Synthesis of Bridged and Metallobridged Bis(β‐cyclodextrin)s Containing Fluorescent Oxamidobisbenzoyl Linkers and Their Selective Binding towards Bile Salts

Abstract

A series of beta-cyclodextrin (beta-CD) dimers containing fluorescent 2,2'-oxamidobisbenzoyl and 4,4'-oxamidobisbenzoyl linkers--that is, 6,6'-[2,2'-oxamidobis(benzoylamino)]ethyleneamino-6,6'-deoxy-bis(beta-CD) (2), 6,6'-[2,2'-oxamidobis(benzoylamino)]diethylenediamino-6,6'-deoxy-bis(beta-CD) (3), 6,6'-[4,4'-oxamidobis(benzoylamino)]ethyleneamino-6,6'-deoxy-bis(beta-CD) (4), and 6,6'-[4,4'-oxamidobis(benzoylamino)]diethylenediamino-6,6'-deoxy- bis(beta-CD) (5)--were synthesized from the corresponding oxamidobis(benzoic acid)s through treatment with mono[6-aminoethyleneamino-6-deoxy]-beta-CD or mono[6-diethylenetriamino-6-deoxy]-beta-CD. Further treatment of 2-5 with copper perchlorate gave their Cu(II) complexes 6-9 in satisfactory yields. The conformation and binding behavior of 2-9 towards two bile salt guests--sodium cholate (CA) and sodium deoxycholate (DCA)--was comprehensively investigated by circular dichroism, 2D NMR spectroscopy, and fluorescence spectroscopy in Tris-HCl buffer solution (pH 7.2) at 25 degrees C. Thanks to the cooperative host-linker-guest binding mode, the stoichiometric 1:1 complexes formed by bis(beta-CD)s 2-5 with bile salts gave high stability constants (KS values) of up to 10(3)-10(4) M(-1). Significantly, benefiting from the intramolecular 1:2 or 2:4 binding stoichiometry, the resulting complexes of metallobis(beta-CD)s 6-9 with bile salts gave much higher KS values of up to 10(6)-10(7) M(-2). The enhanced binding abilities of bis(beta-CD)s and metallobridged bis(beta-CD)s are discussed from the viewpoints of induced-fit interactions and multiple recognition between host and guest.

Thermodynamics of Resulting Complexes Between Cyclodextrins and Bile Salts

“…The stoichiometry for the inclusion complexation of hosts 65-72 with bile salts has been determined by Job's method [37]. The results indicate that each of the Job's plots for the inclusion complexation of 65-68 with bile salts shows a maximum at a -CD dimer molar fraction of 0.5, confirming the 1:1 binding stoichiometry between host and guest.…”

“…Except for 66, all of the hosts examined display higher binding abilities for CA than for DCA [37]. One possible reason for the stronger affinities for CA may involve hydrogen bond interactions between the 7-hydroxy group of CA and the 2-and 3-hydroxy groups of CD.…”

“…Significantly, metallobridged -CDs 69-72 show greatly enhanced binding abilities with regard to the bridged -CDs 65-68 [37]. These significant enhancements in the binding abilities may be attributable to a more complicated multiple recognition mechanism involving the cooperative binding of several CD cavities, conformation adjustment by the metal coordination, and additional binding interactions between the metal-coordinated linker group and the accommodated guest molecules.…”

“…1 H ROESY experiments have been performed in D2O to investigate the binding modes between bridged and metallobridged -CDs with oxamidobisbenzoyl linkers and bile salts [37]. The results show a "host-linker-guest" binding mode between 66 and CA.…”

“…The bile salts CA and DCA are better bound by bridged -CD 65, which possesses the shortest linker group, than by the long-linked bridged -CDs [37]. This may be attributable to the strict size-fit between these bile salts and the short-linked bridged -CD 65, which consequently gives strong van der Waals and hydrophobic interactions between host and guest.…”