Protected Maleimide Building Blocks for the Decoration of Peptides, Peptoids, and Peptide Nucleic Acids

Abstract

Monomers allowing for the introduction of [2,5-dimethylfuran]-protected maleimides into polyamides such as peptides, peptide nucleic acids and peptoids were prepared, as well as the corresponding oligomers. Suitable maleimide deprotection conditions were established in each case. The stability of the adducts generated by Michael-type maleimide-thiol reaction and Diels-Alder cycloaddition to maleimide deprotection conditions was exploited to prepare a variety of conjugates from peptide and PNA scaffolds incorporating one free and one protected maleimide. The target molecules were synthesized by using two subsequent maleimide-involving click reactions separated by a maleimide deprotection step. Carrying out maleimide deprotection and conjugation simultaneously gave better results than performing the two reactions subsequently.

Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

“…General Procedure for the Synthesis of Tert-butyl-(2-hydroxyethyl)carbamate 3a and Its Derivatives (3b-e) [25][26][27][28][29] To a solution of 2a (or 2b-e, 20 mmol) in a mixture of dioxane (15 mL) and H 2 O (7 mL), was added 5N NaOH (4.8 mL) and a solution of Boc 2 O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred at rt overnight, the reaction mixture was concentrated in vacuo.…”

Orthogonal Protection of Peptides and Peptoids for Cyclization by the Thiol–Ene Reaction and Conjugation

“…However, since we had observed that the quality of cyclic peptide crudes was a bit lower when cyclization took place upon treatment with TFA, 22 we incorporated the 2,5-dimethylfuran-protected maleimidopropanoic acid. 27 To introduce maleimide moieties at other positions of the chain, 2-[(2,5-dimethylfuranprotected) maleimide]-1-aminoethane 23 should be employed. In the absence of two orthogonal maleimide protecting groups, this precludes use of maleimides for subsequent conjugation.…”

“…23 When the peptide is linear, H 2 O 2 oxidizes the free thiol to sulfonic acid (and the mass increases 48 units), whereas when the peptide is cyclic the thioether is oxidized to sulfoxide (and the mass increases 16 units).…”

Syntesis and Crystalline Structure of the Exo-3,6-Dimethyl-3,6-Epoxi-1,2,3,6-Tetrahydrophtlalimide and Its N-Bromodecyl Analog: Two Thermally Labile Diels-Alder Adducts

“…exo-3,6-dimethyl-3,6-epoxi-1,2,3,6-tetrahydrophthalimide (1) was prepared following the previous report of Elduque, X. et al 10 , introducing slightly modifications; the more remarkable feature of the 1 H NMR spectrum for (1) reported by Elduque is the assignation done to the double bond protons (i.e. the CH protons located at positions 4 and 5) they were assigned at 6.31 ppm for both the exo and the endo isomers.…”

“…thermal or light irradiation) 9 . As a thermally labile protecting group has been included in synthetic schemes to provide for peptides, peptoids and peptide nucleic acids 10 and Maleimide functionalized gold nanoparticles 11,12 . From the structural point of view, the DA adducts between Furan and Maleimide, has been studied mainly for its N-substituted analogs, thus in this way the X-ray crystallography of the N-amino 13,14 , N-acetoxyphenyl 15 and N-aryl 16 has been studied; Surprisingly, for the DA adduct of 2,5-dimethylfuran and Maleimide the molecular structure has not been determined using X-ray diffraction analysis.…”