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Revision as of 13:54, 24 February 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers from ChemSpider, CommonChemistry and FDA for the Chem/Drugbox validation project - Updated: ChEMBL.← Previous edit Latest revision as of 23:53, 2 November 2024 edit undoGuccizBud (talk | contribs)Extended confirmed users18,495 editsm →top: Copy edit ▸ Presentation ▸ Outside article reference visually augmented via crossreferencing template.Tags: Mobile edit Mobile app edit Android app edit App full source 
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{{Use dmy dates|date=May 2022}}
{{chembox
{{Chembox
⚫ | verifiedrevid = 402379268
| Verifiedfields = changed
| Watchedfields = changed
⚫ | verifiedrevid = 415688842
| ImageFile = Maleimide.png | ImageFile = Maleimide.png
| ImageSize = | ImageSize = 150
| ImageAlt = Structural formula of maleimide
| ImageFile1 = Maleimide molecule spacefill.png
| ImageSize1 = 170
| ImageAlt1 = Space-filling model of the maleimide molecule
| IUPACName = Maleimide | IUPACName = Maleimide
| PIN = 1''H''-Pyrrole-2,5-dione
| OtherNames = 2,5-Pyrroledione | OtherNames = 2,5-Pyrroledione
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| Abbreviations = | Abbreviations =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
Line 11: Line 19:
| InChI = 1/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7) | InChI = 1/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)
| InChIKey = PEEHTFAAVSWFBL-UHFFFAOYAL | InChIKey = PEEHTFAAVSWFBL-UHFFFAOYAL
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 387762 | ChEMBL = 387762
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
Line 18: Line 27:
| CASNo_Ref = {{cascite|correct|CAS}} | CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 541-59-3 | CASNo = 541-59-3
| EINECS = | EINECS = 208-787-4
| PubChem = 10935 | PubChem = 10935
| SMILES = C1=CC(=O)NC1=O | SMILES = C1=CC(=O)NC1=O
| InChI =
| RTECS = | RTECS =
| MeSHName = | MeSHName =
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI =
| KEGG = | ChEBI = 16072
| KEGG_Ref = {{keggcite|correct|kegg}}
| ATCCode_prefix =
| KEGG = C07272
| ATCCode_suffix =
| 3DMet = B01084
| ATC_Supplemental =}}
| UNII = 2519R1UGP8
⚫ | Section2 = {{Chembox Properties
| UNII_Ref = {{fdacite|correct|FDA}}
}}
⚫ |Section2={{Chembox Properties
| Formula = C<sub>4</sub>H<sub>3</sub>NO<sub>2</sub> | Formula = C<sub>4</sub>H<sub>3</sub>NO<sub>2</sub>
| MolarMass = 97.07 g/mol | MolarMass = 97.07 g/mol
| Appearance = | Appearance =
| Density = | Density =
| MeltingPt = 91-93 °C | MeltingPtC = 91 to 93
| Melting_notes = | MeltingPt_notes =
| BoilingPtC = | BoilingPtC =
| Boiling_notes = | BoilingPt_notes =
| Solubility = organic solvents | Solubility = organic solvents
| SolubleOther = | SolubleOther =
| Solvent = | Solvent =
| pKa = | pKa =
| pKb = }} | pKb =
}}
| Section7 = {{Chembox Hazards |Section7={{Chembox Hazards
| GHSPictograms = {{GHS05}}{{GHS06}}{{GHS07}}
| EUClass =
| EUIndex = | GHSSignalWord = Danger
| HPhrases = {{H-phrases|301|314|317}}
| PPhrases = {{P-phrases|260|261|264|270|272|280|301+310|301+330+331|302+352|303+361+353|304+340|305+351+338|310|321|330|333+313|363|405|501}}
| MainHazards = | MainHazards =
| NFPA-H = | NFPA-H =
| NFPA-F = | NFPA-F =
| NFPA-R = | NFPA-R =
| NFPA-O = | NFPA-S =
| RPhrases = {{R25}} {{R34}} {{R43}}
| SPhrases = {{S26}} {{S36/37/39}} {{S45}}
| RSPhrases =
| FlashPt = | FlashPt =
| Autoignition = | AutoignitionPt =
| ExploLimits = | ExploLimits =
| PEL = }} | PEL =
}}
}} }}


'''Maleimide''' is the ] with the ] H<sub>2</sub>C<sub>2</sub>(CO)<sub>2</sub>NH. This unsaturated ] is an important building block in ]. The name is a contraction of ] and ], the -C(O)NHC(O)- ]. Maleimides also describes a ''class'' of derivatives of the parent maleimide where the N''H'' group is replaced with ] or ] groups such as a ] or ]. The substituent can also be a ] such as ]. Human ] chemically modified with maleimide-polyethylene glycol is a ] called MP4. '''Maleimide''' is a ] with the ] H<sub>2</sub>C<sub>2</sub>(CO)<sub>2</sub>NH (see diagram). This unsaturated ] is an important building block in ]. The name is a contraction of ] and ], the -C(O)NHC(O)- ]. Maleimides also describes a ''class'' of derivatives of the parent maleimide where the N''H'' group is replaced with ] or ] groups such as a ] or ], respectively. The substituent can also be a small molecule (such as ], a fluorescent dye, an ], or a ]), a reactive group, or a ] such as ].<ref name="Hermanson2013">{{cite book | vauthors = Hermanson G | chapter = Chapter 6: Heterobifunctional Crosslinkers |title=Bioconjugate Techniques | doi = 10.1016/B978-0-12-382239-0.00006-6 |publisher= Elsevier |pages=299–339 |isbn=978-0-12-382239-0 |year=2013}}</ref> Human ] chemically modified with maleimide-polyethylene glycol is a ] called MP4.


==Organic chemistry== ==Organic chemistry==
Maleimide and its derivatives are prepared from ] by treatment with ]s followed by dehydration.<ref>{{OrgSynth | author = Cava, M. P.; Deana, A. A.; Muth, K.; Mitchell, M. J. | title = N-Phenylmaleimide | collvol = 5 | collvolpages = 944 | year = 1973 | prep = cv5p0944}}</ref> A special feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by ]s or via ] reactions. '''Bismaleimides''' are a class of compounds with two maleimide groups connected through a molecular unit and used as ]s in polymer chemistry. Maleimide and its derivatives are prepared from ] by treatment with ]s followed by dehydration.<ref>{{OrgSynth | vauthors = Cava MP, Deana AA, Muth K, Mitchell MJ | title = N-Phenylmaleimide | collvol = 5 | collvolpages = 944 | year = 1973 | prep = cv5p0944}}</ref> A special feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by ]s or via ] reactions. '''Bismaleimides''' are a class of compounds with two maleimide groups connected by the nitrogen atoms via a linker, and are used as ]s in ] chemistry. Compounds containing a maleimide group linked with another reactive group, such as an activated ] ester, are called '''maleimide heterobifunctional reagents''' {{xref|(see ] for such an example)}}.<ref name="Hermanson2013" />


==Natural maleimides==
⚫ ==Biotechnology applications==
One natural maleimide is the ] ] from '']'',<ref name="PencolideRef">{{cite journal | vauthors = Birkinshaw JH, Kalyanpur MG, Stickings CE | title = Studies in the biochemistry of micro-organisms. 113. Pencolide, a nitrogen-containing metabolite of Penicillium multicolor Grigorieva-Manilova and Poradielova | journal = The Biochemical Journal | volume = 86 | issue = 2 | pages = 237–243 | date = February 1963 | pmid = 13971137 | pmc = 1201741 | doi = 10.1042/bj0860237 | name-list-style = amp }}</ref> and ] from ''Pe. multicolor''<ref name="PencolideRef" /> – have been reported. ] was first isolated in 2009 from the ] ''Isaria farinosa'' (''Paecilomyces farinosus'') – source H599 (Japan).<ref name="DiscoveryTeam">{{cite journal | vauthors = Putri SP, Kinoshita H, Ihara F, Igarashi Y, Nihira T | title = Farinomalein, a maleimide-bearing compound from the entomopathogenic fungus Paecilomyces farinosus | journal = Journal of Natural Products | volume = 72 | issue = 8 | pages = 1544–6 | date = August 2009 | pmid = 19670877 | doi = 10.1021/np9002806 }}</ref>
Maleimides linked to ] chains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily reacts with the ] group found on ] to form a stable carbon-sulfur bond. Attaching the other end of the polyethylene chain to a bead or solid support allows for easy separation of protein from other molecules in solution, provided these molecules do not also possess thiol groups.

⚫ ==Biotechnology and pharmaceutical applications==
Maleimide-mediated methodologies are among the most used in ].<ref>{{cite journal | vauthors = Koniev O, Wagner A | title = Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation | journal = Chemical Society Reviews | volume = 44 | issue = 15 | pages = 5495–5551 | date = August 2015 | pmid = 26000775 | doi = 10.1039/C5CS00048C | doi-access = free }}</ref><ref>{{cite journal | vauthors = Francis MB, Carrico IS | title = New frontiers in protein bioconjugation | journal = Current Opinion in Chemical Biology | volume = 14 | issue = 6 | pages = 771–773 | date = December 2010 | pmid = 21112236 | doi = 10.1016/j.cbpa.2010.11.006 }}</ref> Due to fast reactions and high selectivity towards ] residues in ], a large variety of maleimide heterobifunctional reagents are used for the preparation of targeted therapeutics, assemblies for studying proteins in their biological context, protein-based microarrays, or proteins immobilisation.<ref>{{cite book | vauthors = Hermanson G | chapter = Chapter 1 - Introduction to Bioconjugation |title=Bioconjugate Techniques | doi = 10.1016/B978-0-12-382239-0.00001-7 |publisher= Elsevier |pages=1–125 |isbn=978-0-12-382239-0|year=2013}}</ref>
For instance, ], are constituted of three main components: a ], a cytotoxic drug, and a linker molecule often containing a maleimide group, which conjugates the drug through thiols or dienes to the antibody.<ref>{{cite journal | vauthors = Beck A, Goetsch L, Dumontet C, Corvaïa N | title = Strategies and challenges for the next generation of antibody-drug conjugates | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 5 | pages = 315–337 | date = May 2017 | pmid = 28303026 | doi = 10.1038/nrd.2016.268 | s2cid = 22045270 }}</ref><ref name=Lahn/>

Maleimides linked to ] chains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily undergoes a retro-Michael reaction with the ] group found on ] to form a stable carbon-sulfur bond. Cysteines are often used for site-selective modifications for therapeutic purposes because of the rapid rate of complete bioconjugation with sulfhydryl groups, allowing for higher levels of cytotoxic drug incorporations.<ref name=":1">{{Cite journal |last1=Ravasco |first1=João M. J. M. |last2=Faustino |first2=Hélio |last3=Trindade |first3=Alexandre |last4=Gois |first4=Pedro M. P. |date=2018-11-19 |title=Bioconjugation with Maleimides: A Useful Tool for Chemical Biology |url=http://dx.doi.org/10.1002/chem.201803174 |journal=Chemistry – A European Journal |volume=25 |issue=1 |pages=43–59 |doi=10.1002/chem.201803174 |pmid=30095185 |issn=0947-6539}}</ref> Attaching the other end of the polyethylene chain to a bead or solid support allows for easy separation of protein from other molecules in solution, provided these molecules do not also possess thiol groups.

Maleimide-functionalised polymers and liposomes exhibit enhanced ability to adhere to mucosal surfaces (]) due to the reactions with thiol-containing mucins.<ref>{{cite journal | vauthors = Tonglairoum P, Brannigan RP, Opanasopit P, Khutoryanskiy VV | title = Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery | journal = Journal of Materials Chemistry B | volume = 4 | issue = 40 | pages = 6581–6587 | date = October 2016 | pmid = 32263701 | doi = 10.1039/C6TB02124G | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kaldybekov DB, Tonglairoum P, Opanasopit P, Khutoryanskiy VV | title = Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder | journal = European Journal of Pharmaceutical Sciences | volume = 111 | pages = 83–90 | date = January 2018 | pmid = 28958893 | doi = 10.1016/j.ejps.2017.09.039 | s2cid = 35605027 | url = https://centaur.reading.ac.uk/72941/5/Manuscript_Maleimide_liposomes_VKaccepted.pdf }}</ref><ref>{{cite journal | vauthors = Moiseev RV, Kaldybekov DB, Filippov SK, Radulescu A, Khutoryanskiy VV | title = Maleimide-Decorated PEGylated Mucoadhesive Liposomes for Ocular Drug Delivery | journal = Langmuir | volume = 38 | issue = 45 | pages = 13870–13879 | date = November 2022 | pmid = 36327096 | pmc = 9671038 | doi = 10.1021/acs.langmuir.2c02086 }}</ref> This could be applicable in the design of dosage forms for transmucosal drug delivery.

The retro-Michael reactions resulting in maleimide-thiol adducts require precise control. The targeting ability of drugs containing the adducts can be easily hindered or lost due to their instability in vivo.<ref name=":2">{{Cite journal |last1=Huang |first1=Wenmao |last2=Wu |first2=Xin |last3=Gao |first3=Xiang |last4=Yu |first4=Yifei |last5=Lei |first5=Hai |last6=Zhu |first6=Zhenshu |last7=Shi |first7=Yi |last8=Chen |first8=Yulan |last9=Qin |first9=Meng |last10=Wang |first10=Wei |last11=Cao |first11=Yi |date=2019-02-04 |title=Maleimide–thiol adducts stabilized through stretching |url=http://dx.doi.org/10.1038/s41557-018-0209-2 |journal=Nature Chemistry |volume=11 |issue=4 |pages=310–319 |doi=10.1038/s41557-018-0209-2 |pmid=30718898 |issn=1755-4330}}</ref> The instability is mainly attributed to the formation of the thiosuccinimide which might be involved in thiol exchange reaction with glutathione. B-elimination reaction follows, resulting in off-target activity and a loss of efficacy of the drugs.<ref name=Lahn>{{Cite journal |last1=Lahnsteiner |first1=Marianne |last2=Kastner |first2=Alexander |last3=Mayr |first3=Josef |last4=Roller |first4=Alexander |last5=Keppler |first5=Bernhard K. |last6=Kowol |first6=Christian R. |date=2020-10-27 |title=Improving the Stability of Maleimide–Thiol Conjugation for Drug Targeting |url=http://dx.doi.org/10.1002/chem.202003951 |journal=Chemistry – A European Journal |volume=26 |issue=68 |pages=15867–15870 |doi=10.1002/chem.202003951 |pmid=32871016 |issn=0947-6539|pmc=7756610 }}</ref>

No general method exist for stabilizing thioesters, such as thiosuccinimides, so that their off-target effects can be eliminated in drugs. Problems associated with thiol exchange can be mitigated by hydrolyzing the thiosuccinimide, which prevents elimination of the maleimide-thiol bond. The process of ring-opening hydrolysis requires special catalysts and bases, which may not be biocompatible and lead to harsh conditions. Alternatively, cysteines in the positively charged environment or an electron-withdrawing group enable the thiosuccinimide ring to undergo self-hydrolysis.<ref name=":2"/>

Another problem with hydrolysis arises if it is applied to ''N''-alkyl-substituted derivatives instead of the N-aryl-substituted derivatives because they hydrolyze at a rate that’s too slow to yield consistently stable adducts.<ref name=Lahn/>


==Technological applications== ==Technological applications==
Analogous to ], ]s of maleimides and ] have been commercialized.<ref>{{cite book |doi=10.1002/14356007.a21_615.pub2 |chapter=Polystyrene and Styrene Copolymers |title=Ullmann's Encyclopedia of Industrial Chemistry |date=2007 |last1=Maul |first1=Jürgen |last2=Frushour |first2=Bruce G. |last3=Kontoff |first3=Jeffrey R. |last4=Eichenauer |first4=Herbert |last5=Ott |first5=Karl-Heinz |last6=Schade |first6=Christian |isbn=978-3-527-30385-4 }}</ref>
Mono- and bismaleimides are used for high temperature applications up to 250°C.{{Fact|date=April 2008}} Maleimides linked to ] chains are often used as flexible linking molecules to reinforce the rubber (]). The double bond readily reacts with all ], ] or ] groups found on the matrix to form a stable carbon-sulfur, carbon-nitrogen or carbon-carbon bond.


Mono- and bismaleimide-based polymers are used for high temperature applications up to {{cvt|250|C|F|sigfig=2}}.<ref>{{cite journal | journal = Polymer | vauthors = Lin KF, Lin JS, Cheng CH | title = High temperature resins based on allylamine/bismaleimides | volume = 37 | pages = 4729–4737 | year = 1996 | doi = 10.1016/S0032-3861(96)00311-4 | issue = 21|url=http://ntur.lib.ntu.edu.tw/bitstream/246246/93332/1/19.pdf }}</ref> Maleimides linked to rubber chains are often used as flexible linking molecules to reinforce rubber in ]. The double bond readily reacts with all ], ] or ] groups found on the matrix to form a stable carbon-oxygen, carbon-nitrogen, or carbon-sulfur bond, respectively. These polymers are used in aerospace for high temperature applications of composites. Lockheed Martin's ] extensively uses thermoset composites, with bismaleimide and toughened epoxy comprising up to 17.5% and 6.6% of the structure by weight respectively.<ref>{{cite journal | vauthors = Anderson WD, Mortara S |date=23-26 April 2007 |title=F-22 Aeroelastic Design and Test Validation |journal=American Institute of Aeronautics and Astronautics (AIAA) |page=4 |doi=10.2514/6.2007-1764 |isbn=978-1-62410-013-0 }}</ref> Lockheed Martin's F-35B (a STOVL version of this US fighter) is reportedly composed of bismaleimide materials, in addition to the use of advanced carbon fiber ] composites.<ref>{{cite web | url=http://www.isciencetimes.com/articles/5929/20130821/lockheed-martin-f35b-ufo-stealth-fighter-video.htm | archive-url = https://web.archive.org/web/20140221074332/http://www.isciencetimes.com/articles/5929/20130821/lockheed-martin-f35b-ufo-stealth-fighter-video.htm | archive-date = 21 February 2014 | title=Lockheed Martin F-35B Boasts UFO Technology, Fights For Team USA | date=21 August 2013 | publisher=International Science Times |access-date=28 January 2014}}</ref>
==See also==
⚫ *]


==References== == See also ==
* ]
<references/>
⚫ * ]


==External links== == References ==
{{Reflist}}
⚫ * , Molecule of the Month, December 2004


== External links==
⚫ * , Molecule of the Month, December 2004


] ]