Organic Letters
Letter
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research was supported by Scientific Independence of
Young Researchers (SIR) 2014 (No. RBSI142AMA) and
University of Campania Luigi Vanvitelli (Valere) to S.D.M.,
Progetti di Rilevante Interesse Nazionale (PRIN) 2015 (No.
2015FCHJ8E_003) and University of Campania Luigi
Vanvitelli (ValerePlus) to S.C.
Figure 3. Optimization study for the synthesis of “difficult
sequences”: Aib-Enk, ACP65−74, JR 10-mer, and Aβ 1−42 peptides.
and ∼35% for Aβ 1−42), representing strong evidence of the
substantial effects of US, especially for aggregation-prone
sequences.
REFERENCES
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(1) Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis
of a tetrapeptide. J. Am. Chem. Soc. 1963, 85 (14), 2149−2154.
(2) Milroy, L. G.; Grossmann, T. N.; Hennig, S.; Brunsveld, L.;
Ottmann, C. Modulators of protein-protein interactions. Chem. Rev.
2014, 114 (9), 4695−4748.
(3) Hamley, I. W. Small bioactive peptides for biomaterials design
and therapeutics. Chem. Rev. 2017, 117 (24), 14015−14041.
(4) Henninot, A.; Collins, J. C.; Nuss, J. M. The current state of
peptide drug discovery: back to the future? J. Med. Chem. 2018, 61
(4), 1382−1414.
(5) Behrendt, R.; White, P.; Offer, J. Advances in Fmoc solid-phase
peptide synthesis. J. Pept. Sci. 2016, 22 (1), 4−27.
(6) Paradís-Bas, M.; Tulla-Puche, J.; Albericio, F. The road to the
synthesis of “difficult peptides. Chem. Soc. Rev. 2016, 45 (3), 631−
654.
(7) Pedersen, S. L.; Tofteng, A. P.; Malik, L.; Jensen, K. J.
Microwave heating in solid-phase peptide synthesis. Chem. Soc. Rev.
2012, 41 (5), 1826−1844.
(8) Nissen, F.; Kraft, T. E.; Ruppert, T.; Eisenhut, M.; Haberkorn,
U.; Mier, W. Hot or notthe influence of elevated temperature and
microwave irradiation on the solid phase synthesis of an affibody.
Tetrahedron Lett. 2010, 51 (48), 6216−6219.
(9) Palasek, S. A.; Cox, Z. J.; Collins, J. M. Limiting racemization
and aspartimide formation in microwave-enhanced Fmoc solid phase
peptide synthesis. J. Pept. Sci. 2007, 13 (3), 143−148.
(10) Mason, T. J. Ultrasound in synthetic organic chemistry. Chem.
Soc. Rev. 1997, 26 (6), 443−451.
(11) Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Applications of
ultrasound in organic synthesis - a green approach. Curr. Org. Chem.
2013, 17 (16), 1790−1828.
(12) Perez, J.; Wilhelm, E. J.; Sucholeiki, I. The use of power
ultrasound coupled with magnetic separation for the solid phase
synthesis of compound libraries. Bioorg. Med. Chem. Lett. 2000, 10
(2), 171−174.
In conclusion, the present study describes an unprecedented
method for the SPPS (US-SPPS), which can be placed among
the current highly efficient peptide synthetic ones. These data
set the stage for extensively applying low-frequency US to
SPPS, encouraging future studies to fully unveil the potential of
their cooperation. For instance, the replacement of the solid
supports, as well as the use of canonical and not canonical
solvents for SPPS, could allow for probing the effects of
different features, such as alternative polymeric composition
and/or size of the beads and the solvent viscosity and density,
on the US-SPPS performance. The optimization of these
parameters will provide a powerful and accessible method not
solely for the main peptide modifications, including the
introduction of nonpeptidic moieties (e.g., fatty acids,
nucleobases, fluorophores) and conformational constrains
(e.g., cyclization, N-alkylation), but also for the solid-phase
organic synthesis (SPOS), increasing the strategies for the
synthesis of small molecules for medical and biological
application.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Detailed experimental procedures; additional optimiza-
tion data; representative HPLC chromatograms and
mass spectra of all described peptides (PDF)
(13) Takahashi, S.; Shimonishi, Y. Solid phase peptide synthesis
using ultrasonic waves. Chem. Lett. 1974, 3 (1), 51−56.
(14) Bray, A. M.; Lagniton, L. M.; Valerio, R. M.; Maeji, N.
Sonication-assisted cleavage of hydrophobic peptides. application in
multipin peptide synthesis. Tetrahedron Lett. 1994, 35 (48), 9079−
9082.
(15) Anuradha, M.; Ravindranath, B. Ultrasound in peptide
synthesis. 4: rapid cleavage of polymer-bound protected peptides by
alkali and alkanolamines. Tetrahedron 1995, 51 (19), 5675−5680.
(16) Cravotto, G.; Cintas, P. Power ultrasound in organic synthesis:
moving cavitational chemistry from academia to innovative and large-
scale applications. Chem. Soc. Rev. 2006, 35 (2), 180−196.
(17) Legay, M.; Gondrexon, N.; Le Person, S.; Boldo, P.; Bontemps,
A. Enhancement of heat transfer by ultrasound: review and recent
advances. Int. J. Chem. Eng. 2011, 2011, 1−17.
AUTHOR INFORMATION
Corresponding Authors
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ORCID
Author Contributions
(18) Varanda, L. M.; Miranda, M. T. M. Solid-phase peptide
synthesis at elevated temperatures: a search for an optimized synthesis
condition of unsulfated cholecystokinin-12. J. Pept. Res. 1997, 50 (2),
102−108.
All authors have given approval to the final version of the
manuscript.
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