Nanomolar Binding of Steroids to Cucurbit[n]urils: Selectivity and Applications

Abstract

Cucurbit[n]urils (CBn, n = 7, 8) serve as artificial receptors for steroids (21 tested), including the hormones testosterone and estradiol as well as steroidal drugs. Fluorescence displacement titrations and isothermal titration calorimetry (ITC) provided up to nanomolar binding affinities in aqueous solution for these hydrophobic target molecules, exceeding the values of known synthetic receptors. Remarkable binding selectivities, even for homologous steroid pairs, were investigated in detail by NMR, X-ray crystal diffraction, ITC, and quantum chemical calculations. Notably, the CBn•steroid complexes are stable in water and buffers, in artificial gastric acid, and even in blood serum. Numerous applications have been demonstrated, which range from the solubility enhancement of the steroids in the presence of the macrocycles (up to 100 times, for drug delivery) and the principal component analysis of the fluorescence responses of different CBn•reporter dye combinations (for differential sensing of steroids) to the real-time monitoring of chemical conversions of steroids as substrates (for enzyme assays).

HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host–Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions

“…53–57 The parent homologue CB6 is able to accommodate small hydrocarbons (gases) in its cavity with high affinities (up to micromolar), 21 while the larger homologue CB7 also complexes large hydrocarbons or steroids strongly. 53,58,59 …”

Chemical Sensors Based on Cucurbit[n]uril Macrocycles

“…The formation of such inclusion complexes enables size-selective binding of analytes, [16,17,21,37,41,42,43,44] which is of importance for designing selective chemosensors (see Figure 1 for CBn dimensions). The formation of such inclusion complexes enables size-selective binding of analytes, [16,17,21,37,41,42,43,44] which is of importance for designing selective chemosensors (see Figure 1 for CBn dimensions).…”

“…The formation of such inclusion complexes enables size-selective binding of analytes, [16,17,21,37,41,42,43,44] which is of importance for designing selective chemosensors (see Figure 1 for CBn dimensions). [13,16,20,21,25,42,43] Substituted and acyclic CBn derivatives ( Figure 2) show different analyte-size binding preferences, enriching the set of CBn-based binding modules for constructing size-selective chemosensors and sensor arrays, see section "signal generation through indicator displacement assays (IDA)" for some examples. [13,16,20,21,25,42,43] Substituted and acyclic CBn derivatives ( Figure 2) show different analyte-size binding preferences, enriching the set of CBn-based binding modules for constructing size-selective chemosensors and sensor arrays, see section "signal generation through indicator displacement assays (IDA)" for some examples.…”

“…[13,17,100,101] The high-energy water release driving force is maximal for CB7, such that CB7 usually shows the largest affinities in the CBn family, [9,10,13,17,25,33,102] unless the guests are too small (= > incomplete cavity water release and low dispersion binding energy) or too large (steric repulsion). [42] This affinity asset in combination with the good water solubility explains the predominant role of CB7 amongst the cucurbit[n]uril-based chemosensors.…”

“…The host CB8 forms 1 : 1 complexes with a wide range of natural and artificial steroid hormones and drugs, [42] with terpenes, [103,104] with a range of metal complexes such as ferrocene, [105,106] and with adamantane-based guests such as memantine, [13,17,33,102] see Tables 4 and S2. Moreover, the group of Kim discovered that CB8 uniquely forms 2 : 1 and 1 : 1 : 1 ternary complexes with two aromatic guests, which became the cornerstone of most CB8-based applications.…”