Product Code Database
Maleimide is a chemical compound with the chemical 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 are also a class of derivatives of the parent maleimide where the N H 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. (2025). 9780123822390, Elsevier. ISBN 9780123822390 Human hemoglobin chemically modified with maleimide-polyethylene glycol is a blood substitute called MP4.
A defining feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by or via Diels-Alder reactions. In this context, bismaleimides, compounds with two maleimide groups connected by the nitrogen atoms via a linker, 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 .
Maleimide is weakly acidic, with a pKa estimated at 10.
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. 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. 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. 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.
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.
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.
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. The double bond readily reacts with all Hydroxyl, 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.
Technological applications
Analogous to Styrene maleic anhydride, of maleimides and styrene have been commercialized. (2025). 9783527303854 ISBN 9783527303854
9781624100130 ISBN 9781624100130 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.
See also
External links
|
|
