Salinomycin: Difference between revisions

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 373936925

| ImageFile=Salinomycin.png

| IUPACName=(2''R'')-2-[(5''S'',6''R'')-6-[(1''S'',2''S'',3''S'',5''R'')-5-[(2''S'',5''R'',7''S'',9''S'',10''S'',12''R'',15''R'')-2-[(2''R'',5''R'',6''S'')-5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl]-15-hydroxy-2,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5⁷.3⁵]pentadec-13-en-9-yl]-2-hydroxy-1,3-dimethyl-4-oxoheptyl]-5-methyl-2-tetrahydropyranyl]butanoic acid

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| UNII = 62UXS86T64

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| CASNo=53003-10-4

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| ChEMBL = 1208572

| SMILES = O=C([C@H]([C@H]([C@@H]([C@]3([H])O[C@]([C@@H](CC)C(O)=O)([H])CC[C@@H]3C)C)O)C)[C@H](CC)[C@@]([C@@H](C)C[C@H]2C)([H])O[C@]12O[C@@]4(CC[C@]([C@]5([H])O[C@@H](C)[C@](CC)(O)CC5)(C)O4)[C@H](O)C=C1

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| InChI = 1/C42H70O11/c1-11-29(38(46)47)31-15-14-23(4)36(50-31)27(8)34(44)26(7)35(45)30(12-2)37-24(5)22-25(6)41(51-37)19-16-32(43)42(53-41)21-20-39(10,52-42)33-17-18-40(48,13-3)28(9)49-33/h16,19,23-34,36-37,43-44,48H,11-15,17-18,20-22H2,1-10H3,(H,46,47)/t23-,24-,25+,26-,27-,28-,29+,30-,31+,32+,33+,34+,36+,37-,39-,40+,41-,42-/m0/s1

| InChIKey = KQXDHUJYNAXLNZ-XQSDOZFQBR

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| C=42 | H=70 | O=11

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| Density=

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| BoilingPt=

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|Section6={{Chembox Pharmacology

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|Section7={{Chembox Hazards

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== Antibacterial activity ==

Salinomycin and its derivatives exhibit high antimicrobial activity against [[Gram-positive bacteria]], including the most problematic bacteria strains such as [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] and [[methicillin-resistant Staphylococcus epidermidis|methicillin-resistant ''Staphylococcus epidermidis'']], and ''[[Mycobacterium tuberculosis]]''. Salinomycin is inactive against fungi such as [[Candida (fungus)|''Candida'']] and [[Gram-negative bacteria]].

<ref>

{{cite journal

| author = M. Antoszczak| year = 2014

| volume =19

| issue = 12

| pages= 19435–19459

| title = Synthesis, Anticancer and Antibacterial Activity of Salinomycin N-Benzyl Amides

| journal = [[Molecules (journal)|Molecules]]

| doi = 10.3390/molecules191219435

| pmid = 25429565

| pmc = 6271077

| display-authors=etal| doi-access = free

}}</ref>

== Cancer research ==

===Pre-clinical===

Salinomycin has been shown by Piyush Gupta et al. of the [[Massachusetts Institute of Technology]] and the [[Broad Institute]] to kill [[breast cancer]] [[stem cell]]s in mice at least 100 times more effectively than the anti-cancer drug [[paclitaxel]]. The study screened 16,000 different chemical compounds and found that only a small subset, including salinomycin and [[etoposide]], targeted [[cancer stem cells]] responsible for metastasis and relapse.<ref>{{cite news

| title=Drug shows cancer stem cells not invulnerable

| publisher=[[New Scientist]]

| url=https://www.newscientist.com/article/dn17610-drug-shows-cancer-stem-cells-not-invulnerable.html

| date=2009-08-13}}

</ref><ref>

{{cite news

| access-date=2009-08-13

}}

</ref><ref>

{{cite journal

| last1=Gupta

| first1=P.

| pmc=4892125

| journal=[[Cell (journal)|Cell]]

| pages=645–59

|display-authors=etal}}

</ref><ref>

{{cite journal

| author = Adam Huczynski

| year = 2012

| volume =79

| issue = 3

| pages=235–238

| title = Salinomycin – a New Cancer Drug Candidate

| journal = [[Chemical Biology & Drug Design]]

| doi = 10.1111/j.1747-0285.2011.01287.x

| pmid = 22145602

| s2cid = 40843415

}}

</ref>

The [[mechanism of action]] by which salinomycin kills cancer stem cells involves lysosomal iron sequestration, leading to the production of reactive oxygen species, lysosome membrane permeabilization and ferroptosis.<ref>{{cite journal |last1=Mai |first1=Trang Thi |last2=Hamaï |first2=Ahmed |last3=Hienzsch |first3=Antje |last4=Cañeque |first4=Tatiana |last5=Müller |first5=Sebastian |last6=Wicinski |first6=Julien |last7=Cabaud |first7=Olivier |last8=Leroy |first8=Christine |last9=David |first9=Amandine |last10=Acevedo |first10=Verónica |last11=Ryo |first11=Akihide |last12=Ginestier |first12=Christophe |last13=Birnbaum |first13=Daniel |last14=Charafe-Jauffret |first14=Emmanuelle |last15=Codogno |first15=Patrice |last16=Mehrpour |first16=Maryam |last17=xRodriguez |first17=Raphaël Rodriguez |title=Salinomycin kills cancer stem cells by sequestering iron in lysosomes |journal=Nature Chemistry |date=Oct 2017 |volume=9 |issue=10 |pages=1025–1033 |doi=10.1038/nchem.2778 |pmid=28937680 |pmc=5890907 |bibcode=2017NatCh...9.1025M }}</ref> Studies performed in 2011 showed that salinomycin could induce [[apoptosis]] of human cancer cells at higher concentrations. C20 amino derivatives such as [[ironomycin]] have shown to be more potent in vitro models of [[persister cells|persister]] cancer cells and in vivo {{doi| 10.1038/nchem.2778}}. Promising results from a few clinical pilot studies reveal that salinomycin is able to effectively eliminate cancer stem cells and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both cancer stem cells and therapy-resistant cancer cells (persister) may define the compound as a novel and an effective anticancer drug.<ref>C. Naujokat, R. Steinhart "Salinomycin as a Drug for Targeting Human Cancer Stem Cells”, ''[[Journal of Biomedicine and Biotechnology]]'', Volume 2012 (2012), Article ID 950658, {{doi| 10.1155/2012/950658}}, [http://downloads.hindawi.com/journals/bmri/2012/950658.pdf open access review article]</ref><ref>A. Huczyński, ”Polyether ionophores—promising bioactive molecules for cancer therapy”, ''[[Bioorganic & Medicinal Chemistry Letters]]'', 2012,22, 7002-7010,{{doi|10.1016/j.bmcl.2012.09.046}}, [http://pdn.sciencedirect.com/science?_ob=MiamiImageURL&_cid=271398&_user=10&_pii=S0960894X12011924&_check=y&_origin=article&_zone=toolbar&_coverDate=2012--01&view=c&originContentFamily=serial&wchp=dGLzVlt-zSkzV&md5=84788aa32c6c31005037121056abfe26&pid=1-s2.0-S0960894X12011924-main.pdf open access review article]</ref> It has been also shown that salinomycin and its derivatives exhibit potent antiproliferative activity against the drug-resistant cancer cell lines.<ref>A. Huczyński, J. Janczak, M. Antoszczak, J. Wietrzyk, E. Maj, B. Brzezinski, ” Antiproliferative activity of salinomycin and its derivatives”, ''[[Bioorganic & Medicinal Chemistry Letters]]'', 2012, 22, 7146-7150,{{doi|10.1016/j.bmcl.2012.09.068}},</ref><ref>

{{cite journal

| first1 = Michal | last1 = Antoszczak | first2 = Adam | last2 = Huczynski

| year = 2015

| volume =15

| issue = 5

| pages= 575–591

| title = Anticancer Activity of Polyether Ionophore-Salinomycin

| journal = [[Anti-Cancer Agents in Medicinal Chemistry]]

| doi = 10.2174/1871520615666150101130209

| pmid = 25553435 }}[http://www.eurekaselect.com/127288/article review article]

</ref> Salinomycin is the key compound in the pharmaceutical company Verastem's efforts to produce an anti-cancer-stem-cell drug.{{cn|date=December 2022}}

Salinomycin is used in chicken feed as a [[coccidiostat]].{{cn|date=December 2022}}

== Biosynthesis ==

A team from the [[University of Cambridge]] has cloned and sequenced the biosynthetic cluster responsible for salinomycin production, from ''[[Streptomyces albus]]'' DSM 41398.<ref>{{cite journal

| doi=10.1002/cbic.201100590

| last1=Yurkovich

| first1=Marie E.

| pmid= 22076845

| title=A Late-Stage Intermediate in Salinomycin Biosynthesis Is Revealed by Specific Mutation in the Biosynthetic Gene Cluster

| journal=[[ChemBioChem]]

| date=2011-11-11

| last2=Tyrakis

| first2=Petros A.

| last3=Hong

| first3=Hui

| last4=Sun

| first4=Yuhui

| last5=Samborskyy

| first5=Markiyan

| last6=Kamiya

| first6=Kohei

| last7=Leadlay

| first7=Peter F.

| volume=13

| issue=1

| pages=66–71

| s2cid=22332727

|display-authors=etal}}</ref> This has shown that the [[polyketide]] backbone of salinomycin is synthesised on an assembly line of nine [[polyketide synthase]]) multienzymes. Furthermore, the cluster contains genes involved in oxidative cyclization including ''salC'' (epoxidase) and ''salBI/BII/BIII'' (epoxide hydrolase) genes. The cluster also contains genes suspected to be involved in self-resistance, export, precursor supply and regulation. The cluster contains a NRPS{{clarify|reason=What is NRPS?|date=June 2018}}-like carrier protein, SalX, that is suspected to tether “pre-salinomycin” during oxidative cyclization. By inactivating salC the researchers have demonstrated that salinomycin biosynthesis proceeds via a diene intermediate.{{cn|date=December 2022}}

* [[Narasin]] a derivative of salinomycin which has an additional methyl group.

==References==

{{Reflist}}

[[Category:Ionophores]]

[[Category:Polyketides]]

[[Category:Spiro compounds]]