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19F-NMR A COLLECTION OF LABELS FOR PEPTIDE STUDIES Igor V. Komarov,a Pavel K. Mykhailiuk,a Dmytro S. Radchenko,b Anton N. Tkachenko,b Oleksiy S. Artamonov,a Andrii V. Bezdudnyb a Kiev National Taras Shevchenko University, Kiev, Ukraine b Enamine Ltd, Kiev, Ukraine, www.enamine.net Solid-state NMR of peptides labeled with 19F-substituted amino acids has been established as an efficient tool of structural studies of the peptides in biomembranes. Successful application of this tool critically depends on careful design, synthesis and incorporation in the peptides under study the fluorine-substituted amino acids (F-labels). The design principles important for the F-labels included molecular rigidity, maximal similarity to the natural counterpart, and synthetic availability. Guided by these principles, we aimed at creation of a collection of the labels mimicking all the natural amino acid types. THE KNOWN F-LABELS MIMIC AMINO ACIDS WITH HYDROPHOBIC SIDE CHAINS: NEW F-LABELS MIMIC THE NATURAL AMINO ACIDS OF ALL TYPES: COOH NH2 COOH HN F3C COOH N H H N NH2 CF3 H2N COOH CF3 CF3 NH2 F NH2 HO COOH NH2 COOH N H COOH NH2 COOH O Br CH2(CO2iPr)2 NaH O 53% CO2iPr CO2iPr O CO2iPr CO2iPr F 56% 3. D 4. HCl 42% F F N BocNH COOMe BocNH COOH O COOiPr F3C COOiPr 65% LiOH NH2 O F Ph F Ph h N H COOMe B: N COOMe 66% F COOH COOMe N N Ph COOH + H O H Cl- O COOiPr (NH4)2CO3 Me3SiO O COOiPr HN N H O Me3SiO F3C LiOH COOiPr COOH HN N H O COOH COOiPr SF4 COOiPr DEAD CF3 N H N3 H2 NHBoc Pd/C COOiPr O CF3 HN O N H O O HN O F3C HCl GLUTAMIC ACID AND ARGININE ANALOGUES F3C LiOH COOMe F F OTs Curtius NHBoc BocNH COOMe COOMe O Me3SiO BocNH O COOiPr CF3SiMe3 + F O COOiPr CF3 CF3 separated by column chromatography SERINE ANALOGUE Me3SiO N CF3CHN2 CO2iPr 1. SOCl2 2. NaN3 COOH F COOH O CO2iPr NaOH F COOiPr COOH CF3 100% O NSF3 H2N SYNTHESIS: HYDROPHOBIC AMINO ACIDS AND A PROLINE ANALOGUE CO2iPr HCl F CF3 F SYNTHESIS: HYDROPHOBIC AMINO ACID 60% H2N NH2 NH2 Br2/MeOH CF3 CF3 F Br NH2 H COOH F3C 100% COOH COOH NH2 O F CF3 N H COOH N H COOH F3C O CF3 H2N COOH H3C HOOC HN PPh3 O HN3 N H 1. DMPCN 2. Boc2O 3. aq. KOH 4. FmocCl NH2 O OH CF3 HN NaBH4 CF3 N H 1. Boc2O 2. aq. KOH 3. FmocCl O O HO FmocNH COOiPr HO CF3 H N FmocNH NBoc BoCNH CF3 COOH
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