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Maleimide

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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 100.007.990 Edit 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-N checkY
  • 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
GHS labelling:
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 their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Maleimide is a chemical compound with the formula H2C2(CO)2NH (see diagram). This unsaturated imide is an important building block in organic synthesis. The name is a contraction of maleic acid and imide, the -C(O)NHC(O)- functional group. Maleimides also describes a class of derivatives of the parent maleimide where the NH group is replaced with alkyl or aryl groups such as a methyl or phenyl, respectively. The substituent can also be a small molecule (such as biotin, a fluorescent dye, an oligosaccharide, or a nucleic acid), a reactive group, or a synthetic polymer such as polyethylene glycol.[1] Human hemoglobin chemically modified with maleimide-polyethylene glycol is a blood substitute called MP4.

Organic chemistry

Maleimide and its derivatives are prepared from maleic anhydride by treatment with amines followed by dehydration.[2] A special feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by Michael additions or via Diels-Alder reactions. Bismaleimides are a class of compounds with two maleimide groups connected by the nitrogen atoms via a linker, and are used as crosslinking reagents in thermoset polymer chemistry. Compounds containing a maleimide group linked with another reactive group, such as an activated N-hydroxysuccinimide ester, are called maleimide heterobifunctional reagents (see SMCC reagent for such an example).[1]

Natural maleimides

One natural maleimide is the cytotoxic showdomycin from Streptomyces showdoensis,[3] and pencolide from Pe. multicolor[3] – have been reported. Farinomalein was first isolated in 2009 from the entomopathogenic fungus Isaria farinosa (Paecilomyces farinosus) – source H599 (Japan).[4]

Biotechnology and pharmaceutical applications

Maleimide-mediated methodologies are among the most used in bioconjugation.[5][6] Due to fast reactions and high selectivity towards cysteine residues in proteins, 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: a monoclonal 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 to polyethylene glycol chains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily undergoes a retro-Michael reaction with the thiol group found on cysteine 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.[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 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.[9]

Technological applications

Analogous to Styrene maleic anhydride, copolymers of maleimides and styrene have 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 in tires. The double bond readily reacts with all hydroxy, amine or thiol 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 F-22 extensively 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 fiber thermoset polymer matrix composites.[18]

See also

References

  1. ^ a b Hermanson G (2013). "Chapter 6: Heterobifunctional Crosslinkers". Bioconjugate Techniques. Elsevier. pp. 299–339. doi:10.1016/B978-0-12-382239-0.00006-6. ISBN 978-0-12-382239-0.
  2. ^ Cava MP, Deana AA, Muth K, Mitchell MJ (1973). "N-Phenylmaleimide". Organic Syntheses; Collected Volumes, vol. 5, p. 944.
  3. ^ a b Birkinshaw 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. PMC 1201741. PMID 13971137.
  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. PMID 19670877.
  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. PMID 26000775.
  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. PMID 21112236.
  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. ISBN 978-0-12-382239-0.
  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. PMID 28303026. S2CID 22045270.
  9. ^ a b c Lahnsteiner, 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. ISSN 0947-6539. PMC 7756610. PMID 32871016.
  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. ISSN 0947-6539. PMID 30095185.
  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. PMID 32263701.
  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. PMID 28958893. S2CID 35605027.
  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. PMC 9671038. PMID 36327096.
  14. ^ a b Huang, 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. ISSN 1755-4330. PMID 30718898.
  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. ISBN 978-3-527-30385-4.
  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. ISBN 978-1-62410-013-0.
  18. ^ "Lockheed Martin F-35B Boasts UFO Technology, Fights For Team USA". International Science Times. 21 August 2013. Archived from the original on 21 February 2014. Retrieved 28 January 2014.
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