Abstract
The protection of side-chain arginine in solid-phase peptide synthesis requires attention since current protecting groups have several drawbacks. Herein, the NO2 group, which is scarcely used, has been revisited. This work shows that it prevents the formation of δ-lactam, the most severe side-reaction during the incorporation of Arg. Moreover, it is stable in solution for long periods and can be removed in an easy-to-understand manner. Thus, this protecting group can be removed while the protected peptide is still anchored to the resin, with SnCl2 as reducing agent in mild acid conditions using 2-MeTHF as solvent at 55 °C. Furthermore, we demonstrate that sonochemistry can facilitate the removal of NO2 from multiple Arg-containing peptides.
Highlights
Arginine (Arg) is a key natural amino acid that is found in many biologically active peptides [1]
We demonstrate that sonochemistry can facilitate the removal of NO2 from multiple Arg-containing peptides
Several active pharmaceutical ingredients (APIs) contain one or even several Arg residues. This intriguing amino acid is found in desmopressin, leuprolide, and the more recently approved abaloparatide, angiotensin II, bremelanotide and afamelanotide from the α-melanocyte-stimulating hormone (α-MSH), semaglutide and other drugs approved earlier from the glucagon-like peptide family (GLP) [5]
Summary
Arginine (Arg) is a key natural amino acid that is found in many biologically active peptides [1]. This group is strongly basic, with a pKa value of 12.5, which means the side-chain remains protonated under physiological conditions [2,3] This guanidino moiety is key for the biological activity of Arg-containing peptides [4]. It is important to consider atom economy, which is 0.27 for the former and 0.40 for the latter These figures mean that the synthesis of a peptide containing Arg is approximately 15 times more expensive in comparison with those containing Phe or other amino acids. In this scenario, approaches to optimize Arg protection, coupling, and protecting group removal could have an important impact in the industrial sector. FFigiguurree77. .HHPPLLCCoofftthheerreemmoovvaalloofftthheeNNOO22 ggrroouuppss ffrroomm HH--[[TTrrpp((BBoocc))--AArrgg((NNOO22))]]22--PPrroo--NNHH--RRiinnkk--aammiiddee rMe0res.2aisnqiMn(HA(aAC)q)al nHainndCd2Hl-HMi-n[-Te[2rTTp-rHM(pBFe(oBTacoHt)-c5AF)5-rAag◦trC(g5N.5(OaN°:2COp)].2r3)ao]-:3tP-epPrcorrto-eoNtd-eNHcptH-eeRpd-Ritnipidknee-kpa;-tmbaid:miedui;ednbrep:errsuoeinntsepi(ncrBtoe()Btdue)csputieenspdgint2ipgdeMe2p.tMSeidnluCSet.nli2eoC-ln0ul2:.t-0i054o.-0n9M45: %5Mp-h9op5efn%hBoeloni-nf0ot.lBo2Ainitno1A5 mini1n5. min
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