Synthesis of Macrocyclic β-Strand Templates by Ring Closing Metathesis

Abell, Andrew D.; Alexander, Nathan A.; Aitken, Steven G.; Chen, Hong‐Yuan; Coxon, James M.; Jones, Matthew A.; McNabb, Stephen B.; Muscroft-Taylor, Andrew C.

doi:10.1021/jo802723w

Cited by 44 publications

(28 citation statements)

References 9 publications

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“…24 In this study the geometry of a related sequence was confirmed by X-ray crystallography. 24 For both of these peptides a single alkene isomer was obtained which was assigned the ( E )-configuration based on the alkene coupling constant 27 (15.8 Hz for 7 ). The C-terminal ferrocenyl group and N -terminal free amine were introduced as above.…”

Section: Experimental Methodsmentioning

confidence: 99%

Unraveling the Interplay of Backbone Rigidity and Electron Rich Side-Chains on Electron Transfer in Peptides: The Realization of Tunable Molecular Wires

Horsley

Moore

et al. 2014

J. Am. Chem. Soc.

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Electrochemical studies are reported on a series of peptides constrained into either a 310-helix (1–6) or β-strand (7–9) conformation, with variable numbers of electron rich alkene containing side chains. Peptides (1 and 2) and (7 and 8) are further constrained into these geometries with a suitable side chain tether introduced by ring closing metathesis (RCM). Peptides 1, 4 and 5, each containing a single alkene side chain reveal a direct link between backbone rigidity and electron transfer, in isolation from any effects due to the electronic properties of the electron rich side-chains. Further studies on the linear peptides 3–6 confirm the ability of the alkene to facilitate electron transfer through the peptide. A comparison of the electrochemical data for the unsaturated tethered peptides (1 and 7) and saturated tethered peptides (2 and 8) reveals an interplay between backbone rigidity and effects arising from the electron rich alkene side-chains on electron transfer. Theoretical calculations on β-strand models analogous to 7, 8 and 9 provide further insights into the relative roles of backbone rigidity and electron rich side-chains on intramolecular electron transfer. Furthermore, electron population analysis confirms the role of the alkene as a “stepping stone” for electron transfer. These findings provide a new approach for fine-tuning the electronic properties of peptides by controlling backbone rigidity, and through the inclusion of electron rich side-chains. This allows for manipulation of energy barriers and hence conductance in peptides, a crucial step in the design and fabrication of molecular-based electronic devices.

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Section: Experimental Methodsmentioning

confidence: 99%

Unraveling the Interplay of Backbone Rigidity and Electron Rich Side-Chains on Electron Transfer in Peptides: The Realization of Tunable Molecular Wires

Horsley

Moore

et al. 2014

J. Am. Chem. Soc.

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“…In addition, an X-ray crystallographic analysis of (10), an intermediate in the synthesis of (9b) (see ORTEP [249] diagram in Fig. (9)), shows the desired extended -strand conformation for the macrocycle [250]. The 17-membered peptide aldehyde (9b) is particularly active (IC 50 = 30 nM) towards calpain 2, with greater than 7-fold selectivity for this isoform.…”

Section: Peptide Aldehydesmentioning

confidence: 99%

“…(9). ORTEP [249] diagram of the X-ray crystal structure of the peptide macrocycle (10), an intermediate in the synthesis of (9b) [250]. cellular calpain assays with IC 50 values in the low micromolar range [255].…”

Section: Peptide Hemiacetals (Aldehyde Prodrugs)mentioning

confidence: 99%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

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The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

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“…113 Abell et al demonstrated the ring closing metathesis approach in the synthesis of S-containing bridged benzannulated macrocycle 189 (E/Z ratio: 11 : 1) from scaffold 188 using MW irradiation combined with Lewis acid conditions (Scheme 6h). 114 Ring-closing metathesis (RCM) has been extensively used for the synthesis of resorcylic acid lactones (RALs). 115 There are numerous parameters that inuence metathesis reactions; therefore, there are no general conditions that can be given that will guarantee the success of the process.…”

Section: Ring-closing Metathesis (Rcm)mentioning

confidence: 99%

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

2014

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Cyclic molecular frameworks, especially the benzannulated medium-sized and macrocyclic ring (BMR) systems, constitute an integral component of a large number of biologically significant natural or synthetic molecules. Many of these BMR compounds are either approved as drugs or have reached the late developmental stages in clinical trials. Such cyclic systems have been shown to possess great potential, especially in the discovery of new anticancer leads. Efforts from synthetic chemists have led to the development of elegant new strategies for the construction of BMR scaffolds of medicinalimportance. This review intends to highlight the importance of benzannulated medium-sized and macrocyclic rings (BMRs) and the strategies developed over the years for their synthesis.

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Synthesis of Macrocyclic β-Strand Templates by Ring Closing Metathesis

Cited by 44 publications

References 9 publications

Unraveling the Interplay of Backbone Rigidity and Electron Rich Side-Chains on Electron Transfer in Peptides: The Realization of Tunable Molecular Wires

Unraveling the Interplay of Backbone Rigidity and Electron Rich Side-Chains on Electron Transfer in Peptides: The Realization of Tunable Molecular Wires

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

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