Chemical Modification and Structure-Activity Correlation of Salinomycin

Miyazaki, Y.; Kinashi, Haruyasu; Ōtake, Noboru; Mitani, Mitsuaki; Yamanishi, Tadashi

doi:10.1080/00021369.1976.10862252

Cited by 9 publications

(14 citation statements)

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“…Salinomycin selectively binds cations in the sequence K+ > Rb+ > Na+ > Ca2+, Mg2+ (Table VII). These results are consistent with those of Mitani et al (1975) and Miyazaki et al (1976). For the measurement of ionophoric activity @Rb was used rather than 22Na, since salinomycin exhibited a greater affinity for Rb+ than Na+.…”

Section: Tissue Residue Levelssupporting

confidence: 86%

“…It can be extrapolated that approximately 20% of the extractable salinomycin residue possesses ionophoric activity or that tissue metabolites have lower binding affinities than that of unchanged salinomycin. The data of Miyazaki et al (1976) show that salinomycin derivatives vary in their ability to bind radioactive cations and inhibit microbial growth.…”

Section: Tissue Residue Levelsmentioning

confidence: 98%

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Effect of antibiotic combination, dosing period, dose vehicle, and assay method on salinomycin residue levels and their ionophoricity in chicken tissues

Dimenna¹,

Lyon²,

Thompson³

et al. 1989

J. Agric. Food Chem.

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Studies were conducted to determine the effect of antibiotic combinations (lincomycin or bacitracin MD and roxarsone), length of dosing period, pretreatment with medicated feed, and dose vehicle on salinomycin residue levels in chicken tissues. Salinomycin was determined by high-performance liquid chromatography and thin-layer chromatography. Ionophoric activity was determined by a radiolabeled rubidium binding assay. Salinomycin residue levels were unaffected by treatment and assay method. Total residue levels were less than the established tolerance limits for muscle and skin/fat but approached the tolerance limit of 1.8 ppm for liver. Total drug residue levels in liver could be estimated by unchanged salinomycin level in skin/fat. Unchanged salinomycin did not account for all of the ionophoric activity present in liver. The affinity for rubidium binding by the salinomycin metabolites is approximately 20% of that of unchanged drug. Since liver metabolites have minimal ionophoric activity, the residues would have no toxicologic consequences.Sodium salinomycin ( Figure 1) is a polyether, carboxylic ionophore currently being marketed for its anticoccidial activity in chickens at a use level of 40-60 g/ton. Previous residue studies with unlabeled drug conducted at our facilities suggested that feeding salinomycin in combination with other antibiotics may affect the level of salinomycin in skin/fat, which was designated as the target tissue. The levels of salinomycin in skin/fat as determined by a thin-layer bioautographic method similar to that described by Dimenna et al. (1986b) were 0.039, 0.029, and 0.200 ppm, when salinomycin and roxarsone were fed in combination with bacitracin MD, zinc bacitracin, or virginiamycin, respectively. The levels of salinomycin in skin/fat as determined by a high-performance liquid chromatographic (HPLC) method described by Dimenna et al. (1986a) were 0.180, <0.100, and <0.100 ppm, when salinomycin and roxarsone were fed in combination with lincomycin, oxytetracycline, or chlortetracycline, respectively. Because of these results, residue studies were conducted to determine the effect of antibiotic combination and assay methodology on salinomycin residue levels in chicken tissues.In the first study (hereafter designated study A) unchanged salinomycin ,levels were determined in chicken tissues by two independent assay methods: HPLC and radiometric thin-layer chromatography (TLC). Salinomycin (75 g/ton) was administered by itself or in combination with roxarsone plus lincomycin for 20 days in the feed, followed by oral administration by gavage of [14C]-salinomycin at 6.7 mg/kg per day (equivalent to 75 g/ton) in sodium bicarbonate for 5 days. The HPLC method of Dimenna et al. (1986a) was modified in order to lower the quantifiable limit of detection. During the course of study A, it was discovered that the liver total drug residue levels were a t the tolerance limit of 1.8 ppm and were not affected by antibiotic combination. This was in contrast to an earlier residue study, in which c...

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Section: Tissue Residue Levelssupporting

confidence: 86%

Section: Tissue Residue Levelsmentioning

confidence: 98%

Effect of antibiotic combination, dosing period, dose vehicle, and assay method on salinomycin residue levels and their ionophoricity in chicken tissues

Dimenna¹,

Lyon²,

Thompson³

et al. 1989

J. Agric. Food Chem.

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“…Early synthetic work by Miyazaki revealed that the 20‐hydroxy group could be selectively esterified directly by treatment with aliphatic and non‐bulky anhydrides in pyridine . In our hands, these protocols were not general and obtaining material of sufficient homogeneity for biological testing was difficult.…”

Section: Resultsmentioning

confidence: 93%

“…Besides the carboxylate group, the only accessible functionality of salinomycin that is directly involved in ion‐coordination is the C11 ketone. Reduction of salinomycin using NaBH 4 was early shown to give close to a 50:50 mixture of diastereomers 11 and 12 , though the relative stereochemistry was not established (Scheme ). To facilitate preparative access to these compounds in stereochemically pure form, we investigated the possibility of increasing the distereoselectivity of the reduction.…”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi‐synthetic Derivatives

Borgström

Huang

Hegardt

et al. 2016

Chemistry A European J

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The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure-activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.

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“…The samples of II, V and VI were prepared according to the previous paper. 12 ) 18,l9-Dihydro-20-deoxysalinomycin methyl ester (VIl) A solution of VI (1.0 g) in NaHC0 3 saturated methanol (50 ml) was hydrogenated in the presence of platinum oxide (I50 mg) for 72 hr at room temperature. After removal of the catalyst, the solution was concentrated and purified by silica gel column chromatography using benzene-ethyl acetate to afford an amorphollS powder (0.15 g); mp 67~69°C; …”

Section: L9-dihydrosy-l Methyl Ester (Lv)mentioning

confidence: 99%