Polyether Antibiotic Salinomycin Research Articles

A REVIEW OF ADVANCED NANOTECHNOLOGIES AND DRUG DELIVERY SYSTEMS OF SALINOMYCIN AND THEIR ROLE IN TRIPLE-NEGATIVE BREAST CANCER

Cancer cells spread to other tissues and organs when they divide incorrectly. Breast cancer (BC) is the main cause of cancer-related mortality globally. Some recent studies on cancer stem cells (CSCs), drug resistance, tumor recurrence and metastasis, and the significance of CD44+in targeted treatment for breast cancer are covered. Breast cancer stem cells (BCSCs) and bulk BC cells must be eliminated for the disease to be eliminated. Researchers have shown that Streptomyces Albus-derived monocarboxylic polyether antibiotic salinomycin kills human cancer stem cells (CSCs) and prevents the spread and growth of breast cancer cells. Several drug and apoptosis resistance mechanisms may also trigger apoptosis in breast cancer cells when salinomycin is used in combination with the treatment. Apoptosis-resistant cancer cells and cancer stem cells are both susceptible to the anticancer drug salinomycin. Salinomycin may be able to inhibit CSCs, as well as the source and structure modification of salinomycin analog exhibit potent anticancer activity, the effect of salinomycin on chemotherapeutic-resistant CSCs, and the various mechanisms by which salinomycin inhibits cancer stem cells in this study. Method and delivery technique for salinomycin Nano formulation in triple-negative breast cancer and also contains pharmacokinetics and toxicity of salinomycin. Salinomycin-based drug delivery system is the subject of the patent information. Tumor genesis, development, and invasion are all aided by salinomycin. It's possible to boost the effectiveness of cancer therapy by focusing on cancer stem cells (CSCs).

Antibacterial activity of singly and doubly modified salinomycin derivatives

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−1. 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.

Comparative study on the effects of salinomycin, monensin and meso-2,3-dimercaptosuccinic acid on the concentrations of lead, calcium, copper, iron and zinc in lungs and heart in lead-exposed mice

Background and aimEnvironmental lead (Pb) exposure damages the lungs and is a risk factor for death from cardiovascular disease. Pb induces toxicity by a mechanism, which involves alteration of the essential elements homeostasis. In this study we compare the effects of salinomycin (Sal), monensin (Mon) and meso-2,3-dimercaptosuccinic acid (DMSA) on the concentrations of lead (Pb), calcium (Ca), copper (Cu), iron (Fe) and zinc (Zn) in the lungs and heart of lead-exposed mice. MethodsSixty days old male ICR mice were divided into five groups: control (Ctrl) – untreated mice obtained distilled water for 28 days; Pb-intoxicated group (Pb) – exposed to 80 mg/kg body weight (BW) Pb(NO3)2 during the first 14 days of the experimental protocol; DMSA-treated (Pb + DMSA) – Pb-exposed mice, subjected to treatment with an average daily dose of 20 mg/kg BW DMSA for two weeks; Monensin-treated (Pb + Mon) – Pb-exposed mice, obtained an average daily dose of 20 mg/kg BW tetraethylammonium salt of monensic acid for 14 days; Pb + Sal - Pb-exposed mice, treated with an average daily dose of 20 mg/kg BW tetraethylammonium salt of salinomycinic acid for two weeks. On the 29th day of the experiment the samples (lungs and heart) were taken for atomic absorption analysis. ResultsThe results revealed that exposure of mice to Pb for 14 days significantly increased the concentration of the toxic metal in both organs and elevated the cardiac concentrations of Ca, Cu and Fe compared to untreated mice. Pb exposure diminished the lung concentrations of Ca and Zn compared to that of untreated controls. DMSA, monensin and salinomycin decreased the concentration of Pb in the lungs and heart. Among the tested chelating agents, only salinomycin restored the cardiac Fe concentration to normal control values. ConclusionThe results demonstrated the potential application of polyether ionophorous antibiotic salinomycin as antidote for treatment of Pb-induced toxicity in the lungs and heart. The possible complexation of the polyether ionophorous antibiotics with Ca(II) and Zn(II), which can diminish the endogenous concentrations of both ions in the lungs should be taken into account.

Salinomycin inhibits cholangiocarcinoma growth by inhibition of autophagic flux.

IntroductionCholangiocarcinoma is characterized by aggressive tumor growth, high recurrence rates, and resistance against common chemotherapeutical regimes. The polyether-antibiotic Salinomycin is a promising drug in cancer therapy because of its ability to overcome apoptosis resistance of cancer cells and its selectivity against cancer stem cells. Here, we investigated the effectiveness of Salinomycin against cholangiocarcinoma in vivo, and analyzed interference of Salinomycin with autophagic flux in human cholangiocarcinoma cells.ResultsSalinomycin reduces tumor cell viability, proliferation, migration, invasion, and induced apoptosis in vitro. Subcutaneous and intrahepatic cholangiocarcinoma growth in vivo was inhibited upon Salinomycin treatment. Analysis of autophagy reveals inhibition of autophagic activity. This was accompanied by accumulation of mitochondrial mass and increased generation of reactive oxygen species.ConclusionsThis study demonstrates the effectiveness of Salinomycin against cholangiocarcinoma in vivo. Inhibition of autophagic flux represents an underlying molecular mechanism of Salinomycin against cholangiocarcinoma.MethodsThe two murine cholangiocarcinoma cell lines p246 and p254 were used to analyze tumor cell proliferation, viability, migration, invasion, and apoptosis in vitro. For in vivo studies, murine cholangiocarcinoma cells were injected into syngeneic C57-BL/6-mice to initiate subcutaneous cholangiocarcinoma growth. Intrahepatic tumor growth was induced by electroporation of oncogenic transposon-plasmids into the left liver lobe. For mechanistic studies in human cells, TFK-1 and EGI-1 were used, and activation of autophagy was analyzed after exposure to Salinomycin.

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells.

BackgroundThe polyether antibiotic Salinomycin (Sal) is regarded as an inhibitor of cancer stem cells. Its effectiveness on human colorectal cancer (CRC) cells in vitro has been demonstrated before. The aim of this study was to establish a murine model to investigate the effectiveness of Sal in vivo. Furthermore, we investigated the impact of Sal on Wnt/β-catenin signaling in human CD133+ CRC cells.MethodsThe two murine CRC cell lines MC38 and CT26 were used to analyze the impact of Sal on tumor cell proliferation, viability, migration, cell cycle progression and cell death in vitro. For in vivo studies, CT26 cells were injected into syngeneic BALB/c mice to initiate (i) subcutaneous, (ii) orthotopic, or (iii) metastatic CRC growth. Sal was administered daily, 5-Fluoruracil served as a control. For mechanistic studies, the CD133+and CD133- subpopulations of human CRC cells were separated by flow cytometry and separately exposed to increasing concentrations of Sal. The impact on Wnt/β-catenin signaling was determined by Western blotting and quantitative PCR.ResultsSal markedly impaired tumor cell viability, proliferation and migration, and induced necrotic cell death in vitro. CRC growth in vivo was likewise inhibited upon Sal treatment. Interference with Wnt signaling and reduced expression of the Wnt target genes Fibronectin and Lgr5 indicates a novel molecular mechanism, mediating anti-tumoral effects of Sal in CRC.ConclusionSal effectively impairs CRC growth in vivo. Furthermore, Sal acts as an inhibitor of Wnt/β-catenin signaling. Thus, Salinomycin represents a promising candidate for clinical CRC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2879-8) contains supplementary material, which is available to authorized users.

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

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.

Effects of salinomycin on human bone marrow-derived mesenchymal stem cells in vitro

Various hypotheses on the origin of cancer stem cells (CSCs) exist, including that CSCs develop from transformed human bone marrow mesenchymal stem cells (hBMSC). Since the polyether antibiotic salinomycin selectively kills CSCs, the present study aims to elucidate the effects of salinomycin on normal hBMSC.The immunophenotype of hBMSC after salinomycin exposure was observed by flow cytometry. The multi-differentiation capacity of hBMSC was evaluated by Oil Red O and van Kossa staining. Cytotoxic effects of salinomycin were monitored by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay. Furthermore, spheroid formation and migration capacity were assessed.There were no differences in the immunophenotype and multi-differentiation capacity of hBMSC induced by salinomycin treatment. Cytotoxic effects were observed at concentrations of 30μM and above. Neither the migration capability nor the ability to form spheroids was affected.Essential functional properties of hBMSC were unaffected by salinomycin. However, dose-dependent cytotoxicity effects could be observed. Overall, low dose salinomycin showed no negative effects on hBMSC. Since mesenchymal stem cells from various sources respond differently, further in vitro studies are needed to clarify the effect of salinomycin on tissue-specific stem cells.

Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic—salinomycin

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic—salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical Gram-positive cocci, Gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256μg/mL to active with MIC of 2μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against Gram-positive bacteria, MRSA and MSSA.

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

BackgroundThe natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in in vivo experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their in vitro complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).ResultsNew metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)2(H2O)2] (1) and [Pb(Sal)(NO3)] (2), respectively. ion of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield 1. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex 2 consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.ConclusionThe formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.

Radical oxidative cyclization of spiroacetals to bis-spiroacetals: an overview.

The use of iodobenzene diacetate and iodine under photolytic conditions provides and efficient method for the oxidative cyclization of spiroacetals bearing an hydroxyalkyl side chain to bis-spiroacetals. An overview is provided of the use of this reaction for the synthesis of several bis-spiroacetal containing natural products such as the polyether antibiotics salinomycin and CP44,161 and the shellfish toxins, the spirolides.

Approaches to the D-E ring of the polyether antibiotic salinomycin using sharpless asymmetric dihydroxylation

The work described herein provides a model system for appendage of the E ring of epi-17-deoxy-( O-8)-salinomycin 3 onto bis-spiroacetal aldehyde 6. The conversion of aldehyde 7 to bicyclic ether 8 via silver assisted ring expansion of the mesylate derived from tetrahydrofuran alcohol 33 is described. Attempts to provide a stereoselective synthesis of epoxide 27 required for the preparation of 33 and hence 8 are reported. Alcohol 9 was prepared by chelation controlled addition of the Grignard reagent derived from bromide 15 to aldehyde 7. Bromide 15 in turn was prepared as a 9:1 E: Z mixture of isomers with the required E-stereochemistry being introduced via a stereoselective Julia ring opening of cyclopropane 20. Sharpless asymmetric dihydroxylation of alkenes 10 and 11 readily provided diols 22 and 25 [or 23 and 26 respectively], however, their subsequent conversion to epoxides 27 and 30 with retention of stereochemistry proved unsuccessful. Cyclic sulfites 37, 39 and sulfates 42, 45 were investigated as epoxide equivalents. Base induced cyclization of sulfites 37, 39 only afforded triols 21, 24. Analogous reaction using sulfates 42, 45 favoured endo cyclization to a tetrahydropyran ring, however, the acidic conditions required for hydrolysis of the initial alkyl sulfate effected undesired elimination of the resultant tertiary alcohol. Whilst a stereoselective synthesis of the correct epoxide 27 required for preparation of tetrahydropyran 8 via ring expansion of tetrahydrofuran 33 has not been achieved, these latter conversions have been successfully demonstrated by the conversion of epoxides 28 and 31 to a 1:1 mixture of tetrahydrofurans 33 and 34 which were separable by flash chromatography. Subsequent ring expansion of these tetrahydrofurans 33 and 34 to tetrahydropyrans 8 and 14 was effected upon treatment with methanesulfonyl chloride followed by silver carbonate.

ChemInform Abstract: Stereocontrolled Synthesis of a Key Lactone Intermediate Required for the Synthesis of Salinomycin.

The stereocontrolled synthesis of lactone (1b), a key intermediate required for the synthesis of the polyether antibiotic salinomycin, is described.

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 24. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 2. Synthesis of Right (C18‐C30) Segments from D‐Glucose, D‐Mannitol, and Ethyl L‐Lactate.

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 24. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 2. Synthesis of Right (C18‐C30) Segments from D‐Glucose, D‐Mannitol, and Ethyl L‐Lactate.

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 26. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 4. Chemical Degradation of Salinomycin for the Structure Confirmation of Synthetic Key Intermediates.

ChemInformVolume 21, Issue 9 Natural Products ChemInform Abstract: Chiral Synthesis of Polyketide-Derived Natural Products. Part 26. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 4. Chemical Degradation of Salinomycin for the Structure Confirmation of Synthetic Key Intermediates. K. HORITA, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorS. NAGATO, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorY. OIKAWA, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorO. YONEMITSU, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this author K. HORITA, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorS. NAGATO, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorY. OIKAWA, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorO. YONEMITSU, Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this author First published: February 27, 1990 https://doi.org/10.1002/chin.199009340AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume21, Issue9February 27, 1990 RelatedInformation

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 25. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 3. Total Synthesis of Salinomycin via Coupling of C1‐C9, C10‐C17, and C18‐C30 Segments.

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 25. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 3. Total Synthesis of Salinomycin via Coupling of C1‐C9, C10‐C17, and C18‐C30 Segments.

ChemInform Abstract: Chiral Synthesis of Polyketide‐Derived Natural Products. Part 23. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 1. Synthesis of the Left (C1‐C9) and Middle (C10‐C17) Segments from D‐Glucose.

ChemInformVolume 21, Issue 9 Natural Products ChemInform Abstract: Chiral Synthesis of Polyketide-Derived Natural Products. Part 23. Highly Stereocontrolled Total Synthesis of the Polyether Antibiotic Salinomycin. Part 1. Synthesis of the Left (C1-C9) and Middle (C10-C17) Segments from D-Glucose. K. HORITA, K. HORITA Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorY. OIKAWA, Y. OIKAWA Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorO. YONEMITSU, O. YONEMITSU Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this author K. HORITA, K. HORITA Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorY. OIKAWA, Y. OIKAWA Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this authorO. YONEMITSU, O. YONEMITSU Fac. Pharm. Sci., Hokkaido Univ., Sapporo 060, JapanSearch for more papers by this author First published: February 27, 1990 https://doi.org/10.1002/chin.199009337AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume21, Issue9February 27, 1990 RelatedInformation

Synthesis of a functionalised bis-spiroacetal

The synthesis of bis-spiroacetal (15) bearing an hydroxymethyl group at C-2 is described establishing a methodology for preparation of the polyether antibiotics salinomycin and narasin. Formation of an important iodohydrin intermediate has been accomplished by a highly efficient reaction of an epoxide with LiI catalysed by BF 3.Et 2O in THF. Displacement of the resulting neopentyl iodide was achieved in high yield by reaction of the iodide with potassium superoxide in dimethylsulphoxide/tetrahydrofuran in the presence of 18-crown-6.

Stereocontrolled Synthesis of a Key Lactone Intermediate Required for the Synthesis of Salinomycin

The stereocontrolled synthesis of lactone (1b), a key intermediate required for the synthesis of the polyether antibiotic salinomycin, is described.

Highly stereocontrolled total synthesis of the polyether antibiotic salinomycin. III. Total synthesis of salinomycin via coupling of C1-C9, C10-C17, and C-18-C30 segments.

Highly stereocontrolled total synthesis of the polyether antibiotic salinomycin. III. Total synthesis of salinomycin via coupling of C1-C9, C10-C17, and C-18-C30 segments.

Highly stereocontrolled total synthesis of the polyether antibiotic salinomycin. I. Synthesis of the left (C1-C9) and middle (C10-C17) segments from D-glucose.

The required left (C1-C9) segment, (R)-2-[(2R, 5S, 6R)-6-[(R)-1-formylethyl]-5-methyltetrahydropyran-2-yl]butanoic acid, for a total synthesis of salinomycin was highly stereoselectively synthesized from D-glucose via a chelation-controlled Grignard reaction and a decarbonylation with Wilkinson's catalyst as important steps. The stereoselective synthesis of the middle (C10-C17) segment, (2R, 4S, 5S, 6R)-6-ethyl-2, 4-dimethyl-7-oxononan-5-olide, starting from D-glucose is also described.