Maleimide is a

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

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 Maleic acid or ''cis''-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the ''cis''-isomer of butenedioic acid, whereas fumaric ac ...

and imide, the -C(O)NHC(O)-

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...

. Maleimides also describes a ''class'' of derivatives of the parent maleimide where the N''H'' group is replaced with

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloa ...

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromaticity, aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar ...

groups such as a methyl or

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

, respectively. The substituent can also be a small molecule (such as biotin, a fluorescent dye, an

oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...

, or a nucleic acid), a reactive group, or a synthetic polymer such as

polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...

. Human

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...

chemically modified with maleimide-polyethylene glycol is a blood substitute called MP4.

Organic chemistry

Maleimide and its derivatives are prepared from

maleic anhydride Maleic anhydride is an organic compound with the formula C2H2(CO)2O. It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and pol ...

by treatment with

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen Hydrogen is the chemical element wi ...

s followed by dehydration. A special feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by

Michael addition In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...

s 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 (for example, see SMCC reagent).

Natural maleimides

Only a handful of natural maleimides – exemplified by the cytotoxic showdomycin from ''

Streptomyces showdoensis ''Streptomyces showdoensis'' is a bacterium species from the genus of ''Streptomyces'' which has been isolated from soil in Shōdoshima, Japan.Deutsche Sammlung von Mikroorganismen und Zellkulturenbr>/ref> ''Streptomyces showdoensis'' produces ...

'', and

pencolide Pencolide is a maleimide isolate of ''Penicillium'' and seaweed endophytic fungi An endophyte is an endosymbiont, often a bacterium or fungus, that lives within a plant for at least part of its life cycle without causing apparent disease. Endop ...

from ''Pe. multicolor'' – have been reported.

Farinomalein Farinomalein is a natural maleimide with formula C10H13NO4 - was first isolated from the entomopathogenic fungus '' Isaria farinosa'' (''Paecilomyces farinosus'') - source H599 (Japan). Farinomalein has shown potent and selective inhibition (0.15 ...

was first isolated in 2009 from the

entomopathogenic fungus An entomopathogenic fungus is a fungus that can kill or seriously disable insects. Typical life cycle These fungi usually attach to the external body surface of insects in the form of microscopic spores (usually asexual, mitosporic spores also ...

''Isaria farinosa'' (''Paecilomyces farinosus'') – source H599 (Japan).Sastia P. Putri, Hiroshi Kinoshita, Fumio Ihara, Yasuhiro Igarashi and Takuya Nihira. "Farinomalein, a Maleimide-Bearing Compound from the Entomopathogenic Fungus Paecilomyces farinosus". ''J. Nat. Prod.'', 2009, 72 (8), pp. 1544–1546.

Biotechnology and pharmaceutical applications

Maleimide-mediated methodologies are among the most used in bioconjugation. Due to exceptionally fast reaction rates and significantly 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. For instance, emerging promising targeted drug therapies,

antibody-drug conjugates Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

, are constituted of three main components: a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

, a cytotoxic drug, and a linker molecule often containing a maleimide group, which binds the drug and the antibody. Maleimides linked to

chains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily reacts with the

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

group found on cysteine 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. Maleimide-functionalised polymers and liposomes exhibit enhanced ability to adhere to mucosal surfaces (

mucoadhesion Mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are gener ...

) due to the reactions with thiol-containing mucins. This could be applicable in the design of dosage forms for transmucosal drug delivery.

Technological applications

Mono- and bismaleimide-based polymers are used for high temperature applications up to . Maleimides linked to rubber chains are often used as flexible linking molecules to reinforce rubber in

tires A tire (American English) or tyre (British English) is a ring-shaped component that surrounds a wheel's rim to transfer a vehicle's load from the axle through the wheel to the ground and to provide traction on the surface over which t ...

. The double bond readily reacts with all hydroxy,

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 The Lockheed Martin F-22 Raptor is an American single-seat, twin-engine, all-weather stealth tactical fighter aircraft developed for the United States Air Force (USAF). As the result of the USAF's Advanced Tactical Fighter (ATF) program, the ...

extensively uses thermoset composites, with bismaleimide and toughened epoxy comprising up to 17.5% and 6.6% of the structure by weight respectively. 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.

References

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External links