Cyclic peptide-polymer complexes and their self-assembly

2009, Chemistry (Weinheim an der Bergstrasse, Germany)

Abstract

The efficient synthesis of novel chiral cyclic peptides cyclo[NHCHX-CH=CHCH(2)CO(NHCH(2)CH=CHCH(2)CO)(2)] designed to develop hydrogen-bonding interactions with suitable polymers is described. Complexation of a carboxylic acid derivatized cyclic peptide 2 (X = CH(2)OCOCH(2)CH(2)CO(2)H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the anisotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hyd...

Figures (11)

Scheme 1. Schematic illustration of the stacking of cyclic peptides func- tionalized with a side group capable of developing strong interactions with polymers. Herein, we present a different approach of combining cyclic peptides and polymers. The basic idea, illustrated in Scheme 1, is to functionalize cyclic peptide 1 with a side

Scheme 2. Complexation through hydrogen bonding of the carboxylic acid derivatized cyclic peptide 3 with PVA.

Scheme 3. Synthesis of chiral 6-amino acid benzyl ester 12. i) Boc,O (Boc = tert-butyloxycarbonyl), K,CO;, dioxane, H,O, RT, 16h; ii) Mel, K,CO;, DMF, 0°C, 16h; iii) DMP, p-toluenesulfonic acid (PTSA), ben- zene (Bz), reflux, 30 min; iv) LiAlH,, Et,O, reflux, 2 h; v) trichloroisocya- nuric acid (TCU), 2,2,6,6,-tetramethylpiperidine N-oxyl (TEMPO), CH,CL, 0°C, 30 min; vi) NaH, Bz, THF, 0°C, 1h; vii) TosN; (Tos = tosyl), Bz, RT, 2 h; viii) K,CO3;, MeOH, 0°C, 1h, RT, 16h; ix) H,, Lindlar cata- lyst (5%), quinoline, EtOH, RT, 16h; x) benzyl chloroformate, pyridine, CH,ClL, RT, 16h; xi) Grubbs catalyst (2nd generation), CH,Cl,, reflux, 12h.

Scheme 4. Synthesis of alcohol cyclopeptide 21 and its succinate deriva- tive 3. i)0.5mM NaOH, MeOH, RT, 16h; ii) PfpOH, DCC, EtOAc, RT, 3h; iii) trifluoroacetic acid (TFA), CH,CL, RT, 1h; iv) K,CO3;, MeAc, H,0, RT, 16h; v) PfpOH, DIC, EtOAc, RT, 12 h; vi) ACOH, PTSA, Bz, H,O, RT, 12h; vii) TFA, CH,CL, RT, 40 min; viii) N-methyl morpholine (NMM), dioxane, 80°C, 48 h.

[a] One peptide molecule for one or three PVA OH groups. Table 1. Composition information for mixtures of 1 and 3 and PVA.

Figure 1. Infrared spectra of cyclic peptides 1 and 3, PVA, and their com- plexes.

Figure 3. Polarized infrared spectra at room temperature for a film of peptide/PVA (24 wt %) stretched to 100% strain at 95°C. Whereas the peptide is in an oily soft state under ambient conditions, a thin film of the complex can be solution cast and peeled off from the glass surface after drying. This dra- matic change in mechanical strength and integrity should be accounted for by the presence of the small amount of PVA chains that, by establishing an extensive hydrogen-bonding network with the cyclic peptides, act as a glue to bind the peptides together over large distances. Actually, the film of the 3/PVA (24 wt%) complex could readily be stretched at an elevated temperature. Figure 3 shows the polarized infra- red spectra for a film stretched to 100% deformation at

Figure 2. Photo showing 3 in an oily state at room temperature and the peelable film of the peptide complexed with 9.4 wt% PVA. Figure 2 shows the photo of the peptide and its complex with 9.4 wt % of PVA side by side on a glass slide.

Figure 4. SEM images for films of peptide/PVA (24 wt%) on a silicon wafer cast from a 0.1 mgmL” solution of the complex. Image b shows the magnification of the marked region on image a. Dilute aqueous solutions of the 3/PVA complexes were cast on silicon wafer for SEM observations. Presented in Figures 4 and 5 are the results obtained with peptide/PVA

Figure 5. SEM images for films of peptide/PVA (24 wt%) on a silicon wafer cast from a 0.5 mgmL”' solution of the complex. Image b shows the magnification of the marked region on image a.

Figure 6. SEM images for a) pure functionalized peptide 3, b) pure un- functionalized peptide 1, and c) unfunctionalized peptide 1 blended with 90 wt % of PVA.