Cyclic tetrapeptides via the ring contraction strategy: chemical techniques useful for their identification

Horton, Douglas A.; Bourne, Gregory T.; Coughlan, Justin F.; Kaiser, Sonya M.; Jacobs, Carolyn; Jones, Ashley; Rühmann, Andreas; Turner, Jill Y.; Smythe, Mark L.

doi:10.1039/b800464a

Cited by 38 publications

(46 citation statements)

References 40 publications

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“…More recently, after optimization of the cyclization and photolysis steps, a family of cyclic tetrapeptides has been synthesized, which are not accessible by other means [35]. Nevertheless, the success of the synthesis depends highly on the sequences and, in general, overall yields are low, a fact that is attributed to the photolysis step.…”

Section: Cyclic Peptides: Challenges and New Methodologymentioning

confidence: 98%

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

2009

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Although not complying with Lipinski's rule, peptides are to an increasing extent being developed into new active pharmaceutical ingredients. This is mainly due to novel application routes, formulations and chemical modifications, which confer on the peptides improved uptake and increased metabolic stability. A brief survey of currently approved peptide drugs and the present scope of the application of peptides as drugs is provided. Cyclic peptides are emerging as an interesting class of peptides with conformational rigidity and homogeneity, high receptor affinity and selectivity, increased metabolic stability and - in special cases - even oral availability. Challenges and new methodology for the synthesis of cyclic peptides are outlined and an overview of approaches toward the design of peptide conformation and peptide modification by nonproteinogenic building blocks is given.

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Section: Cyclic Peptides: Challenges and New Methodologymentioning

confidence: 98%

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

2009

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“…1d) linked to HnB, was cyclized in 45% yield at a 0.001 M concentration. The authors have also applied this ring-contraction strategy to the synthesis of cyclic tetrapeptide libraries 77 . They were even able to show that this strategy is amenable to the synthesis of highly constrained all-l cyclic tetrapeptides 78 .…”

Section: Ring-contraction Strategies Involving Lactonesmentioning

confidence: 99%

Contemporary strategies for peptide macrocyclization

2011

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Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.

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“…然而, 由于环四肽的结构中含有高度限制的 12 元环, 使得通常具有平面结构的酰胺键被扭曲 [5,7] . 结果导致环四肽具有较大的分子内张力, 造成其合成非常困难 [8,9] . 使用常规方法将线性四肽进行环合, 即使在高度稀释的条件下, 也将主要生成分子间寡聚物, 而不是分子内环化产物 [10,11] .…”

Section: Lactobacillus Helveticus 中分离得到的环(L-脯-l-酪-l-脯 -L-异亮 ) 四肽具 unclassified

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

Tang¹,

Zheng²,

Yang³

et al. 2012

Acta Chim. Sinica

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Naturally occurring or man-made cyclic tetrapeptides have unique rigid skeletons and therefore, represent an interesting class of candidate bioactive molecules in drug discovery. However, efficient chemical synthesis of cyclic tetrapeptides often presents a difficult problem due to the large strain involved in this category of target compounds. To overcome this problem we describe in the present study the use of peptide hydrazides for the preparation of highly strained 12-membered all-L cyclic tetrapeptides. The new synthetic route starts with the easy Fmoc solid phase synthesis of a linear N-Cys-tetrapeptide hydrazide precursor. Upon quick activation by NaNO 2 at pH 3 and -10 ℃ for 20 min followed by treatment with a pH 7 buffer containing an external thiol (4-mercaptophenylacetic acid, 40 equiv.) at room temperature, the N-Cys-tetrapeptide hydrazide precursor is converted in situ to an N-Cys-tetrapeptide thioester. This thioester undergoes a fast intramolecular thioester exchange reaction to generate a 13-membered thiolactone intermediate. Then an S-to-N acyl shift is expected to take place to create an amide bond, which affords the desired cyclic tetrapeptide in a modest overall yield (ca. 40%). Finally, desulfurization of the cyclic peptide product can be carried out to produce the target cyclic tetrapeptide that does not contain any Cys residue. Through detailed 1 H, 13 C, and TOSCY NMR and HPLC analyses, it is found that the new method for tetrapeptide synthesis can be carried out at relatively high substrate concentrations (0.8-1.0 mmol/L) without causing the formation of much cyclic octapeptide byproduct. Our test also showed that the reaction can generate the desired cyclic tetrapeptide in an epimerization free manner. By using the new method we have successfully prepared several cyclic tetrapeptides including cyclo(Ala-Leu-Ala-Leu), cyclo(Ala-His-Gly-Trp), and cyclo(Ala-Val-Gly-Ile) in 18%-25% overall yields. We expect that our method of cyclic tetrapeptide synthesis may find applications in the development of cyclic peptide libraries for bioactivity screening.

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Cyclic tetrapeptides via the ring contraction strategy: chemical techniques useful for their identification

Cited by 38 publications

References 40 publications

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

Contemporary strategies for peptide macrocyclization

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

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