# Bambusuril as an effective astatide sequestrator agent by hydrogen bonding

Clémence Maingueneau, Julie Patissou, Marine Lafosse, Elise Cartier, Jean-François Gestin, Gregory Pieters, Frederic Taran, Jean-Pierre Dognon, François Guérard, Marie-Pierre Heck

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Clémence Maingueneau, Julie Patissou, Marine Lafosse, Elise Cartier, Jean-François Gestin, et al. Bambusuril as an effective astatide sequestrator agent by hydrogen bonding. Chemical Communications, 2025, 61 (66), pp.12361-12364. 10.1039/D5CC02762D. hal-05149177

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# Bambusuril as Effective Astatide Sequestrator Agent by Hydrogen Bonding

Received 00th January 20xx,
Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x

Clémence Maingueneau,ª Julie Patissou,ᵇ Marine Lafosse,ᵇ Elise Cartier,ᵇ Jean-François Gestin,ª Grégory Pieters,ᵇ Frédéric Taran,ᵇ Jean-Pierre Dognon,ᶜ François Guérard a, * and Marie-Pierre Heckᵇ

Herein, we report a molecular-cage allowing strong chelation of the ²¹¹At radioanion. Propargylated bambus[6]uril shows good affinity towards iodide and astatide radiohalides, affording promising inclusion complexes that are stable in phosphate buffer saline and human serum. Density functional theory calculations support the presence of C-H···At non-covalent cooperative interactions governing the formation of astatinated cage-complexes. To our knowledge, this work is the first to report ²¹¹At-labeling using encapsulation via hydrogen bonds, which opens new perspectives in the design of ²¹¹At-based radiopharmaceuticals.

Radioisotopes of heavy halogens as iodine I, and atstatine At, are of significant interest in nuclear medicine for both imaging and therapeutic applications.¹ Astatine, the heaviest halogen of group 17 periodic elements, exists as 32 unstable isotopes. Among them, ²¹¹At is considered as one of the most promising α-emitting radionuclides for targeted alpha therapy in cancer treatments. ²¹¹At exhibits several favorable properties for medical applications: a simple decay scheme leading in 100% of case to the emission of one high-energy (5.9–7.4 MeV), a short track (50-90 µm) α particle limiting irradiation of nearby healthy tissues, a short half-life (7.2 h) and a scalable production from a cheap ²⁰⁹Bi. Together, these features position ²¹¹At as a radionuclide with high potential for effective targeted α-therapies.²,³ Consequently, several clinical trials of ²¹¹At-labeled drugs are currently underway.⁴ Among its identified oxidation states (-1, 0, 1, 5, 7), atstatide At⁻, is the easiest species to obtain due to its stability in reducing media over a broad pH range.⁵ As atstatine has no stable isotope, iodine, its closest halogen neighbour with similar physicochemical properties, is commonly used as model of At. Therefore, iodine or general halogen chemistry is often applied to astatination although differences in chemical reactivity between the two elements have also been reported.⁶ Classical methods for At' labelling generally afford aryl atstatine-

carbon bonds either by nucleophilic or electrophilic reactions (see Fig 1A)). Electrophilic substitutions occur with At⁺ species including direct aromatic electrophilic substitution (SEAr, Fig 1a)), astatodestannylation (Fig 1b)), and astatodeboronation (Fig 1c)), while nucleophilic substitutions with At⁻ species can be carried out through copper catalyzed astatodeboronation (Fig 1d)), halogen exchange (Fig 1e)), and S<sub>N</sub>Ar reactions reported with aryliodonium salts (Fig 1f)) or spirocyclic aryliodonium ylides (Fig. 1g)).⁷

<figure><img src="image_2.png" /><figcaption>B) This work :</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>Fig. 1. A) Classical methods for astatination, and B) our approach</figcaption></figure>

Although several radiosynthesis routes can provide astato-aryl compounds, their interest for in vivo applications is questioned by the low C-At bond stability predicted by theoretical calculations⁸ and confirmed experimentally, leading to uncontrolled release of At in healthy organs.⁹ To limit de-astatination, other bonding modalities have been studied such as B-At bonds in boron clusters,¹⁰ metal-At bonds such as AtHg,¹¹ Rh(III) or Ir(III)-(16aneS₄-diol)-At¹² and Rh(I)¹³ or Au(I)-NHC-At¹⁴ complexes that are, apart metal toxicity, promising strategies for At-labeling.

In this context, host-molecules, promoting noncovalent interactions with anion guest, could be an interesting approach to capture At⁻ through host-guest complex (Fig 1B), this work). Nevertheless, encapsulation of anion with large atomic radius, low charge density and low ability to engage in hydrogen bonds, is an important challenge.¹⁵ In this regard, bambus[6]uril (BUs), synthetic neutral cavitands formed by six glycoluril units connected by six

<footnote>ª Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, Nantes, France.
Email: francois.guerard@univ-nantes.fr</footnote>

<footnote>ᵇ Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologie pour la Santé (DMTS), SCBM, 91191 Gif-sur-Yvette, France.
Email: marie-pierre.heck@cea.fr</footnote>

<footnote>ᶜ Université Paris-Saclay, CEA, CNRS, NIMBE, 91191 Gif-sur-Yvette, France.</footnote>

<footnote>† Electronic supplementary information (ESI) available: Containing experimental</footnote>

<footnote>Sections, see DOI: xxxx</footnote>
methylene bridges¹⁶ are known as the best large anions chelators, and their complexation properties for iodide, phosphate and perchlorate anions have been described.¹⁷ Surprisingly, to the best of our knowledge the use of BUs as radioactive anion-sequestering agents has not been reported so far. In this communication, we demonstrate the ability of R₁₂BU[6] (R = propargyl) **BU 1** to act as a powerful ¹²⁵I⁻ and ²¹¹At⁻ receptor by sequestering these radioactive anions thanks to twelve cooperative hydrogen-radioanions interactions. While our experimental data highlight the (radio)stability of the obtained radioactive complexes, DFT calculations were employed to gain deeper insight into the interaction energies between the host (**BU**) and the two radioactive guests, ¹²⁵I and ²¹¹At.

As we previously reported, **BU 1** (Scheme 1) exhibits high affinity for iodide, and crystals of I@propargyl₁₂BU 2 confirmed the presence of the I⁻ anion within the BU's cavity.¹⁸ Accordingly, **BU 1** was selected as potential receptor for ²¹¹At⁻. First, we investigated the binding properties of Br⁻@**BU 1**¹⁹ with I⁻ by ¹H NMR titrations (see Supporting Information (SI) for experimental procedures and data processing details). In CD₃CN, the stepwise addition of I⁻ to **BU 1** resulted in a slow exchange on the NMR timescale, indicating a strong affinity of **BU 1** for I⁻ (Kₐ = 4.4 × 10³ M⁻¹ in CD₃CN see Figures S1-S2 in the SI). This result is consistent with the well-established higher affinity of bambusurils for I⁻ compared to Br⁻ anions.¹⁷,²⁰ The interaction between **BU 1** and I⁻ anions was also evaluated using isothermal titration calorimetry (ITC). In MeOH, **BU 1** exhibited a strong affinity for iodide (Kₐ = 2.1 × 10⁶ M⁻¹, Fig. S3). The ITC data clearly indicate that the formation of the I@**BU 2** complex is enthalpy-driven (ΔH = - 20.9 kJ/mol) and follows a 1:1 binding stoichiometry (Fig. S3).²⁰ The measured affinity for iodide is comparable to values previously reported for bambusurils.¹⁷

Based on these results, we investigated the complexation of ²¹¹At and ¹²⁵I radioanions (used as model of ²¹¹At) with **BU 1** (Scheme 1). Preliminary experiments with sodium sulfite (Na₂SO₃), sodium metabisulfite (Na₂S₂O₅), and dithiothreitol (DTT), were performed to identify a reductive agent capable of stabilizing ²¹¹At as the astatide species, amendable for the complexation reaction with **BU 1** in CH₃CN (see Table S1 and Fig. S4). DTT appeared as the best reductive agent for astatine complexation with **BU 1**.

<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Synthesis of ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** radiocomplexes (conditions a), and I@**BU 2** (conditions b).</figcaption></figure>

Although commercially available ¹²⁵I is provided as sodium iodide in basic solution (NaOH), DTT was added to ¹²⁵I[Nal] solution

to study the complexation in the same experimental conditions as used for ²¹¹At. The non-radioactive iodinated complex I@propargyl₁₂**BU 2**¹⁸ was first prepared as an analytical reference of ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** radiocomplexes. **BU 2** was synthesized from Br⁻@**BU 1** and TBAI (tetrabutylammonium iodide) in CH₃CN (90% yield) as reported in Scheme 1, conditions b). Then, radiolabelled complexes ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** were prepared from **BU 1** (1.2 mM in CH₃CN) by adding a solution of ¹²⁵I or ²¹¹At in the presence of DTT (see SI and Fig. S5 for details). After 30 min at room temperature, the complexes ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** were obtained in very good radiochemical yields (RCYs) respectively 99% and 90%. These results showed that the radiocomplexation reactions of ¹²⁵I and ²¹¹At are rapid, and that the radiolabelled complexes **BU 3-4** are stable and detectable at trace radionuclide concentrations, demonstrating the capacity of **BU 1** to efficiently encapsulate radioactive iodide and astatide anions. The complexes **BU 3-4** were identified by radio-HPLC analysis. As expected, nearly identical retention times were obtained for ²¹¹At@**BU 4**, ¹²⁵I@**BU 3** and for non-radioactive iodinated reference I@**BU 2** (See Fig. S6).

Subsequently, various BUs concentrations and solvents were studied as they can influence radioanion complexation (see Fig S7-S10). ¹²⁵I and ²¹¹At radioanions were reacted at room temperature for 30 min with varying concentrations of **BU 1** in CH₃CN, CH₂Cl₂ or CHCl₃ solutions (see Fig. 2 A), B)). Starting from **BU 1** (concentration of 293.9 µM), the corresponding complexes ²¹¹At @**BU 4** (Fig 2A)) and Fig S7) and ¹²⁵I @**BU 3** (Fig 2B)) and Fig. S8-S9) were obtained in high RCYs (90%, 88%, 91%) for ²¹¹At @**BU 4** and (99%, 99%, 99%) for ¹²⁵I @**BU 3** in CH₃CN, CH₂Cl₂, and CHCl₃, respectively. The efficient complexation of ²¹¹At @**BU 4** in CHCl₃ is very promising as purified ²¹¹At is frequently delivered in CHCl₃. Given the limited radiolabelling reactions described in CHCl₃, the complexation can be performed immediately after astatide purification, avoiding the additional concentration evaporation step usually required. We observed that ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** complexes are formed within 10 min of reaction, indicating a rapid anion capture kinetic (Fig. S9-S10). The radiolabelled ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** complexes were subsequently purified on silica cartridge before prior to further evaluation (see SI for details).

Then, the stabilities of radiocomplexes ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** were evaluated in human blood serum (HS) at 37°C and phosphate buffered saline (PBS) at room temperature (see Fig 2 C), D) and Fig. S11-S14). In fact, bambusurils having a strong affinity for anions, PBS is an interesting medium to study as it contains chlorides, at the same concentration and same pH (7.4) than in the blood, which are potential competitors of At⁻. Both ¹²⁵I@**BU 3** and ²¹¹At@**BU 4** showed some dehalogenation in PBS but remained in majority intact after 6h of incubation (respectively 60% and 55%, see Fig 2 C), D), Fig. S11-S12). In HS, the stability of the complexes was higher than in PBS with again a slight superiority of ¹²⁵I@**BU 3** over ²¹¹At@**BU 4** (respectively 80% and 70% of intact complex after 6h, see Fig 2 C), D), Fig. S13-S14). Overall, observing the retention of the ¹²⁵I and ²¹¹At in the BU's cage over several hours validates our complexation concept and the strong encapsulation of these halides.
<figure><img src="image_5.png" /><figcaption>**Fig. 2:** A) Influence of **BU 1** concentration on radiolabelling of <sup>211</sup>At in DCM (●), CHCl<sub>3</sub> (■), CH<sub>3</sub>CN (▲), B) Influence of **BU 1** concentration on radiolabelling of <sup>125</sup>I in DCM (●), CHCl<sub>3</sub> (■), CH<sub>3</sub>CN (▲), standard conditions: 0.5-1.5 MBq, DTT (0.16 µmol), at rt for 30 min; RCY determined by TLC; C) Stability study of <sup>211</sup>At@**BU 4** in PBS(●) and in HS(■) at 37°C, D) Stability study of <sup>125</sup>I @ **BU 3** in PBS(●) and in HS(■) at 37°C with RCY (%) as function of time (hours), E) Bonding energy analysis using ZORA-DFT with the revDOD-PBE-D4 functional, focusing on interactions between At<sup>-</sup>/I<sup>-</sup> and **BU 1** fragments (see SI for details), F) Isosurface map to visualize C-H···At non-covalent interactions in **BU 4**; for ease of reading, only H atoms interaction with At are shown. The molecular structure is color-coded according to the contribution of various atoms to the interfragment interaction, using a Blue-Green-Red color scale. Atoms appearing in red indicate a greater involvement in the **At-BU** cage interaction, highlighting regions of stronger interaction.</figcaption></figure>

To gain deeper insights into the stability of the <sup>125</sup>I@**BU 3** and <sup>211</sup>At@**BU 4** complexes, density functional theory (DFT) calculations were performed. The factors affecting the stability of **BU 1** complexes with I<sup>-</sup> and At<sup>-</sup> anions were analyzed using an energy decomposition approach (see Fig. 2E) and Fig. S15 for details. For both complexes <sup>211</sup>At@**BU 4** and <sup>125</sup>I@**BU 3**, similar trends were observed in the noncovalent interactions involved. The dominant contribution to the interaction energy arises from the electrostatic interaction, accounting for approximately 64% of the total

attractive interactions in both complexes. This is followed by orbital interactions, contributing around 22.5% for <sup>211</sup>At@**BU 4** and 24.5% for <sup>125</sup>I@**BU 3**. To a lesser extent, the MP2 interaction energies associated with the noncovalent C-H···X interaction are also notable, with values of approximately 10.9 kcal/mol for <sup>211</sup>At@**BU 4** compared to 8.6 kcal/mol for <sup>125</sup>I@**BU 3**. Finally, dispersion interactions further contribute to the overall stability of the complexes. The total bonding energy for I<sup>-</sup> and At<sup>-</sup> exhibits a 3 kcal/mol difference, with greater stabilization observed in the
$^{125}$I@BU 3 complex (-68.8 versus -65.8 kcal/mol for I and At, respectively). This indicates that **BU 1** has a slightly higher affinity for iodide than for atstatine. This trend has been confirmed experimentally since the **BU 1** concentration can be decreased by 8-fold (34 µmol/L) for complexation with $^{211}$At, and by 32-fold (8.6 µmol/L) for $^{125}$I @**BU 3** formation, without affecting the RCY (see Fig. S7-S10). Here, the difference of stability of the two complexes ($^{211}$At@**BU 4** and $^{125}$I@**BU 3**) could be explained by either this slightly lower affinity of At⁻ versus I⁻, or the tendency of At⁺ to be oxidized in At⁺ cation exhibiting no affinity for **BU 1** cage.⁵

Quantum chemical calculations were also employed to determine the volume of the central bambusuril cavity, both for the empty **BU**-cage and including the anions encapsulated (See Fig. S16-S17). The volume of the central cavity in the empty **BU**'s cage **BU 1** was found to be 32.6 Å. In the presence of atstatine and iodide anions, the cavity volume decreased to 32.0 Å and 31.5 Å, respectively. The smaller cavity size observed with iodide compared to atstatine suggests a stronger interaction between the iodide anion and the cage, consistent with the interaction energy analysis. Furthermore, the non-covalent C–H···I and C–H···At interactions in I@**BU 3** and At@**BU 4** were analyzed using Multiwfn software²¹ (Fig. 2F) and Fig S14). The computed isosurfaces (green regions) clearly highlight the presence of C–H···I interactions (Fig. S16 a)) and C–H···At interactions (Fig. 2F) and Fig. S16 b)).

In summary, we reported the first radiolabelling of a BU[6] cage with atstatine-211 and iodine-125, yielding stable $^{211}$At@**BU 4** and $^{125}$I@**BU 3** complexes in both organic and biologically relevant media. These experimental and theoretical results constitute the first evidence of atstatide sequestration within a host molecule through hydrogen bonds interactions, demonstrated here using a bambusuril cage. To our knowledge, radiopharmaceuticals based on anion chelation remain unexplored, in contrast to the widespread use of cation-complexing agents with radiometal in nuclear medicine.²² This preliminary study thus paves the way for new opportunities in the field of radiopharmaceuticals.

This work was financially supported by the "Ministère de l'Éducation nationale de l'Enseignement supérieur et de la Recherche", the French National Agency for Research (ANR-24-CE07-5913), (ANR-11-LABX-18-01 (Labex IRON)), and the INCADGOS-INSERM-ITMO Cancer_18011. The Radioactivity Technical Platform (SFR Santé François Bonamy) is thanked for the technical support, and the Arronax GIP for providing $^{211}$At. The "Service de Chimie Bioorganique et de Marquage" (SCBM, CEA) is a partner of NOMATEN, a Centre of Excellence in Multifunctional Materials for Industrial and Medical Applications (EU H2020 Teaming #857470).

**Conflicts of interest**

There are no conflicts to declare.

**Data availability**

The data supporting this article have been included as part of the ESI.†

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