Synthesis and Self-Assembly Processes of Monofunctionalized Cucurbit[7]uril

Abstract

We present a building block approach toward functionalized CB[7] derivatives by the condensation of methylene bridged glycoluril hexamer 1 and glycoluril bis(cyclic ethers) 2 and 12. The CB[7] derivatives Me2CB[7] and CyCB[7] are highly soluble in water (264 mM and 181 mM, respectively). As a result of the high intrinsic solubility of Me2CB[7], it is able to solubilize the insoluble benzimidazole drug albendazole. The reaction of hexamer 1 with glycoluril derivative 12 which bears a primary alkyl chloride group gives CB[7] derivative 18 in 16% isolated yield. Compound 18 reacts with NaN3 to yield azide-substituted CB[7] 19 in 81% yield which subsequently undergoes click reaction with propargylammonium chloride (21) to yield CB[7] derivative 20 in 95% yield which bears a covalently attached triazolyl ammonium group along its equator. The results of NMR spectroscopy (1H, variable temperature, and DOSY) and electrospray mass spectrometry establish that 20 undergoes self-assembly to form the cyclic tetrameric assembly (204) in aqueous solution. CB[7] derivatives bearing reactive functional groups (e.g. N3, Cl) are now available for incorporation into more complex functional systems.

Supramolecular PEGylation of biopharmaceuticals

“…Three synthetic routes have recently been described to prepare functionalized CB [7] derivatives with synthetically useful chemical handles (27)(28)(29)(30). Using the Isaacs group methods, an azido-functional CB [7] derivative (CB [7]-N 3 ) was synthesized to conjugate the macrocycle to PEG using copperfree "click" chemistry.…”

“…Two synthetic routes have recently been described to prepare monofunctionalized CB [7] derivatives with synthetically useful handles (27)(28)(29). CB [7]-N 3 was synthesized according to the methods developed and reported previously by the laboratory of L.I.…”

“…CB [7]-N 3 was synthesized according to the methods developed and reported previously by the laboratory of L.I. (27). This compound was then used to prepare supramolecular PEG conjugates using copper-free "click" chemistry.…”

“…This compound was then used to prepare supramolecular PEG conjugates using copper-free "click" chemistry. DBCO-functional PEG (PEG-DBCO) with molecular weights of 5, 10, and 30 kDa were purchased from Click Chemistry Tools, whereas monofunctional CB [7]-N 3 was synthesized as described previously (27). Commercially sourced PEG-DBCO derivatives (100 mg, 1.05 eq) were mixed with CB [7]-N 3 (1 eq) in H 2 O/DMSO [4 mL, 1:1 (vol/vol)] and stirred at 60°C for 24 h. The reaction mixture was lyophilized, and the product was characterized by MALDI-MS (Fig.…”

Sequence-Specific, Nanomolar Peptide Binding via Cucurbit[8]uril-Induced Folding and Inclusion of Neighboring Side Chains

“…[11][12][13] Numerous Qn homologues, 14,15 derivatives, [16][17][18][19][20] and acyclic congeners 21 have extended the family to myriad structures and applications. 22 Q8 and its homologue cucurbit [7]uril (Q7) have been shown to bind amino acids, peptides, and proteins, with preference for the aromatic residues tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr), especially when located at the N-terminal position in the polypeptide chain.…”