455219 One-Pot Peptide Synthesis Assisted By Hydrophobic Magnetic Nanoparticles

Tuesday, November 15, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Hitomi Asama, Yohei Okada and Hidehiro Kamiya, Graduate School of Bio-Applications Systems Engineering (BASE), Tokyo University of Agriculture and Technology, Tokyo, Japan

[Introduction]

In addition to traditional small molecules and antibodies, peptides have recently been recognized as promising pharmaceutical candidates. Typically, solid-phase liquid phase method are widely used for peptide syntheses. Due to the easy separation process, the solid-phase method is widely used for peptide syntheses, while high reaction efficiency and real-time monitoring are achieved in the liquid-phase method, also enabling facile scale-up. Recently, a new peptide synthesis method has been reported that uses hydrophobic benzyl alcohols as soluble supports[1] with hydrophobic magnetic nanoparticles.[2] In this method, the supported hydrophobic products are precipitated by the addition of poor solvent and rapid magnetic collection of the desired products can be realized with hydrophobic magnetic nanoparticles. However, the examples reported so far are limited and the detached hydrophobic modifiers from the particles cause undesired side reactions since the modifiers are attached through weak ionic interactions. The purpose of this study is the preparation of hydrophobic magnetic nanoparticles which are tightly interacted between particles and modifiers. And these particles are applied in the liquid-phase peptide syntheses. By using new modifiers which has strong bond such as chemical bond on the particles, it will be refrain from undesired side reactions. In this research, octadecyl isocyanate is used as hydrophobic moiety. It has been reported that isocyanate forms carbamate bond with hydroxy groups on the particles.[3] Then, the modified particles are applied for synthesis of typical repeating sequence of elastin as model peptide. It is known that the synthesis of elastin is difficlut because of the gelation property.

[Experimental method]

Iron (III) oxide particles were purchased from Sigma-Aldrich and were characterized several analyses, including SEM, IR, and BET before use. The iron (III) oxide particles and octadecyl isocyanate were added in dry toluene and the mixture was sonicated. Disperse particles were collected by magnet, dried in vacuum, and characterized by FT-IR, FE-SEM and elemental analysis. By using these modified particles, the model peptide was synthesized. The peptide was elongated by repeating couplings and deprotections over 9 steps using valine, glycine and proline. All the reactions were monitored by TLC and yields were determined by the recovered weights.

[Results and discussion]

From FT-IR analysis, the corresponding peaks to the modifiers were observed compared to iron (III) oxide particles before treatment. The particles are formed fiber-like structure composed of iron (III) oxide nanoparticles and loading amount was estimated to be 4 μmol/m2 from elemental analysis. The peptide was synthesized using these modified particles and monitored by TLC analysis. Based on TLC analysis, no significant side reactions were observed in all steps and the desired peptide was obtained in 87% over 9 steps in one pot. By adding this nanoparticles, all steps are completed without gelation.

[Conclusion]

Iron (III) oxide particles were hydrophobically modified using octadecyl isocyanate and these particles were applied for synthesis of typical repeating sequence of elastin. By using this method, all the reaction were proceeded with no significant side reactions and the desired product was prepared in 87% yield.

[References]

[1] (a) Okada, Y. et. al. Org. Lett. 2015, 17, 4264−4267. (b) Okada, Y. et. al. J. Org. Chem. 2013, 78, 320−327. (c) Tana, G. et. al. Chem. Commun. 2010, 46, 8219−8221.

[2] Iijima, M. et. al, Langmuir 2009, 25, 11043−11047.

[3] Carrara, C. et al., Org. Lett. 2014, 16, 460-463.


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