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 In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwee ...

H₂C₂(CO)₂NH (see diagram). This unsaturated

imide In organic chemistry, an imide is a functional group consisting of two acyl groups bound to nitrogen. The compounds are structurally related to acid anhydrides, although imides are more resistant to hydrolysis. In terms of commercial applications, ...

is an important building block in

organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...

. 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

, 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 rest ...

. 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 cycloalk ...

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

groups such as a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

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 Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name ''biotin'', bor ...

, 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 sugar ...

, or a

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...

), 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 (erythrocyte ...

chemically modified with maleimide-polyethylene glycol is a

blood substitute A blood substitute (also called artificial blood or blood surrogate) is a substance used to mimic and fulfill some functions of biological blood. It aims to provide an alternative to blood transfusion, which is transferring blood or blood-based ...

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 atoms have been replaced by a substituen ...

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 reagent In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...

s 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 Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

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 Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

residues in

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

, 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 ca ...

, 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

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 Rim (wheel), wheel's rim to transfer a vehicle's load from the axle through the wheel to the ground and to provide Traction (engineering), 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, th ...

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 A thermoset polymer matrix is a synthetic polymer reinforcement where polymers act as binder or matrix to secure in place incorporated particulates, fibres or other reinforcements. They were first developed for structural applications, such as gla ...

composites.

References

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External links