Design, synthesis, srystal structure, and host-guest properties of polymethylene-bridged cystine-based cyclobisamides: a facile entry into hydrogen-bonded peptide nanotubes

Abstract

A general design strategy for the synthesis of cystine-based peptide nanotubes is described. The design essentially involves closing of the polymethylene chains with cystine diOMe. The cystine-based nanotubes are constructed by the self-assembly of a simple cyclobisamide building block, a key structural feature of which is the presence of two amide groups at almost opposite poles of the ring. A large variety of cyclobisamides with the general structure cyclo(-CO-(CH₂)_n-CO-Cyst-) have been prepared by a single-step procedure involving the condensation of 1,ω-alkane dicarbonyl dichloride [(CH₂)_n(COCl)₂, n = 2, 3, ..., 10, 20] with cystine diOMe providing macrocyclic bisamides with ring size varying from 14 to 30 members. Single-crystal X-ray studies with four members (n = 4, 6, 8, and 10, respectively) have shown that the polymethylene-bridged cystine-based cyclobisamides possess the intrinsic property of self-assembling into highly ordered parallel arrays of solid-state nanotubes. The hydrogen-bonded cystine tubes are hollow and open ended and extend to infinity. The interior of the tubes is totally hydrophobic. As a result, the polymethylene-bridged peptide tubes (a) are able to enhance the solubility of highly lipophilic compounds in water, as demonstrated here, with pyrene and perylene polycyclic arenes, (b) are able to bind to fluorescent probe dyes such as Nile Red, and (c) can even induce an ordered secondary structure in linear peptides as shown here with the 26-residue bee-venom peptide melittin, in the 30-membered cystine tubule. Crystallographic parameters are (C₁₄H₂₂N₂O₆S₂, P2₁2₁2) a= 16.489(1) Å, b = 23.049(1) Å, c = 4.864(1) Å; (C₁₆H₂₆N₂O₆S₂, P2₁2₁2) a = 19.171(2) Å, b = 21.116(2) Å, c = 5.0045(4) Å; (C₁₈H₃₀N₂O₆S_2, P2₁2₁2₁) a = 5.022(1) Å, b = 17.725(3) Å, c = 25.596(2) Å; and (C₂₀H₃₄N₂O₆S₂, C2) a = 40.698(15) Å, b = 5.083(3) Å, c = 12.105(5) Å, β = 99.66(3)°.