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Spiroligomer scaffolds
Spiroligomer Scaffolds - (A) bis-amino acids (B) 3D Mock up of a bis-amino acids (C) Spiroligomer Trimer (D) 3D Mock up of a Spiroligomer

Spiroligomers (also known as bis-peptides) are synthetic oligomers made by coupling pairs of bis-amino acids into a fused ring system. [1] Spiroligomers are rich in stereochemistry and functionality because of the variety of bis-amino acids that are capable of being incorporated during synthesis. [2] Due to the rigidity of the fused ring system,[3] the three-dimensional shape of a spiroligomer – as well as the display of any functional groups – can be predicted, allowing for molecular modeling and dynamics.

Synthesis[edit]

Synthesis of spiroligomer building blocks (bis-amino acids)
Synthesis of spiroligomer building blocks (bis-amino acids). (a) Cbz-Cl, NaHCO3, 1:10 dioxane/water (b) Jones reagents, acetone, 0 oC to rt; (c) Isobutylene, H2SO4 (cat.), CH2Cl2, 0 oC to rt; (d) (NH4)2CO3, KCN, 1:1 EtOH/water, sealed tube; (e) (i) AcOH/Ac2O, Reflux; (ii) 2M HCl, reflux; (iii) Recrystallization

Spiroligomers are synthesized in a step-wise approach by adding a single bis-amino acid at each stage of the synthesis. This stepwise elongation allows for complete control of the stereochemistry, as any bis-amino acid can be incorporated to allow for elongation; or any mono-amino acid can be added to terminate a chain. This can be accomplished using either solution-phase or solid-phase reactions.[4] The original synthesis of spiroligomers allowed for functionalization on the ends of the oligomers, but it did not allow for the incorporation of functionality on the interior diketopiperazine (DKP) nitrogens.[5] Much work has been done to allow for the functionalization of the entire Spiroligomer, as opposed to just the ends.[2] By exploiting a neighboring group effect, [6] spiroligomers can be synthesized with a variety of functional groups along the length of the molecule.

Structure[edit]

Spiroligomers can be synthesized in any direction, and between any pair of bis-amino acids. Spiroligomer diketopiperazines can be created between either end of a bis-amino acid. Spiroligomers are known to be conformationally rigid, due to the fused-ring backbone. [3]


Chemical Characteristics[edit]

Spiroligomers are peptidomimetics. Completely Resistant to proteases. Not likely to raise an immune response.

Uses[edit]

Spiroligomers have been utilized for a variety of applications which include catalysis, protein binding, metal-binding, molecular scaffolds, and charge-transfer studies, et al.

Catalysis[edit]

Two unique types of spiroligomer catalysts (spiroligozymes) have been developed, an esterase mimic and a Claisen catalyst.

Transesterification[edit]

The first spiroligomer catalyst was an esterase-mimic, which catalyzed the transfer of a trifluoroacetate group. [7]

Transesterification of vinyl-trifluoroacetate with a Spiroligozyme
Transesterification of vinyl-trifluoroacetate with a Spiroligozyme

Aromatic Claisen Rearrangement[edit]

The second spiroligomer catalyst accelerated an aromatic Claisen rearrangement with a catalytic dyad similar to that found in Ketosteroid Isomerase.[8]

Aromatic Claisen Rearrangement with a Spiroligozyme
Aromatic Claisen Rearrangement with a Spiroligozyme

Protein Binding[edit]

A spiroligomer was designed to mimic P53 and bind HDM2. The molecule enters cells through passive diffusion, and interestingly, this mimic was shown to stabilize HDM2 in cell culture. [9]

Chemdraw of a Spiroligomer that penetrates cells and binds HDM2
Chemdraw of a Spiroligomer that penetrates cells and binds HDM2

Metal Binding[edit]

Binuclear Metal Binding [10]

A spiroligomer that binds manganese and zinc
A spiroligomer that binds manganese and zinc

Molecular Scaffolds[edit]

Rods used for distance measuring with spin probes [3]

Electron Transfer[edit]

Donor-Bridge-Acceptor [11]


References[edit]

  1. ^ Christian E. Schafmeister, Zachary Z. Brown, and Sharad Gupta “Shape-Programmable Macromolecules” Accounts of Chemical Research, (2008), 41(10), 1387-1398 doi:10.1021/ar700283y
  2. ^ a b Zachary Z. Brown and Christian E. Schafmeister, “Synthesis of Hexa- and Pentasubstituted Diketopiperazines from Sterically Hindered Amino Acids” Organic Letters, (2010), 12(7), 1436-1439 doi:10.1021/ol100048g
  3. ^ a b c Gregory H. Bird, Soraya Pornsuwan, Sunil Saxena, and Christian E. Schafmeister, “Distance Distributions of End-Labeled Curved Bispeptide Oligomers by Electron Spin Resonanace” ACSNano (2008), 2(9), 1857-1864 doi:10.1021/nn800327g
  4. ^ Zachary Z. Brown, Jennifer Alleva, and Christian E. Schafmeister, “Solid-Phase Synthesis of Functionalized Bis-Peptides” Biopolymers, (2011), 96(5), 578-585 doi:10.1002/bip.21591
  5. ^ Christopher G. Levins and Christian E. Schafmeister, “The Synthesis of Functionalized Nanoscale Molecular Rods of Defined Length” Journal of the American Chemical Society, (2003), 125(16), 4702-4703 doi:10.1021/ja0293958
  6. ^ Zachary Z. Brown and Christian E. Schafmeister, “Exploiting an Inherent Neighboring Group Effect of alpha-Amino Acids to Synthesize Extremely Hindered Dipeptides” Journal of the American Chemical Society, (2008), 130(44), 14382-14383 doi:10.1021/ja806063k
  7. ^ Mahboubeh Kheirabadi and Christian Schafmeister, et al, “Spiroligozymes for Transesterifications: Design and Relationship of Structure to Activity” Journal of the American Chemical Society, (2012), 134, 18345-18353 doi:10.1021/ja3069648
  8. ^ Matthew F. L. Parker and Christian E. Schafmesiter, et al, “Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad” Journal of the American Chemical Society, (2014), 136(10), 3817-3827 doi:10.1021/ja409214c
  9. ^ Zachary Z. Brown, Kavitha Akula, and Christian Schafmeister, et al, “A Spiroligomer alpha-Helix Mimic That Binds HDM2, Penetrates Human Cells, and Stabilizes HDM2 in Cell Culture” PLOSOne (2012), 7(10), doi:10.1371/journal.pone.0045948
  10. ^ Shivaiah Vaddypally, Chongsong Xu, Senzhi Zhao, Yanfeng Fan, Christian E. Schafmeister and Michael J. Zdilla “Architectural Spiroligomers Designed for Binuclear Metal Complex Templating” Inorganic Chemistry, (2013), 52, 6457-6463 doi:10.1021/ic4003498
  11. ^ Subhasis Chakrabarti, Matthew F. L. Parker, Christopher W. Morgan, Christian E. Schafmeister, and David H. Waldeck, “Experimental Evidence for Water Mediated Electron Transfer Through Bis-Amino Acid Donor-Bridge-Acceptor Oligomers” Journal of the American Chemical Society, (2009), 131(6), 2044-2045 doi:10.1021/ja8079324