Improved Cyclodextrin‐Based Receptors for Camptothecin by Inverse Virtual Screening

Abstract

We report the computer-aided optimization of a synthetic receptor for a given guest molecule, based on inverse virtual screening of receptor libraries. As an example, a virtual set of beta-cyclodextrin (beta-CD) derivatives was generated as receptor candidates for the anticancer drug camptothecin. We applied the two docking tools AutoDock and GlamDock to generate camptothecin complexes of every candidate receptor. Scoring functions were used to rank all generated complexes. From the 10 % top-ranking candidates nine were selected for experimental validation. They were synthesized by reaction of heptakis-[6-deoxy-6-iodo]-beta-CD with a thiol compound to form the hepta-substituted beta-CDs. The stabilities of the camptothecin complexes obtained from solubility measurements of five of the nine CD derivatives were significantly higher than for any other CD derivative known from literature. The remaining four CD derivatives were insoluble in water. In addition, corresponding mono-substituted CD derivatives were synthesized that also showed improved binding constants. Among them the 9-H-purine derivative was the best, being comparable to the investigated hepta-substituted beta-CDs. Since the measured binding free energies correlated satisfactorily with the calculated scores, the applied scoring functions appeared to be appropriate for the selection of promising candidates for receptor synthesis.

Access to Versatile β‐Cyclodextrin Scaffolds through Guest‐Mediated Monoacylation

“…[55][56][57] Guests 2 and 3 contain alkyl linkers of differing length which will affect the rate of reaction with CD 1 and the propensity to form an intramolecular self-inclusion complex following monoderivatization. [45] The guests were activated as esters of salicylic acid to increaset he guests'a queous solubility and to provide favorable electrostatic interactions between the activated ester and the primary amines of 1.…”

“…[43,44] Using covalent capture, we reported the selectivem onoderivatization of heptakis[6-deoxy-6-(2-aminoethylsulfanyl)]-b-CD (1). [45] Host-guest complexation between 1 and at hioester functionalized7 -diethylaminocoumarin-3-carboxylic acid (DEAC) guest (first-generation guest, FFG)f acilitated S!Na cyl transfer with rate acceleration and high monoderivatization selectivity (Scheme 1). [45] The high selectivity of this reactioni s the result of self-inclusion complex formationo ft he monoderivatizedp roduct, which preventsa ssociation of additional activated guestsa nd limits furthera cylations.…”

“…[45] Host-guest complexation between 1 and at hioester functionalized7 -diethylaminocoumarin-3-carboxylic acid (DEAC) guest (first-generation guest, FFG)f acilitated S!Na cyl transfer with rate acceleration and high monoderivatization selectivity (Scheme 1). [45] The high selectivity of this reactioni s the result of self-inclusion complex formationo ft he monoderivatizedp roduct, which preventsa ssociation of additional activated guestsa nd limits furthera cylations. While this provided access to ah igh yield of monoderivatized 1,t he scope of the reactionw as limited to direct covalent functionalization with aD EAC guest.…”

“…Amine-functionalized CD 1 is av ersatile scaffold, which has been used for the design of fluorescent sensors, [10,45] synthetic receptors, [46] investigated as ap recursor to forming glycoclusters, [47] controlling protein self-assembly, [48] DNA transfection, [49] and as an inhibitor of anthraxl ethal toxin. [50][51][52][53] In these examples, the amine groups of 1 were either per-functionalized, or monofunctionalized nonselectively with desired reagents.…”

Cellular delivery of polynucleotides by cationic cyclodextrin polyrotaxanes

“…The resulting CD derivatives, such as hydroxypropyl-CD, often show higher solubility in water and lower toxicity than the corresponding native CDs [20]. Amino functionalities have been multivalently attached to CDs via thioether linkages at the primary positions leading to highly water-soluble CD derivatives, which show improved binding affinities and aqueous solubilities compared to native CDs [21][22][23]. CDs can complex not only monomeric guests but also polymeric ones.…”