The cyclization of peptides and depsipeptides

Davies, John S.

doi:10.1002/psc.491

Cited by 417 publications

(256 citation statements)

References 228 publications

(185 reference statements)

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“…From Scheme 10, one can easily infer that peptide cyclization could be used in prodrug design by two different approaches: (i) linear peptides acting as cyclization-activated prodrugs of bioactive cyclic peptides; (ii) linear peptides acting as drug carriers in prodrugs that can be activated through cyclization of the peptide moiety. Approach (i) is not easy to accomplish if a strictly chemical drug release pathway is desired, as spontaneous cyclization of oligopeptides in solution does not easily occur without the intervention of specific enzymes; exception is made to some dipeptides that easily cyclize to piperazine-2,5-diones or diketopiperazines (DKP, 15) [43][44][45][46][47][48][49]. The DKP scaffold is widely found in compounds of biological interest and could serve as a drug template with appropriate arrayed pharmacophores.…”

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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“…Nevertheless, for cyclic peptide synthesis in solution or solid phase, the yield of cyclization strongly relies on choice of cyclization sites, i.e.,ütheütwoüterminalüresiduesüofülinearüpeptidesü [42]. This means that the two terminal residues possibly affectü bü ionü cyclizations.…”

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confidence: 99%

Cyclization reaction of peptide fragment ions during multistage collisionally activated decomposition: An inducement to lose internal amino-acid residues

Jia

2007

J. Am. Soc. Mass Spectrom.

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During characterization of some peptides (linear precursors of the cyclic peptides showing potential to be anticancer drugs) in an ion trap, it was noted that many internal amino acid residues could be lost from singly charged b ions. The phenomenon was not obvious at the first stage of collisionally activated decomposition (CAD), but was apparent at multiple stages of CAD. The unique fragmentation consisting of multiple steps is induced by a cyclization reaction of b ions, the mechanism of which has been probed by experiments of N-acetylation, MS n , rearranged-ion design, and activation-time adjustment. The fragmentation of synthetic cyclic peptides demonstrates that a cyclic peptide intermediate (CPI) formed by b ion cyclization exhibits the same fragmentation pattern as a protonated cyclic peptide. Although no rules for the cyclization reaction were discerned in the experiments of peptide modification, the fragmentations of a number of b ions indicate that the "Pro and Asn/Gln effects" can influence ring openings of CPIs. In addition, large-scale losses of internal residues from different positions of a-type ions have been observed when pure helium was used as collision gas. The fragmentation is initiated by a cyclization reaction forming an a-type ion CPI. This CPI with a fixed-charge structure cannot be influenced by the "Pro effect", causing a selective ring opening at the amide bond Pro-Xxx rather than Xxx-Pro. With the knowledge of the unique fragmentations leading to internal residue losses, the misidentification of fragments and sequences of peptides may be avoided. [5,6] sequencings. For the top-down sequencing, the protein sample without enzymatic digestion is transferred into the gas phase intact, which has the potential for 100% sequence coverage of the protein and improved detection of post-translational modifications [4]. The bottom-up sequencing requires MS/MS analysis of the proteolytic fragments and database searching using algorithms such as Mascot and Sequest [5,6]. In addition, structural elucidations of natural or synthetic peptides, including linear peptides [7,8], cyclic peptides [9,10], and peptide analogues [11] also rely on MS/MS analysis. Undoubtedly, all of the applications described above are based on understanding the dissociation mechanisms of peptides, which have been well summarized in recent reviews [12][13][14][15][16]. However, conventional knowledge of fragmentation pathways and rules cannot reasonably explain many anomalous fragmentations. For example, some groups have reported that certain peptides show enhanced cleavage at special amino acid residues to produce incomplete sequence information [15]. Hence, the study on fragmention intensity relationship was of further concern and specially reviewed by Paizs and Suhai [16]. Also, another class of anomalous fragmentations introduced in this paper should receive attention.For peptide sequencing, the ideal fragmentation pattern of peptides is that the amino acid residues are sequentially lost from the C/N-terminus. However,...

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“…Several successful cyclizations via ester bond formation (lactonization) have been reported [1][2][3], but ring closure via formation of an amide bond (lactamization) [4][5][6] is usually easier and therefore preferred [7].…”

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confidence: 99%

Synthesis of Enniatin‐like Cyclic Depsipeptides via ‘Direct Amide Cyclization’

Köttgen

Linden

Heimgartner

2006

Helvetica Chimica Acta

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The synthesis of several 18-membered cyclodepsipeptides with an alternating sequence of a,adisubstituted a-amino acids and a-hydroxy acids (compounds 14a-14e) is described. The ring closure via macrolactonization was accomplished by treatment of a diluted suspension of the corresponding linear precursors 12a-12e in toluene with HCl gas, i.e., the so-called 'direct amide cyclization'. The incorporation of the a,a-disubstituted a-amino acids was achieved via the 'azirine/oxazolone method' with 2H-azirin-3-amines of type 6 and 9 as building blocks. The structure of the cyclic depsipeptide 14a was established by X-ray crystallography.

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The cyclization of peptides and depsipeptides

Cited by 417 publications

References 228 publications

Cyclization-activated Prodrugs

Cyclization-activated Prodrugs

Cyclization reaction of peptide fragment ions during multistage collisionally activated decomposition: An inducement to lose internal amino-acid residues

Synthesis of Enniatin‐like Cyclic Depsipeptides via ‘Direct Amide Cyclization’

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