Simple and Rapid Synthesis of Branched Peptides through Microwave-Assisted On-Bead Ligation

Molakaseema, Vijayasimha; Selvaraj, Anand; Chen, Hui Ting; Chen, Yen Wei; Liu, Yi Chang; Kao, Ching Huei

doi:10.1021/acs.joc.1c01455

Cited by 6 publications

(13 citation statements)

References 30 publications

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“…This fact hampered the efficiency of the nucleophilic addition at the cleave step and led to the low yield. Furthermore, in an earlier investigation, 11 Scheme 2. Synthetic Routes for 3 and 4 a a Reaction conditions: (i) 20% piperidine in DMF, 2 × 10 min; (ii) Boc-Lys(Fmoc)-OH (29 mM, 3.5 equiv), HBTU (3.5 equiv), 5% NMM in DMF, 1 h, rt; (iii) Fmoc-Lys(Boc)-OH (29 mM, 3.5 equiv), HBTU (3.5 equiv), 5% NMM in DMF, 1 h, rt; (iv) Boc-Lys(Boc)-OH (29 mM, 3.5 equiv), HBTU (3.5 equiv), 5% NMM in DMF, 2 h, rt; (v) isoamylnitrite (125 mM, 10 equiv), DMF, 1.5 h, rt; (vi) propargylamine (53 mM, 4 equiv), DIPEA in DMF (8 equiv), 6 h, rt; (vii) TFA:H 2 O (95:5).…”

Section: ■ Results and Discussionmentioning

confidence: 95%

“…This fact hampered the efficiency of the nucleophilic addition at the cleave step and led to the low yield. Furthermore, in an earlier investigation, 11 longer reaction time leads to hydrolytic product accumulation, which increases the purification effort. Therefore, no further optimization proceeded.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Using orthogonally protected lysine residues, G2 lysine defect dendrimers (2−4) with various configurations were prepared in 82−88% yield within 13 h. The same method with higher reagent concentrations was applied to prepare G3 (11) and G4 (15) analogs in 48 and 79% yields, respectively. Remarkably, higher reactant concentrations effectively shortened the preparation time.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Lys) 2 Lys)-( ε NH 2 )Lys) 2 -Lys-Gly-Propargylamine(11). 5 was shaken in the solution of 20% piperidine in DMF (1.5 mL) for 10 min twice for deprotection.…”

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confidence: 99%

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Facile Solid-Phase Synthesis of Well-Defined Defect Lysine Dendrimers

et al. 2022

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An efficient solid-phase method has been reported to prepare well-defined lysine defect dendrimers. Using orthogonally protected lysine residues, pure G2 to G4 lysine defect dendrimers were prepared with 48–95% yields within 13 h. Remarkably, high-purity products were collected via precipitation without further purification steps. This method was applied to prepare a pair of 4-carboxyphenylboronic acid-decorated defect dendrimers ( 16 and 17 ), which possessed the same number of boronic acids. The binding affinity of 16 , in which the ε-amines of G1 lysine are fractured, for glucose and sorbitol was 4 times that of 17 . This investigation indicated the role of allocation and distribution of peripheries for the dendrimer’s properties and activity.

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Section: ■ Results and Discussionmentioning

confidence: 95%

Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

“…Lys) 2 Lys)-( ε NH 2 )Lys) 2 -Lys-Gly-Propargylamine(11). 5 was shaken in the solution of 20% piperidine in DMF (1.5 mL) for 10 min twice for deprotection.…”

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confidence: 99%

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Facile Solid-Phase Synthesis of Well-Defined Defect Lysine Dendrimers

et al. 2022

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“…Preparation of multimeric, branched forms of peptide reagents has been used to maintain selectivity while increasing avidity, which allows for stronger binding compared to the correspondent monomeric peptides [15][16][17] . However, the synthesis of branched peptides can be challenging due to the shared branching amino acid.…”

Section: Resultsmentioning

confidence: 99%

Branched multimeric peptides as affinity reagents for detection of α-Klotho protein

Zhang

Wang

et al. 2023

Preprint

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α-Klotho is a protein associated with aging that is expressed in the kidney, parathyroid gland, and choroid plexus. As a transmembrane protein, it acts as an essential co-receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. α-Klotho has an extracellular domain that can be cleaved, released and circulated in the blood stream as a soluble form. Decreased levels of α-Klotho are an indication of chronic kidney disease and other age-associated diseases. Detecting or labeling transmembrane and soluble α-Klotho is a longstanding challenge that has impeded the in-depth understanding of its role. Here we describe branched multimeric peptides that recognize α-Klotho with high affinity and selectivity in the biological milieu. The branched peptides are prepared in a single-shot synthesis by parallel automated fast-flow synthesis in under one hour. The branched α-Klotho-binding peptides show improvement in affinity relative to the monomeric versions and can be used to label Klotho for live imaging in kidney cells. Our results demonstrate the potential of automated flow technology to deliver peptide-based reagents with complex architecture and improved affinity for the selective binding of target proteins in physiological settings.

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Solid‐Phase Synthesis of Peptidols via Reductive Cleavage Through a Benzotriazole Linker

Chen,

Chuang,

Rajavel

et al. 2024

Adv Synth Catal

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Peptidols were prepared through the reductive cleavage of benzotriazole intermediates obtained from the on‐bead activation of 3,4‐diaminobenzoyl linkers. Remarkably, this method used commercially available amino acid residues and resins without further modification. Pure peptidols were collected with only filtration in 49%–87% yield. Only the derivatives with aspartic acid as the first C‐terminal residue required sophisticated chromatography purification. Esters and carboxylic acids were identified as side products and were suppressed by additional reduction or reduction in DMF. Remarkably, the reduction of peptides with the first aspartic acid residue at the C‐terminal afforded a C‐terminal lactone, which could be reduced by deprotection at 0°C. For the synthesis of branched peptidols, the bulky wedge structures of the branched peptides resulted in low total yields, which were improved to 23%–28% by using peripheral Boc groups and SPPS on the Tental gel resin. In addition, this method gave two peptaibols, SPF‐5506‐A4 and Ac‐Gramicidin A, in 11% and 46% yields, respectively.

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Simple and Rapid Synthesis of Branched Peptides through Microwave-Assisted On-Bead Ligation

Cited by 6 publications

References 30 publications

Facile Solid-Phase Synthesis of Well-Defined Defect Lysine Dendrimers

Facile Solid-Phase Synthesis of Well-Defined Defect Lysine Dendrimers

Branched multimeric peptides as affinity reagents for detection of α-Klotho protein

Solid‐Phase Synthesis of Peptidols via Reductive Cleavage Through a Benzotriazole Linker

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