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. 2026 Sep 26. Online ahead of print. doi: 10.1039/d6cb00308g

“MIDA masking” of boronic acid therapeutics for enhanced stability and economy

Forrest G FitzGerald a, Jasmin M Frei a, Erika Zhang a, Oscar J Molina b, JoLynn B Giancola a, Malo Le Chevalier a, Volga Kojasoy a, Ronald T Raines a,c,✉
PMCID: PMC13655787  PMID: 42866074

Abstract

Boronic acids are invaluable chemical reagents that enable the synthesis of complex organic molecules and are uniquely leveraged by medicinal chemists to target biological nucleophiles via an electrophilic boron center, thereby functioning as reversible covalent inhibitors. Despite their prevalence, boronic acids remain difficult to purify and are notoriously unstable in the presence of air, moisture, and reactive oxygen species—a major impediment to biological applications. We reasoned that the boronic acid protecting group N-methyliminodiacetic acid (MIDA), typically restricted to synthetic organic chemistry, could offer a superior protection strategy for boronic acid-containing bioactive molecules. Using the FDA-approved anticancer proteasome inhibitors bortezomib and ixazomib as proof-of-concept substrates, we demonstrate a several-hundred-fold increase in hydrolytic stability of a MIDA boronate compared to the current standard (e.g., diols and α-hydroxy acid protecting groups), imparting significant resistance to oxidation and photodegradation while minimally impacting the biological activity of the molecules in cellular assays. We propose that incorporating MIDA boronates into the synthetic routes of boronic acid-containing drugs could eliminate costly deprotection and reformulation steps in pharmaceutical development, enabling a more direct route to shelf-stable “MIDA-masked” boronic acid medicines.

MIDA, a protecting group ubiquitous in synthetic chemistry, is repurposed to shield boronic acid drugs from hydrolysis, oxidation, and photodegradation without compromising cellular potency.graphic file with name d6cb00308g-ga.webp

Introduction

Despite their wide use in organic chemistry,1–3 materials science,4–6 and biology,7–11 boronic acids are sensitive. The Lewis acidity of boron that drives its unique reactivity also makes it susceptible to B–C bond cleavage via oxidative deboronation or protodeboronation.12–16 Chemists have designed protecting groups to withstand harsh chemical reaction conditions, ease purification, and enable long-term storage, yet these strategies perform best in the absence of air and moisture.17,18 Aqueous conditions and oxidative stress in biological environments remain largely unaddressed, as boronic acid protecting groups designed for organic synthesis are generally too hydrophobic and hydrolytically unstable. In contrast, boronic acid protecting groups designed for biological use (e.g., sugar alcohols or α-hydroxy acids) are incompatible with chemical synthesis and too hydrolytically labile, often requiring excess quantities to counteract reversible diol-boronate exchange.19,20

The commercial success of the proteasome inhibitor bortezomib as a frontline therapeutic for multiple myeloma over the past two decades has established boronic acids as valued pharmacophores in targeted covalent drug discovery.21–23 Yet few boronic acid-containing drugs have achieved similar success. In the clinic, bortezomib is resuspended from a lyophilized formulation containing mannitol and is rapidly administered intravenously or subcutaneously,24 thereby avoiding first-pass metabolism and targeting an accessible, highly sensitive population of circulating cancer cells. Most of the administered compound is deposited in red blood cells until release and subsequent oxidative metabolism by hepatic CYP3A4 and CYP2C19.25 The robust glycosylation (e.g., sialylation26,27) of red blood cells, coupled with their abundance (i.e., 4-fold greater than all other cells in the body, combined),28 likely provides a non-specific sink for boronic acid-bearing molecules such as bortezomib to deposit through reversible cis 1,2- and 1,3-diol binding interactions. The highly reducing intracellular environment of RBCs, relative to other somatic cells, may protect the pharmacophore from oxidation. Other boronic acid-containing drugs, such as the PDE-4 inhibitor crisaborole, are limited to topical use and formulated with organic solvents to enhance solubility and limit oxidation.29,30 A robust and versatile protection strategy is needed to realize the full potential of boronic acid therapeutics, particularly for systemic administration.

An optimal biocompatible boronic acid protecting group should possess the following characteristics: (1) trivalent coordination to boron for enhanced stability, (2) hydrogen-bond donor/acceptor capacity to maintain aqueous solubility, and (3) compatibility with synthetic organic reaction conditions. We identified N-methyliminodiacetic acid (MIDA) as a candidate that could accommodate this profile. MIDA has been widely adopted for its stability and selective removal in synthetic organic chemistry applications (e.g., iterative synthesis of small molecules), as well as its hydrolytic stability at neutral-to-acidic pH.17,31,32

Nonetheless, few studies have examined the biological utility of MIDA boronates. Llona-Minguez, Helleday, and their coworkers were arguably the first to leverage MIDA derivatization to improve the absorption, distribution, metabolism, and excretion (ADME) properties and plasma stability of a boronic acid inhibitor in vivo, observing similar target-binding activity for the protected and unprotected forms.33 In another study, a small-molecule library used MIDA boronates as reactive handles in an activity-based protein profiling (ABPP) screen against a serine hydrolase.34 Both studies found similar binding affinities for their protein targets between the MIDA-protected and unprotected boronic acid inhibitors, suggesting that the MIDA group must be hydrolyzed for these molecules to be active inhibitors. A related strategy has been proposed to deliver a boronic acid theranostic via MIDA hydrolysis,35 though the invoked acid-selective release is difficult to reconcile with the well-established base-lability of MIDA boronates.17,36 To our knowledge, studies evaluating the hydrolytic stability of MIDA boronates in a pharmaceutically relevant context are lacking, as are studies on the impact of MIDA protection on pharmacophore activity or susceptibility to degradation.

In this work, we synthesize and evaluate MIDA-protected analogues of bortezomib (BTZ) (Fig. 1) and ixazomib (IXZ), two FDA-approved alkylboronic acid-containing proteasome inhibitors. We provide the first detailed analysis of the hydrolytic stability of a MIDA boronate pharmacophore and its ability to protect the boronic acid moiety from oxidation and photodegradation, and we confirm that the cytotoxic activity of the pharmacophore is not hampered in cellulo.

Fig. 1. MIDA masking offers a superior protection strategy for boronic acid therapeutics. Compared to conventional diol-based protecting groups, which are hydrolytically labile and incompatible with synthetic organic chemistry, the MIDA boronate enables slow hydrolytic release, enhanced oxidative stability, and retained pharmacological potency.

Fig. 1

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Results and discussion

Synthetic strategies

Because alkyl boronic acids such as BTZ and IXZ are inherently unstable, we used milder conditions37 than the traditional methods involving high temperatures (e.g., Dean–Stark azeotrope removal38) to install the MIDA protecting group. A screen of anhydrous organic solvents identified DMSO as optimal, and DMSO carryover was minimized by using only the volume needed to dissolve the starting materials. We achieved successful MIDA installation on BTZ (99% yield) in anhydrous DMSO (Scheme 1). To prepare MIDA-protected IXZ, we selected IXZ–citrate as the starting material because of its lower cost than unprotected IXZ. After citrate deprotection with potassium carbonate, we similarly accessed IXZ–MIDA in good yield (85%). As is commonly observed for MIDA boronates, BTZ–MIDA and IXZ–MIDA were easily purified by silica column chromatography. Although the solid white products were stored under N2(g) at −20 °C and protected from light—in accordance with the recommendations for unprotected BTZ and IXZ—no degradation was observed even when the MIDA-protected analogues were stored at room temperature without light shielding.

Scheme 1. Synthetic routes to MIDA-protected bortezomib (BTZ–MIDA) and ixazomib (IXZ–MIDA) from commercial starting materials.

Scheme 1

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To properly analyze the oxidation reactions of BTZ and IXZ, we also needed to isolate and characterize the oxidation products. We adapted a method39 using H2O2 in dimethyl carbonate to selectively generate the oxidation products in high yield for characterization. Interestingly, as observed in our analytical assays, oxidation of BTZ generates two diastereomeric products, which we isolated as a mixture by flash chromatography. Preparative TLC was required to separate and isolate the two diastereomers for individual characterization. When generating the oxidation products synthetically, LC-MS showed a diastereomeric ratio of approximately 10 : 1 (BTZ-ox-1 : BTZ-ox-2), with BTZ-ox-1 eluting earlier than BTZ-ox-2 during reversed-phase chromatography (Fig. S6 and S7). In our oxidation assays, however, we did not observe such a drastic ratio, although BTZ-ox-1 still predominated. Oxidation of IXZ yielded only a single detectable diastereomer, as determined via LC-MS (Fig. S12).

Hydrolysis studies

Boronic acid complexation with cis 1,2- and 1,3-diols (e.g., glucose, sialic acids, mannitol) and α-hydroxy acids (e.g., citric acid) in aqueous solutions has been extensively studied and used in biosensing applications.10,40 These interactions are often fast, and without high local concentrations of binding partners, equilibrium favors hydrolysis at neutral pH.19,20,41 Accordingly, the protecting groups typically used in the synthesis (e.g., pinanediol, pinacol) or reformulation (e.g., mannitol, citric acid) of BTZ and IXZ are rapidly hydrolyzed upon exposure to aqueous conditions.

We sought to establish the hydrolytic stability of BTZ–MIDA across a range of temperatures, pH values, and aqueous media. We developed an LC-MS assay to monitor changes in BTZ–MIDA over time, treating boronate ester hydrolysis as a pseudo-first-order reaction. We first compared the hydrolysis of BTZ–pinanediol to that of BTZ–MIDA in normal saline, a standard solvent for pharmaceutical storage and administration and the solvent of choice for BTZ administration. Pinanediol is the most commonly used protecting group in BTZ synthesis and represents the penultimate intermediate before deprotection.42 The half-life (t½) of BTZ–MIDA was 250-fold greater than that of BTZ–pinanediol (69 h versus ∼0.3 h; Fig. 2A). The addition of mannitol, which is present in the clinical formulation of BTZ to aid solubility and prevent boroxine trimer formation,43 did not alter the half-life, demonstrating that the MIDA ester is resistant to transesterification with diols. In sodium phosphate buffer at pH 7.0, we observed a t½ of ca. 48 h and a trend toward a decreasing half-life with increasing pH, though the effect remained robust. This trend is consistent with the known base-lability of MIDA boronates, which are selectively cleaved under basic conditions in organic synthesis. The MIDA ester was also more stable at a lower temperature (4 °C), and stability can be enhanced via chilled storage. Finally, comparing BTZ–MIDA with the similarly structured alkyl boronic acid IXZ–MIDA, we observed a slight decrease in relative stability (t½ = 34 h). The phenyl group adjacent to the boron in BTZ–MIDA is absent in IXZ–MIDA, and we suspect this group provides some steric shielding from hydrolysis in BTZ–MIDA.

Fig. 2. MIDA protection dramatically enhances the hydrolytic and oxidative stability of BTZ and IXZ, and the photolytic stability of BTZ. (A) Hydrolytic half-lives (t½, in hours) of BTZ and IXZ boronate esters under the indicated conditions. (B) Time-dependent oxidation of BTZ, IXZ, and their protected analogues in the presence of H2O2 (330 µM) in 50 mM sodium phosphate buffer, pH 7.0. Values are the mean ± SE for three replicates. (C) Photodegradation of BTZ in normal saline under UV irradiation (λ = 254 nm) through borosilicate glass over 29 h. (D) Photodegradation of BTZ–MIDA under identical conditions. MIDA protection suppresses the formation of the oxidation products BTZ-ox-1 and BTZ-ox-2.

Fig. 2

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Oxidation studies

Our primary goal for MIDA protection of boronic acids is to protect the boron moiety from oxidation in biological settings rich in reactive oxygen species (ROS). We chose H2O2 as the oxidant because it is the most biologically relevant ROS and, as a two-electron oxidant, it simplifies experimental procedures relative to radical species.44–46 We devised an LC-MS method to ratiometrically monitor the production of the two diastereomers, BTZ-ox-1 and BTZ-ox-2, from boronic acid oxidation over time. We first compared oxidation of BTZ, BTZ–MIDA, and BTZ–pinanediol in normal saline (pH 4.0–6.5) and found that after 70 min, 97% of BTZ and BTZ–pinanediol had been oxidized, whereas only 3% of BTZ–MIDA had been oxidized (Fig. S21).

We then evaluated oxidation in phosphate buffer at neutral pH. BTZ was completely oxidized within 24 min, whereas only ∼2% of BTZ–MIDA oxidized over the same period (Fig. 2B). IXZ–MIDA behaved nearly identically to BTZ–MIDA, whereas unprotected IXZ oxidized faster than BTZ, with complete oxidation in the first few minutes. IXZ lacks the adjacent phenyl group present in BTZ, which may attenuate peroxyanion attack on boron through steric shielding and/or π-donation into the vacant p-orbital (Fig. 3A).

Fig. 3. Computational analysis reveals conformational conservation upon MIDA protection and a stabilizing CH–π interaction in BTZ–MIDA. (A) Energy-minimized structures of BTZ, BTZ–MIDA, IXZ, and IXZ–MIDA in water, calculated by DFT at the M06-2X/6-31+G(d,p) level with the SMD solvation model.55–57 Two orientations are shown for each compound; boronic acid and MIDA boronate moieties are circled. Structures were rendered in UCSF ChimeraX.58 (B) SAPT0 energy decomposition analysis (aug-cc-pVDZ basis set59,60) quantifying the intramolecular interaction between the MIDA N-methyl group and the BTZ phenyl ring. The methylated system (left) is compared to an analogous fragment lacking the N-methyl group (right). More negative values indicate stronger stabilizing interactions. Abbreviations: Eelst, electrostatic energy; Eexch, exchange-repulsion energy; Eind, induction energy; Edisp, dispersion energy; Eint, total interaction energy.

Fig. 3

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At lower pH, H2O2 is more stable, albeit less reactive (i.e., generates a lower concentration of peroxyanion via deprotonation), which explains the slower oxidation in normal saline compared to phosphate buffer at pH 7.0. Interestingly, both conditions demonstrate a sigmoidal oxidation profile for BTZ–pinanediol. This phenomenon can be explained by an initially slow oxidation phase where the pinanediol provides some protection. As BTZ–pinanediol rapidly hydrolyzes, oxidation-sensitive BTZ is liberated, and the oxidized fraction quickly converges with the profile observed for unprotected BTZ.

Photodegradation studies

BTZ undergoes photochemical degradation in solution.47 We evaluated how UV light (λ = 254 nm) degrades BTZ and whether MIDA protection ameliorates this degradation. Using LC-MS, we monitored the degradation of BTZ upon exposure to λ = 254 nm and 365 nm using a benchtop UV lamp (Fig. S22). Standard glass vials are made of borosilicate glass, which strongly attenuate short-wavelength (λ = 254 nm) UV light. Because this material is commonly used for compound storage, we first evaluated degradation over the course of 29 h in normal saline using borosilicate vials. The major degradation products, BTZ-ox-1 and BTZ-ox-2, the two diastereomers from boronic acid oxidation, were apparent (Fig. 2C and Fig. S23).

Repeating the experiment with BTZ–MIDA demonstrated minimal production of BTZ-ox-1 and BTZ-ox-2 after 29 h (Fig. 2D and Fig. S24). The abundance of other degradation products decreased likewise. Using quartz glass containers, which do not filter UV light, we observed greater and more rapid production of degradation products, predominantly with short-wave UV light (Fig. S25–S28). Again, MIDA protection greatly reduced BTZ photodegradation. UV-induced photolysis can produce H2O2 and hydroxyl radicals in water, although shorter wavelengths (λ ≤ 254 nm) are more efficient.48 The photolysis is also particularly slow in the absence of a photocatalyst, which informed our experimental design and endpoint selection. These data demonstrate a clear advantage of MIDA protection in preventing light-mediated degradation.

Cytotoxicity studies

BTZ is highly cytotoxic, using an electrophilic boron to form a reversible covalent bond with the side-chain hydroxy group of catalytic threonine in the β5 subunit of the 26S proteasome, causing unfolded proteins to accumulate and aggregate in the cytosol and eventually leading to an apoptotic phenotype.49,50 Accordingly, BTZ–MIDA requires hydrolysis to release the active boronic acid, effectively tuning potency in cells. We observe a ∼3-fold increase in IC50 for BTZ–MIDA relative to BTZ in KMS11, a multiple myeloma (MM) cell line. This difference is modest in absolute terms, shifting from 0.42 to 1.22 nM (Table 1; Fig. S29 and S30). We observed minimal difference for the less potent IXZversusIXZ–MIDA.

Table 1. MIDA protection minimally impacts cytotoxicity in multiple cell lines. IC50 values (mean ± SE; n = 3 technical replicates) were determined by an MTS viability assay 48 h after compound treatment.

Compound IC50 (nM)
KMS11 HeLa M21
BTZ 0.42 ± 0.04 17.0 ± 1.2 16.9 ± 0.6
BTZ–MIDA 1.22 ± 0.12 25.7 ± 1.4 20.1 ± 1.3
IXZ 1.98 ± 0.30 91.3 ± 8.3 110 ± 5
IXZ–MIDA 2.22 ± 0.45 104 ± 12 85.1 ± 2.2
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To expand beyond cancer cell lines with well-established sensitivity to proteasome inhibition (i.e., multiple myeloma), we evaluated cytotoxicity in HeLa (cervical cancer) and M21 (melanoma) cell lines. Again, we observed minimal differences in cytotoxicity between the unprotected and MIDA-protected compounds, though these cell lines were less sensitive (Table 1; Fig. S31–S36). MM cells are more sensitive to proteasome inhibition because they contain 10–100-fold fewer proteasomes than most adherent cells51,52 and overproduce monoclonal immunoglobulins (M proteins), which burden their proteostatic machinery.53

Because IXZ–citrate, rather than free IXZ, is the preferred clinical formulation, we compared its cytotoxicity to that of unprotected IXZ in HeLa cells. A slight increase in potency was observed (Fig. S33), possibly attributable to improved initial solubility conferred by the citrate moiety, which itself rapidly hydrolyzes in aqueous media. Cytotoxicity is attributable entirely to the unmasked boronic acid, as MIDA alone was not cytotoxic (Fig. S31).

To further confirm the mechanism of action of BTZ–MIDA, we directly compared proteasome activity using a chymotrypsin-like fluorescent proteasome substrate in HAP1 cell lysates treated with BTZ, BTZ–MIDA, or MIDA. HAP1 is a haploid human leukemia cell line commonly used in genetic engineering and drug discovery.54 Without inhibition, the substrate was rapidly cleaved. Both BTZ and BTZ–MIDA significantly impeded proteolytic cleavage of the substrate (Fig. S37), though BTZ induced greater inhibition than BTZ–MIDA in a time-course experiment (Fig. S38). MIDA alone did not inhibit the proteasome, and the substrate was fully cleaved within minutes, indicating that the unprotected form of BTZ in BTZ–MIDA is responsible for proteasome inhibition. This result is consistent with the premise that BTZ–MIDA is not directly inhibitory and must hydrolyze to yield the active boronic acid. Our cytotoxicity experiments, regardless of cell line, required at least 48 h to observe maximal cell death. MIDA protection could improve stability and cell permeability, offsetting the slower hydrolysis rate. Alternatively, cellular esterases could hydrolyze the MIDA ester over time, releasing the active compound in cellulo.

To investigate whether the MIDA ester is susceptible to esterase-mediated hydrolysis, we incubated BTZ–MIDA with pig liver esterase (PLE), human paraoxonase/arylesterase 1 (PON1), and human carboxylesterases 1 and 2 (CES1/2)—esterases with broad substrate compatibility. Although hydrolysis increased most with CES2, the effect was marginal and could not be confidently attributed to enzymatic catalysis (Fig. S39–S42). Compared to typical esterase substrates, the MIDA boronate ester is very constrained. Moreover, in typical ester hydrolysis, the leaving group is released before water enters the active site to deacylate the enzyme–substrate intermediate. In the cyclic MIDA boronate, however, the leaving group remains tethered, potentially occluding water access to the active-site nucleophile. More studies are needed to determine whether the MIDA boronate ester is susceptible to esterase-mediated hydrolysis, possibly by other endogenous esterases.

Computational modeling of molecular structures

To determine whether the addition of the MIDA protecting group may impact the preferred conformation of each compound in aqueous conditions, we applied density functional theory (DFT) to calculate energy-minimized structures in water (Fig. 3A). Surprisingly, the overall conformation of BTZ–MIDA remained largely unchanged relative to BTZ, despite the steric bulk of the MIDA group adjacent to the phenyl ring. In the energy-minimized structure of BTZ, the planar face of the trigonal boronic acid stacks against the π-face of the adjacent phenyl ring, positioning the empty p-orbital of boron for potential stabilization by the electron-rich π-face of the adjacent aromatic ring (Fig. 3A and Fig. S43).

Once the MIDA group is added, the core peptide backbone of BTZ twists slightly to accommodate the added steric bulk, but not to the extent expected, because the sp3-hybridized boron no longer seeks stabilization from the adjacent phenyl group. Rather, the N-methyl group of MIDA faces the π-face of the phenyl ring, suggesting that a CH–π interaction stabilizes this energy-minimized conformation in water (Fig. 3 and Fig. S44).

To quantify the potential contribution of the CH–π interaction, we performed an energy decomposition analysis using symmetry-adapted perturbation theory (SAPT)61–64 and compared the interaction energies between the phenyl and MIDA groups with and without the N-methyl moiety. Although the methyl group introduces appreciable steric repulsion, as reflected in the large exchange energy (Eexch), the attractive electrostatic (Eelst) and dispersion (Edisp) contributions outweigh it, yielding a net stabilization of −1.32 kcal mol−1 relative to the unmethylated system (Fig. 3B) at a distance of 3.4 Å between the N-methyl carbon and the center of the phenyl ring (Fig. S44). This agrees with the fact that CH–π interactions are driven predominantly by dispersion forces.65

MIDA has a greater impact on the conformation of IXZ. IXZ has a linear conformation in water with the trigonal boronic acid positioned perpendicular to the peptide backbone and is solvent-exposed (Fig. 3A). Upon the addition of MIDA, there is a major twist at the Cα attached to the boron, positioning the adjacent isopropyl group perpendicular to the linear conformation of the peptide backbone. In the absence of predictable stabilizing interactions, as observed in BTZ and BTZ–MIDA, IXZ–MIDA remains highly flexible. These findings provide insight into the structural impact of MIDA masking on small-molecule conformation and, ultimately, on stability and permeability. Importantly, in both cases, the MIDA group carbonyls adopt the most solvent-exposed conformation, contributing to aqueous solubility.

Conclusions

MIDA boronates have proven themselves indispensable in synthetic organic chemistry. Here, we provide evidence for a new application of the MIDA protecting group: masking of boronic acid therapeutics for use in biological settings. Using two widely recognized boronic acid-containing drugs, bortezomib and ixazomib, we show that a MIDA-protected analogue is hydrolytically stable and resistant to oxidation and photodegradation. This masking strategy does not significantly alter compound activity in cellulo and could additionally prevent non-specific interactions with endogenous diols, including cell-surface carbohydrates. These results may differ depending on the type of therapeutic agent being masked and its target and/or mechanism of action. Therefore, stability and activity studies, such as those reported herein, should be conducted for each boronic acid therapeutic that uses this MIDA masking approach. Finally, because MIDA boronates are compatible with standard organic synthesis conditions, their use as building blocks should enable facile purification and obviate the deprotection and reformulation steps currently required—steps that reduce yields because unprotected boronic acids are difficult to purify by normal-phase chromatography and are susceptible to protodeboronation and oxidative deboronation. MIDA-masked boronic acid therapeutics could eliminate synthetic steps, thereby improving preparation economy (Fig. 4).

Fig. 4. MIDA compatibility with both synthetic chemistry and biological systems reduces the number of steps required to produce shelf-stable boronic acid therapeutics. In a conventional route (top), a synthesis-compatible protecting group (PG) must be removed and replaced with a biology-compatible PG prior to formulation. With MIDA masking (bottom), MIDA serves as a single protecting group throughout synthesis, purification, and formulation, eliminating the need for deprotection and reformulation steps.

Fig. 4

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Author contributions

F. G. F.: conceptualization, methodology, investigation, software, formal analysis, validation, writing – original draft, visualization. J. M. F.: methodology, investigation, formal analysis, writing – review and editing. E. Z.: investigation, software, writing – review and editing. O. J. M.: investigation, writing – review and editing. J. B. G.: investigation, writing – review and editing. M. L. C.: investigation, writing – review and editing. V. K.: software, writing – review and editing. R. T. R.: supervision, funding acquisition, writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

CB-OLF-D6CB00308G-s001

Acknowledgments

F. G. F. and E. Z. were supported by Graduate Research Fellowships from the National Science Foundation. J. M. F. was supported by the Excellence Scholarship and Opportunity Program (ETH–Zürich). M. L. C. was supported by École normale supérieure Paris–Saclay. This work was supported by Grant R35 GM148220 (NIH) and used computational resources through allocation BIO230178 from the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program, which was supported by Grant ACI 1548562 (NSF). UV lamp and vial illustrations were made with BioRender.com.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary information (SI). The SI includes full experimental procedures, compound characterization data (NMR, HRMS, LC-MS), kinetic analyses of hydrolysis and oxidation, cytotoxicity dose response curves, proteasome activity assays, esterase incubation data, and computational details including optimized geometries and SAPT energy decomposition analyses. See DOI: https://doi.org/10.1039/d6cb00308g.

Notes and references

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

CB-OLF-D6CB00308G-s001
CB-OLF-D6CB00308G-s001.pdf (11.6MB, pdf)

Data Availability Statement

The data supporting the findings of this study are available within the article and its Supplementary information (SI). The SI includes full experimental procedures, compound characterization data (NMR, HRMS, LC-MS), kinetic analyses of hydrolysis and oxidation, cytotoxicity dose response curves, proteasome activity assays, esterase incubation data, and computational details including optimized geometries and SAPT energy decomposition analyses. See DOI: https://doi.org/10.1039/d6cb00308g.

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