Photochemical formation of quinone methides from peptides containing modified tyrosine

Abstract

We have demonstrated that quinone methide (QM) precursors can be introduced in the peptide structure and used as photoswitchable units for peptide modifications. QM precursor 1 was prepared from protected tyrosine in the Mannich reaction, and further used as a building block in peptide synthesis. Moreover, peptides containing tyrosine can be transformed into a photoactivable QM precursor by the Mannich reaction which can afford monosubstituted derivatives 2 or bis-substituted derivatives 3. Photochemical reactivity of modified tyrosine 1 and dipeptides 2 and 3 was studied by preparative irradiation in CHOH where photodeamination and photomethanolysis occur. QM precursors incorporated in peptides undergo photomethanolysis with quantum efficiency Φ = 0.1-0.2, wherein the peptide backbone does not affect their photochemical reactivity. QMs formed from dipeptides were detected by laser flash photolysis (λ ≈ 400 nm, τ = 100 μs-20 ms) and their reactivity with nucleophiles was studied. Consequently, QM precursors derived from tyrosine can be a part of the peptide backbone which can be transformed into QMs upon electronic excitation, leading to the reactions of peptides with different reagents. This proof of principle showing the ability to photochemically trigger peptide modifications and interactions with other molecules can have numerous applications in organic synthesis, materials science, biology and medicine.

The Phenanthridine-modified Tyrosine Dipeptide

“…Silica gel (0.05-0.2 mm) was used for chromatographic purifications. Precursor molecules 1-Me [11,36] and 2 [25] were prepared according to the published procedures. Methyl ester deprotection of 1-Me and characterization of 1 is given in the SI.…”

“…The dipeptide 4 contains modified tyrosine susceptible to the photoinduced deamination, [23,25] that gives rise to QMs, which again can alkylate DNA or RNA. [26] To preliminary test the photochemical reactivity for dipeptide 4 with DNA/RNA, dipeptide 4 was irradiated (λ=300 nm) in the presence of polynucleotides, followed by recording CD spectra ( Figures 6−8, r = 0.7 irradiated).…”

“…[24] Recently we incorporated QM precursor into tyrosine and showed that 2 (Scheme 1) remains photochemically reactive when incorporated in oligopeptide. [25] Herein we report the synthesis of dipeptide 4 (Scheme 1) containing unnatural amino acids 1 and 2. The N-terminus contains phenanthridine amino acid 1, which is anticipated to bind to polynucleotides by noncovalent interactions.…”

Attention-deficit/hyperactivity disorder - unifying mechanism involving antioxidant therapy: Phenolics, reactive oxygen species, and oxidative stress

“…Analogy can be found in oxidation of phenylalanine to tyrosine, followed by hydroxylation (30) and then presumably oxidation to the ET oquinone. Protein modified tyrosine can be oxidized to the quinone methide [31] . Additionally, quinine methide is believed to play an important role in biosynthesis and in bioactivity of antitumor compounds [32] .…”

Non-Covalent Binding of Tripeptides-Containing Tryptophan to Polynucleotides and Photochemical Deamination of Modified Tyrosine to Quinone Methide Leading to Covalent Attachment

“…These findings prompted us to investigate the non-covalent binding to polynucleotides for a series of tripeptides 1×HCl – 3×HCl ( Figure 1 ) containing bis-tryptophan units, wherein the C-terminus contained Phe, Tyr, or modified Tyr, which is photochemically reactive [ 52 ]. Upon excitation by light, the modified tyrosine undergoes photodeamination delivering QM [ 53 , 54 ], and if such peptide is non-covalently bound to DNA or RNA, that would allow QM to react with DNA/RNA and induce permanent covalent damage.…”