Wikipedia

Maleimide

Maleimideis achemical compoundwith theformulaH2C2(CO)2NH (see diagram). This unsaturatedimideis an important building block inorganic synthesis.The name is a contraction ofmaleic acidandimide,the -C(O)NHC(O)-functional group.Maleimides also describes aclassof derivatives of the parent maleimide where the NHgroup is replaced withalkylorarylgroups such as amethylorphenyl,respectively. The substituent can also be a small molecule (such asbiotin,a fluorescent dye, anoligosaccharide,or anucleic acid), a reactive group, or asynthetic polymersuch aspolyethylene glycol.[1]Humanhemoglobinchemically modified with maleimide-polyethylene glycol is ablood substitutecalled MP4.

Maleimide
Structural formula of maleimide
Space-filling model of the maleimide molecule
Names
IUPAC name
Maleimide
Preferred IUPAC name
1H-Pyrrole-2,5-dione
Other names
2,5-Pyrroledione
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.990Edit this at Wikidata
EC Number
  • 208-787-4
KEGG
UNII
  • InChI=1S/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)checkY
    Key: PEEHTFAAVSWFBL-UHFFFAOYSA-NcheckY
  • InChI=1/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)
    Key: PEEHTFAAVSWFBL-UHFFFAOYAL
  • C1=CC(=O)NC1=O
Properties
C4H3NO2
Molar mass 97.07 g/mol
Melting point 91 to 93 °C (196 to 199 °F; 364 to 366 K)
organic solvents
Hazards
GHSlabelling:
GHS05: CorrosiveGHS06: ToxicGHS07: Exclamation mark
Danger
H301,H314,H317
P260,P261,P264,P270,P272,P280,P301+P310,P301+P330+P331,P302+P352,P303+P361+P353,P304+P340,P305+P351+P338,P310,P321,P330,P333+P313,P363,P405,P501
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).

Organic chemistry

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Maleimide and its derivatives are prepared frommaleic anhydrideby treatment withaminesfollowed by dehydration.[2]A special feature of the reactivity of maleimides is their susceptibility to additions across the double bond either byMichael additionsor viaDiels-Alderreactions.Bismaleimidesare a class of compounds with two maleimide groups connected by the nitrogen atoms via a linker, and are used ascrosslinking reagentsinthermoset polymerchemistry. Compounds containing a maleimide group linked with another reactive group, such as an activatedN-hydroxysuccinimideester, are calledmaleimide heterobifunctional reagents(seeSMCC reagentfor such an example).[1]

Natural maleimides

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One natural maleimide is thecytotoxicshowdomycinfromStreptomyces showdoensis,[3]andpencolidefromPe. multicolor[3]– have been reported.Farinomaleinwas first isolated in 2009 from theentomopathogenic fungusIsaria farinosa(Paecilomyces farinosus) – source H599 (Japan).[4]

Biotechnology and pharmaceutical applications

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Maleimide-mediated methodologies are among the most used inbioconjugation.[5][6]Due to fast reactions and high selectivity towardscysteineresidues inproteins,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.[7] For instance,antibody-drug conjugates,are constituted of three main components: amonoclonal antibody,a cytotoxic drug, and a linker molecule often containing a maleimide group, which conjugates the drug through thiols or dienes to the antibody.[8][9]

Maleimides linked topolyethylene glycolchains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily undergoes a retro-Michael reaction with thethiolgroup found oncysteineto 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.[10]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 (mucoadhesion) due to the reactions with thiol-containing mucins.[11][12][13]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.[14]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.[9]

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.[14]

Another problem with hydrolysis arises if it is applied toN-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.[9]

Technological applications

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Analogous toStyrene maleic anhydride,copolymersof maleimides andstyrenehave been commercialized.[15]

Mono- and bismaleimide-based polymers are used for high temperature applications up to 250 °C (480 °F).[16]Maleimides linked to rubber chains are often used as flexible linking molecules to reinforce rubber intires.The double bond readily reacts with allhydroxy,amineorthiolgroups 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'sF-22extensively uses thermoset composites, with bismaleimide and toughened epoxy comprising up to 17.5% and 6.6% of the structure by weight respectively.[17]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 fiberthermoset polymer matrixcomposites.[18]

See also

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References

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  1. ^abHermanson G (2013). "Chapter 6: Heterobifunctional Crosslinkers".Bioconjugate Techniques.Elsevier. pp. 299–339.doi:10.1016/B978-0-12-382239-0.00006-6.ISBN978-0-12-382239-0.
  2. ^Cava MP, Deana AA, Muth K, Mitchell MJ (1973)."N-Phenylmaleimide".Organic Syntheses;Collected Volumes,vol. 5, p. 944.
  3. ^abBirkinshaw JH, Kalyanpur MG, Stickings CE (February 1963)."Studies in the biochemistry of micro-organisms. 113. Pencolide, a nitrogen-containing metabolite of Penicillium multicolor Grigorieva-Manilova and Poradielova".The Biochemical Journal.86(2): 237–243.doi:10.1042/bj0860237.PMC1201741.PMID13971137.
  4. ^Putri SP, Kinoshita H, Ihara F, Igarashi Y, Nihira T (August 2009). "Farinomalein, a maleimide-bearing compound from the entomopathogenic fungus Paecilomyces farinosus".Journal of Natural Products.72(8): 1544–6.doi:10.1021/np9002806.PMID19670877.
  5. ^Koniev O, Wagner A (August 2015)."Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation".Chemical Society Reviews.44(15): 5495–5551.doi:10.1039/C5CS00048C.PMID26000775.
  6. ^Francis MB, Carrico IS (December 2010). "New frontiers in protein bioconjugation".Current Opinion in Chemical Biology.14(6): 771–773.doi:10.1016/j.cbpa.2010.11.006.PMID21112236.
  7. ^Hermanson G (2013). "Chapter 1 - Introduction to Bioconjugation".Bioconjugate Techniques.Elsevier. pp. 1–125.doi:10.1016/B978-0-12-382239-0.00001-7.ISBN978-0-12-382239-0.
  8. ^Beck A, Goetsch L, Dumontet C, Corvaïa N (May 2017). "Strategies and challenges for the next generation of antibody-drug conjugates".Nature Reviews. Drug Discovery.16(5): 315–337.doi:10.1038/nrd.2016.268.PMID28303026.S2CID22045270.
  9. ^abcLahnsteiner, Marianne; Kastner, Alexander; Mayr, Josef; Roller, Alexander; Keppler, Bernhard K.; Kowol, Christian R. (27 October 2020)."Improving the Stability of Maleimide–Thiol Conjugation for Drug Targeting".Chemistry – A European Journal.26(68): 15867–15870.doi:10.1002/chem.202003951.ISSN0947-6539.PMC7756610.PMID32871016.
  10. ^Ravasco, João M. J. M.; Faustino, Hélio; Trindade, Alexandre; Gois, Pedro M. P. (19 November 2018)."Bioconjugation with Maleimides: A Useful Tool for Chemical Biology".Chemistry – A European Journal.25(1): 43–59.doi:10.1002/chem.201803174.ISSN0947-6539.PMID30095185.
  11. ^Tonglairoum P, Brannigan RP, Opanasopit P, Khutoryanskiy VV (October 2016)."Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery".Journal of Materials Chemistry B.4(40): 6581–6587.doi:10.1039/C6TB02124G.PMID32263701.
  12. ^Kaldybekov DB, Tonglairoum P, Opanasopit P, Khutoryanskiy VV (January 2018)."Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder"(PDF).European Journal of Pharmaceutical Sciences.111:83–90.doi:10.1016/j.ejps.2017.09.039.PMID28958893.S2CID35605027.
  13. ^Moiseev RV, Kaldybekov DB, Filippov SK, Radulescu A, Khutoryanskiy VV (November 2022)."Maleimide-Decorated PEGylated Mucoadhesive Liposomes for Ocular Drug Delivery".Langmuir.38(45): 13870–13879.doi:10.1021/acs.langmuir.2c02086.PMC9671038.PMID36327096.
  14. ^abHuang, Wenmao; Wu, Xin; Gao, Xiang; Yu, Yifei; Lei, Hai; Zhu, Zhenshu; Shi, Yi; Chen, Yulan; Qin, Meng; Wang, Wei; Cao, Yi (4 February 2019)."Maleimide–thiol adducts stabilized through stretching".Nature Chemistry.11(4): 310–319.doi:10.1038/s41557-018-0209-2.ISSN1755-4330.PMID30718898.
  15. ^Maul, Jürgen; Frushour, Bruce G.; Kontoff, Jeffrey R.; Eichenauer, Herbert; Ott, Karl-Heinz; Schade, Christian (2007). "Polystyrene and Styrene Copolymers".Ullmann's Encyclopedia of Industrial Chemistry.doi:10.1002/14356007.a21_615.pub2.ISBN978-3-527-30385-4.
  16. ^Lin KF, Lin JS, Cheng CH (1996)."High temperature resins based on allylamine/bismaleimides"(PDF).Polymer.37(21): 4729–4737.doi:10.1016/S0032-3861(96)00311-4.
  17. ^Anderson WD, Mortara S (23–26 April 2007). "F-22 Aeroelastic Design and Test Validation".American Institute of Aeronautics and Astronautics (AIAA):4.doi:10.2514/6.2007-1764.ISBN978-1-62410-013-0.
  18. ^"Lockheed Martin F-35B Boasts UFO Technology, Fights For Team USA".International Science Times. 21 August 2013. Archived fromthe originalon 21 February 2014.Retrieved28 January2014.
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