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Convergent Synthesis of Thioether Containing Peptides

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Convergent Synthesis of Thioether Containing Peptides molecules Article Convergent Synthesis of Thioether Containing Peptides Spyridon Mourtas 1,2, Christina Katakalou 1, Dimitrios Gatos 1 and Kleomenis Barlos 1,3,* 1 Department of Chemistry, University of Patras, 26510 Rio Patras, Greece; [email protected] (S.M.); [email protected] (C.K.); [email protected] (D.G.) 2 Institute of Chemical Engineering Sciences of the Foundation for Research and Technology Hellas (FORTH/IEC-HT), 26504 Rio Patras, Greece 3 CBL-Patras, Patras Industrial Area, Block 1, 25018 Patras, Greece * Correspondence: [email protected]; Tel.: +30-2610-647600; Fax: +30-2610-647316 Academic Editor: Theodore Tselios Received: 23 December 2019; Accepted: 3 January 2020; Published: 5 January 2020 Abstract: Thioether containing peptides were obtained following three synthetic routes. In route A, halo acids esterified on 2-chlorotrityl(Cltr) resin were reacted with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols. These were either cleaved from the resin to the corresponding (Fmoc-aminothiol) carboxylic acids, which were used as key building blocks in solid phase peptide synthesis (SPPS), or the N-Fmoc group was deprotected and peptide chains were elongated by standard SPPS. The obtained N-Fmoc protected thioether containing peptides were then condensed either in solution, or on solid support, with the appropriate amino components of peptides. In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard SPPS. In route C, the thioether containing peptides were obtained by the condensation of a haloacylated peptide synthesized on Cltr-resin and a thiol-peptide synthesized either on 4-methoxytrityl(Mmt) or trityl(Trt) resin. Keywords: haloacylated peptides; aminothiols; bis(aminoalkyl)dithiols; convergent solid phase peptide synthesis; trityl-type resins 1. Introduction Peptides are used as therapeutic agents for controlling diseases related to peptide functions. However, the use of native peptides for clinical applications has been hampered mainly by their rapid degradation by proteases, poor oral bioavailability, difficult transportation through cell membranes and nonselective receptor binding [1]. These limitations of peptides have led to the synthesis of peptidomimetics through numerous modifications of peptide structures [2–4]. Among the several peptide modifications, isosteric replacement of a peptide bond represents a viable approach in the rational design of peptidomimetics. Peptidomimetics in which the peptide amide bond is replaced by ethylene (1a)-, methyleneimino (1b)-, methyleneoxy (1c)- and methylenethio (1d)-groups (Figure1) were found to exhibit potential pharmaceutical application [4–15]. Such modifications alter the physical and chemical properties of the native peptide, reducing its peptide character and leading to peptide analogues with increased resistance to proteolytic enzymes, flexibility and lipophilicity, while they also confer diverse electrostatic properties and new secondary conformations on the peptidomimetic chain, often resulting in improved pharmacokinetic properties [2,16,17]. Molecules 2020, 25, 218; doi:10.3390/molecules25010218 www.mdpi.com/journal/molecules Molecules 2020, 25, 218 2 of 14 Molecules 2019, 24, x FOR PEER REVIEW 2 of 14 R´ O R H H peptide2 NH CH C N C C peptide1 OH 1 H O R´ R H peptide2 NH CH CH2 Y C C peptide1 OH 2 H O FigureFigure 1.1. PeptidePeptide bondbond isosteres:isosteres: Y = CH2 (a),(a), NH NH (b), (b), O O (c) (c) and and S S (d). (d). Solid-phase synthesissynthesis (SPS) (SPS) is a commonis a common technique tech fornique peptide for synthesis.peptide synthesis. The classical The step-by-step classical solid-phasestep-by-step peptidesolid-phase synthesis peptid (SPPS)e synthesis is a well-established (SPPS) is a methodology well-established for the methodology synthesis of smallfor the to medium-sizedsynthesis of small peptides to medium-sized [18]. Besides peptides SPPS, the [18] convergent. Besides solid-phaseSPPS, the convergent peptide synthesis solid-phase (CSPPS) peptide has beensynthesis developed (CSPPS) for has the been preparation developed of larger for the and prep/or complexaration of peptides larger andand/or proteins complex [19– peptides24], based and on theproteins fact that [19–24], no directional based on restrictions the fact that exist no in CSPPSdirectional and therestrictions chain elongation exist in canCSPPS be performed and the chain with equalelongation possibility can be of performed success to anywith direction. equal possibil CSPPSity methods of success include to any fragment direction. condensation CSPPS methods such as theinclude solid- fragment or solution-phase condensation based such protocols. as the solid- Both methodsor solution-phase consist of based the rational protocols. and retro-syntheticBoth methods detachmentconsist of the of rational segments and in retro-synthetic the native sequence, detachment which of in segments a synthetic in flowthe native would sequence, be connected which in in the a appropriatesynthetic flow manner would in be the connected solid- or in the appropriate solution-phase. manner in the solid- or in the solution-phase. t The very acid labilelabile 2-chlorotrityl2-chlorotrityl (Cltr)(Cltr) resinresin [[25]25] andand thethe FmocFmoc// tBuBu methodology [[23,26]23,26] have been developeddeveloped and and widely widely used used for SPPSfor SPPS and CSPPSand CSPPS of protected of protected peptides. peptides. In general In the general sequential the t condensationsequential condensation of fluorenylmethoxycarbonyl of fluorenylmethoxycarbonyl (Fmoc)/tert-butyl (Fmoc)/tert-butyl ( Bu) protected (t peptideBu) protected fragments peptide on a solidfragments support on toa largersolid peptidessupport (convergentto larger peptides synthesis, (convergent solid phase synthesis, fragment solid condensation phase fragment (SPFC)) iscondensation a simple method (SPFC)) for is the a preparationsimple method of large for orthe di ffipreparationcult peptides of bylarge convergent or difficult methods peptides [27, 28by]. Theconvergent main limitation methods of [27,28]. this method The main is that, limitation in some of cases, this themethodN-Fmoc is that, deprotection in some cases, of the resin-boundthe N-Fmoc peptidedeprotection and theof the subsequent resin-bound condensation peptide and with the the subsequent next fragment condensation proceeds with slowly the and next incomplete. fragment Aproceeds solution slowly to this problemand incomplete. is provided A solution with the cleavageto this problem of the protected is provided peptide with from the the cleavage resin in of order the toprotected perform peptide the N-Fmoc from removalthe resin andin order the condensation to perform the in solution.N-Fmoc removal This type and of condensationthe condensation is also in advantageoussolution. This fromtype of an condensation economical point is also of view,advant sinceageous the C-from and anN economical-components point are usedof view, in equimolar since the amounts.C- and N The-components key step ofare this used method in equimolar is the esterification amounts. of The the protectedkey step peptide, of this whichmethod iscleaved is the fromesterification the resin, of at the the protected C-terminal peptide, carboxyl which function, is cleaved and for from this reason,the resin, the at usefulness the C-terminal of 2-chlorotrityl carboxyl chloridefunction, monomer and for this as a reason, temporary thecarboxy-protecting usefulness of 2-chlorotrityl group has chloride been studied monomer in CSPPS as a [24 temporary]. carboxy-protectingIn this manuscript, group we has describe been studied our efforts in CSPPS in the synthesis [24]. of peptidomimetics of type 2 (Figure1), by usingIn this simple manuscript, methods we of CSPPS.describe In our particular, efforts wein the describe synthesis three of methods peptidomimetics in the convergent of type synthesis2 (Figure of1), typeby using2d peptide simple isosteres, methods inof which CSPPS. the In amide particular, bond we is replaced describe by three CH 2methods-S isostere in bondthe convergent (thioether bond),synthesis using of type methods 2d peptide of solid isosteres, phase peptide in which fragment the amide condensation bond isor replaced solution by fragment CH2-S isostere condensation bond through(thioether the bond), formation using of methods an amide of bond, solid and phase the peptide condensation fragment of two cond fragmentsensation through or solution the formationfragment ofcondensation a thioether bond.through the formation of an amide bond, and the condensation of two fragments through the formation of a thioether bond. 2. Results and Discussion 2. ResultsIn an and eff ortDiscussion to apply standard methods of convergent solid phase peptide synthesis (CSPPS) [21,24,26] in the preparation of the thioether containing peptides 11 (Scheme1), In an effort to apply standard methods of convergent solid phase peptide synthesis (CSPPS) we esterified the halo acids 3 with 2-chlorotrityl(Cltr) resin 4 in dichloromethane (DCM) using [21,24,26] in the preparation of the thioether containing peptides 11 (Scheme 1), we esterified the N,N-diisopropylethylamine (DIPEA) as the hydrogen halide acceptor. The reaction proceeds fast halo acids 3 with 2-chlorotrityl(Cltr) resin 4 in dichloromethane (DCM) using independently from the bulkiness of 3 and resins
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