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

A general design strategy for the synthesis of cystine-based peptide nanotu bes is described. The design essentially involves closing of the polymethyl ene chains with cystine diOMe. The cystine-based nanotubes are constructed by the self-assembly of a simple cyclobisamide building block, a key struct ural feature of which is the presence of two amide groups at almost opposit e poles of the ring. A large variety of cyclobisamides with the general str ucture cyclo(-CO-(CH2)(n)-CO-Cyst-) have been prepared by a single-step pro cedure involving the condensation of 1,omega-alkane dicarbonyl dichloride [ (CH2)(n)(COCl)(2), n = 2, 3,..., 10, 20] with cystine diOMe providing macro cyclic bisamides with ring size varying from 14 to 30 members. Single-cryst al 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 arra ys of solid-state nanotubes. The hydrogen-bonded cystine tubes are hollow a nd open ended and extend to infinity. The interior of the tubes is totally hydrophobic. As a result, the polymethylene-bridged peptide tubes (a) are a ble to enhance the solubility of highly lipophilic compounds in water, as d emonstrated 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 2 6-residue bee-venom peptide melittin, in the 30-membered cystine tubule. Cr ystallographic parameters are (C14H22N2O6S2, P2(1)2(1)2) a = 16.489(1) Angs trom, b = 23.049(1) Angstrom, c = 4.864(1) Angstrom; (C16H26N2O6S2, P2(1)2( 1)2) a = 19.171(2) Angstrom, b = 21.116(2) Angstrom, c = 5.0045(4) Angstrom ; (C18H30N2O6S2 , P2(1)2(1)2(1)) a = 5.022(1) Angstrom, b = 17.725(3) Angst rom, c = 25.596(2) Angstrom; and (C20H34N2O6S2, C2) a = 40.698(15) Angstrom , b = 5.083(3) Angstrom, c 12.105(5) Angstrom, beta = 99.66(3)degrees.