Synthesis of Stapled β<sup>3</sup>-Peptides through Ring-Closing Metathesis

Bergman, Ylva Elisabet; Borgo, Mark P. Del; Gopalan, Romila D.; Jalal, Sania; Unabia, Sharon; Ciampini, Marisa; Clayton, Daniel; Fletcher, Jordan M.; Mulder, Roger J.; Wilce, Jacqueline A.; Aguilar, Marie Isabel; Perlmutter, Patrick

doi:10.1021/ol901803d

Cited by 29 publications

(34 citation statements)

References 32 publications

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“…This analysis, supported by recent work of Perlmutter42 and Seebach44 suggested that a 21-atom bridge could be accommodated between most i and i + 3 positions of a 14-helix. To test this prediction, we synthesized an analog of β-peptide 2 7 containing (O-allyl)-β 3 -L-Ser at positions 3 and 6 ( 2(3-6) , Figure 1), and subjected it to on-resin ring-closing metathesis using bis(tricyclohexylphosphine)benzylidene ruthenium (IV) dichloride34 to generate 2(3-6)s 45.…”

supporting

confidence: 63%

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

et al. 2010

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β-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with α–helical ligands. β–peptides are not usually cell permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg8 sequence to a β–peptide improves uptake but adds considerable mass. We reported that embedding a small cationic patch within a PPII, α– or β–peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i+4 positions of an α–helix also increases cell uptake. Here we describe a series of β–peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of cationic patch and hydrophobic bridge strategies for improving β–peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.

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supporting

confidence: 63%

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

et al. 2010

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“…A wealth of knowledge derived from computational 114,115 and experimental 47,116−118 approaches has illuminated the minimal constraints necessary for achieving RCM on peptides using first- and second-generation or Grubbs–Hoveyda ruthenium catalysts. 119,120 An unmet challenge in the synthesis of stapled peptides has been the ability to control olefin geometry in the product, as the use of noncyclometalated ruthenium catalysts typically gives rise to both E and Z isomers that are often inseparable. This imposes challenges for examining the role of olefin geometry in the stability and biological activity of stapled peptides, which, to date, has not been thoroughly explored.…”

Section: Resultsmentioning

confidence: 99%

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

2014

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Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors.

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“…Note added in proof: While the present paper was in print, an independent synthesis of hydrocarbonchain-tethered b 3 -peptides by P. Perlmutter and his group was published [26]. For structural assignment, a couple of 3 14 -helix-typical NOEs and CD-intensity comparisons were used.…”

mentioning

confidence: 99%

Synthesis and High‐Resolution NMR Structure of a β³‐Octapeptide with and without a Tether Introduced by Olefin Metathesis

Ebert

Gardiner

Ballet

et al. 2009

Helvetica Chimica Acta

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Bridging between (i)-and (i þ 3)-positions in a b3 -peptide with a tether of appropriate length is expected to prevent the corresponding 3 14 -helix from unfolding ( hIle-OH (1; with allylated bhSer residues in 3-and 6-position), and three tethered b-peptides 2 -4 (related to 1 through ring-closing metathesis) have been synthesized (solid-phase coupling, Fmoc strategy, on chlorotrityl resin; Scheme). A comparative CD analysis of the tethered b-peptide 4 and its non-tethered analogue 1 suggests that helical propensity is significantly enhanced (threefold CD intensity) by a (CH 2 ) 4 linker between the b 3 hSer side chains (Fig. 2). This conclusion is based on the premise that the intensity of the negative Cotton effect near 215 nm in the CD spectra of b 3 -peptides represents a measure of helical content. An NMR analysis in CD 3 OH of the two b 3 -octapeptide derivatives without (i.e., 1) and with tether (i.e., 4; Tables 1 -6, and Figs. 4 and 5) provided structures of a degree of precision (by including the complete set of side chainside chain and side chain -backbone NOEs) which is unrivaled in b-peptide NMR-solution-structure determination. Comparison of the two structures (Fig. 5) reveals small differences in side-chain arrangements (separate bundles of the ten lowest-energy structures of 1 and 4, Fig. 5, A and B) with little deviation between the two backbones (superposition of all structures of 1 and 4, Fig. 5, C). Thus, the incorporation of a CH 2 ÀOÀ(CH 2 ) 4 ÀOÀCH 2 linker between the backbone of the b 3 -amino acids in 3-and 6-position (as in 4) does accurately constrain the peptide into a 3 14 -helix. The NMR analysis, however, does not suggest an increase in the population of a 3 14 -helical backbone conformation by this linkage. Possible reasons for the discrepancy between the conclusion from the CD spectra and from the NMR analysis are discussed.

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Synthesis of Stapled β³-Peptides through Ring-Closing Metathesis

Cited by 29 publications

References 32 publications

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Synthesis and High‐Resolution NMR Structure of a β³‐Octapeptide with and without a Tether Introduced by Olefin Metathesis

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Synthesis of Stapled β3-Peptides through Ring-Closing Metathesis

Cited by 29 publications

References 32 publications

Bridged β3-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Bridged β3-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Synthesis and High‐Resolution NMR Structure of a β3‐Octapeptide with and without a Tether Introduced by Olefin Metathesis

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Synthesis of Stapled β³-Peptides through Ring-Closing Metathesis

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Bridged β³-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Synthesis and High‐Resolution NMR Structure of a β³‐Octapeptide with and without a Tether Introduced by Olefin Metathesis