo, LoVo/DX, HepG2) showed that four of the compounds exhibited high antiproliferative activity (IC50 below 3.00 μm) and appeared to be less toxic and more selective against normal cells than two standard anticancer drugs.
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http://dx.doi.org/10.1111/cbdd.12523DOI Listing
October 2015

Anticancer Activity of Polyether Ionophore-Salinomycin.

Anticancer Agents Med Chem 2015 ;15(5):575-91

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

Since the discovery of unusual anti-tumor activity of natural polyether antibiotic - Salinomycin, this compound, along with its derivatives, has been intensively studied against different human cancer cells, both in vivo and in vitro. Salinomycin has shown strong inhibition activity against the proliferation process of many different cancer cells, including multi-drug resistance (MDR) cancer cells, as well as cancer stem cells (CSCs), i.e. leukemic stem cells, colon carcinoma stem cells, prostate cancer stem cells and many others. Additionally, the application of Salinomycin has been proved to enhance the anti-cancer effect of radio- and chemotherapy. Preliminary clinical studies have shown tumor regression and only transient acute side effects after application of Salinomycin. Up to now, major efforts have been devoted to elucidate the biological mechanisms of anti-tumor activity of Salinomycin and it is expected that the results may provide new therapeutic strategies based on biological modulation of Salinomycin activity. This review is focused on and describes the possible role of Salinomycin in cancer therapy and gives an overview of its properties.
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http://dx.doi.org/10.2174/1871520615666150101130209DOI Listing
April 2016

Synthesis, anticancer and antibacterial activity of salinomycin N-benzyl amides.

Molecules 2014 Nov 25;19(12):19435-59. Epub 2014 Nov 25.

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

A series of 12 novel monosubstituted N-benzyl amides of salinomycin (SAL) was synthesized for the first time and characterized by NMR and FT-IR spectroscopic methods. Molecular structures of three salinomycin derivatives in the solid state were determined using single crystal X-ray method. All compounds obtained were screened for their antiproliferative activity against various human cancer cell lines as well as against the most problematic bacteria strains such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), and Mycobacterium tuberculosis. Novel salinomycin derivatives exhibited potent anticancer activity against drug-resistant cell lines. Additionally, two N-benzyl amides of salinomycin revealed interesting antibacterial activity. The most active were N-benzyl amides of SAL substituted at -ortho position and the least anticancer active derivatives were those substituted at the -para position.
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http://dx.doi.org/10.3390/molecules191219435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271077PMC
November 2014
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