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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Photolabile Protecting Groups Based on Novel Thiocoumarinsand Thioquinolones: Synthesis and Photorelease of a ModelAmino Acid ConjugateAndrea S.C. Fonseca, M. Sameiro T. Gonçalves, andSusana P.G. CostaCentre of Chemistry, University of Minho, Campus of Gualtar, 4710-057, Braga, PortugalIntroductionPhotocleavable protecting groups are an interesting alternative to classical acid- and baselabilegroups and have been given particular attention in research areas related to syntheticand combinatorial chemistry. Since the use of light can provide spatial and temporalresolution in the photorelease process, these groups have also been used for elucidatingsignaling mechanisms in biological and metabolic processes within cellular systems, andfor drug delivery with photoresponsive prodrugs. In recent years, a need for new lightsensitiveprotecting groups has evolved considering their importance, for example inmolecular caging, towards the design of more efficient protecting groups that alloworthogonal deprotection/cleavage for application in biomolecules. To be useful inbiological experiments, a photolabile (caging) group must undergo photolysis rapidly, inhigh yield, and at wavelengths not detrimental to the biological system [1]. Coumarinderivatives are well established photolabile protecting groups that have been used in theprotection of various functional groups [2] whereas quinolone derivatives were recentlyreported by us as carboxyl protecting groups cleavable by light [3].Considering our promising findings on the comparison of a series of substitutedcoumarins and quinolones [3], and the fact that the replacement of the carbonyl group by athiocarbonyl group at the heterocycle should induce a shift towards longer wavelengths inthe molecule’s photoresponsive properties (desirable for bioapplications), we now extendthis research to the synthesis of fluorescent conjugates based on novel thiocoumarins andthioquinolones, using phenylalanine as a model amino acid.Results and DiscussionThe synthesis of the thionated coumarin and quinolone derivatives 2 was accomplished byreaction of the corresponding model phenylalanine conjugates 1 previously obtained [3]with Lawesson’s reagent, by refluxing in dry toluene. Following purification by silica gelR 1O1 Y = O2 Y = SR 2 X Ya X = O R 1 = H R 2 = OCH 3b X = NCH 3 R 1 = H R 2 = Hc X = NCH 3 R 1 = OCH 3 R 2 = Hd X = NCH 3 R 1 = H R 2 = OCH 3Fig. 1. Synthesis of conjugates 2. Reagents:a) Lawesson’s reagent, toluene, reflux.OPhNHBocacolumn chromatography, conjugates2a-d were obtained in fair to goodyields (Figure 1, Table 1). The presentcompounds were chosen in order toevaluate the influence of the nature ofthe heterocycle and the position of themethoxy substituent at the heterocyclicmoiety on the photocleavageproperties of the conjugates. Fullcharacterisation by the usual spectroscopictechniques was performed. Thereplacement of the carbonyl at theheterocycle by a thiocarbonyl (leavingthe remaining carbonyl groups in theconjugate unchanged) was supportedby IR spectroscopy (absorption bandsbetween 1255-1290 cm -1 ) andconfirmed by 13 C NMR spectra withthe signals of the thiocarbonyl carbon between δ 181.88 and 197.11 ppm. UV-visspectroscopy characterization was carried out in absolute ethanol and by comparison withthe data reported for precursor conjugates 1, the thiocarbonyl conjugates 2 displayed anUV-vis absorption band with a bathochromic shift as expected (73 nm for thiocoumarin 2aand ca. 50 nm for thioquinolones 2b-d).8