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J Am Chem Soc
J Am Chem Soc
ja
jacsat
Journal of the American Chemical Society
0002-7863
1520-5126
American Chemical Society

39248674
10.1021/jacs.4c07754
Communication
Tunable and Photoactivatable Mimics of Calicheamicin γ1 for DNA Cleavage
Ben-Zvi Benjamin †
Lian Christina †
Brusco Maureen F. †
https://orcid.org/0000-0003-3916-8372
Diao Tianning *†
† Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States
* diao@nyu.edu
09 09 2024
18 09 2024
146 37 2541625421
07 06 2024
05 09 2024
05 09 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

Calicheamicin γ1 and related natural products are renowned for their potency in DNA cleavage, serving as the warheads in commercial ADCs used for treating leukemia. Their mechanism of action involves the formation of aryl radicals, which abstract hydrogen atoms from nucleic acids. However, the complex strained enediyne structure of calicheamicin γ1 presents significant challenges in synthesis, resulting in high production costs and limited structural and activity modularity for tuning the therapeutic window. This report describes the development of simple molecular mimics based on diazonium salts, synthesized in fewer than 3 steps, capable of generating aryl radicals upon green or red light irradiation. SAR studies conducted on over 30 analogues reveal a wide range of potencies in DNA cleavage, with EC50 values ranging from low nanomolar to micromolar. Forming benzenoid diradicals does not appear to be necessary for potent DNA cleavage; instead, DNA cleavage can be achieved with radicals distributed among different arenes when connected with proper linkages. The potency is influenced by electronic effects, stereochemistry, orbital orientations, the distance between multiradicals, and the number of diazonium motifs within the molecule. In addition to providing a more cost-effective, efficient, and modular alternative to calicheamicin γ1, this technology offers the potential for enhanced specificity through spatiotemporal control.

National Institute of General Medical Sciences 10.13039/100000057 R01 GM-127778 National Science Foundation Graduate Research Fellowship Program 10.13039/100023581 NA New York University 10.13039/100006732 NA document-id-old-9ja4c07754
document-id-new-14ja4c07754
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pmcGemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa) are FDA-approved antibody-drug-conjugates (ADCs) used for treating leukemia (Scheme 1).1,2 While these ADCs utilize different antibodies, they share a common warhead: calicheamicin γ1, a natural product responsible for inducing cancer cell death.3,4 The mechanism of action (MoA) involves the formation of 1,4-benzenoid diradicals through Bergman cyclization of the strained enediyne motif.5,6 The highly reactive aryl radicals undergo hydrogen atom abstraction from the C5′ position of 2-deoxyribose in DNA, forming 2-deoxyribosyl radicals. Trapping of the radicals by oxygen is followed by irreparable DNA backbone cleavage, leading to cell-cycle arrest and apoptotic cell death.3,7,8

Scheme 1 Diazonium Compounds as Alternative Warheads in ADCs for Cancer Therapeutics

The synthesis of calicheamicin γ1 and related natural products containing strained enediynes9−13 presents significant synthetic challenges due to the instability of the strained enediyne motif and the complexity of the molecular scaffolds.14 The total synthesis of calicheamicin γ1 requires 36 steps.15 Commercially, the production of calicheamicin γ1 relies on the extraction of the core structure from bacteria cultures, a process that necessitates rigorous and expensive purification and quality control measures.16,17

It is even more challenging to synthetically access analogues and derivatives of calicheamicin γ1 for adjusting its potency and efficacy to achieve a versatile therapeutic window. The modularity of payload toxicity is crucial for developing a successful ADC, as the toxicity should be within an optimal range rather than maximized.18 The lack of tunability in the toxicity of calicheamicin γ1 may have contributed to its severe side effects.19

A small molecule mimic of calicheamicin γ1, capable of generating aryl radicals, could address challenges related to production costs and tunability. While Nicolaou’s strained enediyne mimic exhibits high cytotoxicity,20 the simpler analogues are much less potent in DNA cleavage assays.21−27 Many synthetic mimics display EC50 values ranging from millimolar (mM) to micromolar (μM), which are significantly higher than the low nanomolar (nM) concentrations effective for calicheamicin γ1. Moreover, the synthesis of these mimics involves numerous steps, and some require transition metal reductants or catalysts for their activation, further limiting their potential as drug candidates.28

We hypothesize that the active species for DNA cleavage, benzenoid radicals, could be generated from diazonium salts through photoredox activation upon nitrogen extrusion (Scheme 1).29−31 The reduction potentials of aryl diazonium salts (E = −0.16 V/SCE) suggest the feasibility of activation using low-energy, long-wavelength light.32 Moreover, diazonium salts are readily available and inexpensive, derived from aryl amine precursors in just 1–3 synthetic steps, and offer a broad range of functionalities and structural motifs for activity adjustment. Besides providing a more economical, efficient, and modular mimic to calicheamicin γ1, this technology offers the potential to improve specificity via spatiotemporal control.

We synthesized a library of diazonium salts by converting the corresponding aryl amines under modified diazotization conditions.33 Diethyl ether or acetone as a cosolvent to water facilitated the precipitation of diazonium salts, which were obtained in yields ranging from 40 to 95% (Figure 1A). After washing with ether, the diazonium compounds were confirmed to be pure by 1H and 13C NMR spectroscopy and were used without further purification.

Figure 1 (A) Synthesis of diazonium compound 11 and conditions for DNA cleavage. (B) Agarose gel-electrophoresis of the pBR322 DNA cleavage (40 μM/bp) treated with 11 (2 h, 22 °C). Form I = supercoiled DNA; Form II = nicked DNA; Form III = linear DNA. (C) Dose–response curve from which EC50 was determined.

We used bis-diazonium 11 as a model compound to develop the protocol for evaluating its DNA cleavage potency. We employed a common assay, using supercoiled DNA pBR322 (Form I), which can undergo single and double-strand cleavage, resulting in nicked (Form II) and linear (Form III) forms, respectively. On agarose gel-electrophoresis, the various forms of pBR322 travel different distances, calibrated through cleavage with digestion enzymes such as the nicking enzyme, Nb.BtsI, and the double-strand cleaving enzyme, EcoRV-HF (Figure S1). We incubated pBR322 with 11 at room temperature in neutral pH water, in the presence of 525 nm green light irradiation for 2 h and observed the cleavage of pBR322 by gel-electrophoresis (Figure 1B). By varying the concentration of 11 in the presence of a standardized 0.5 μg of DNA (40 μM/bp), we generated a dose–response curve from which we derived an EC50 value of 37.1 nM (Figure 1C). At a low [11], the supercoiled pBR322 underwent single-strand cleavage to afford Form II. As [11] increased, Form II underwent double-strand cleavage to yield Form III. Further increase in [11] led to complete DNA degradation to low molecular weight fragments.

We investigated a library of diazonium compounds to determine the structure–activity-relationship (SAR) (Scheme 2). Most diazonium compounds remain stable in solid form for weeks and in aqueous solutions for longer than 6 h (Figure S12). Phenyl diazonium salt 1 exhibited limited activity with an EC50 of 18.8 μM. The more electron-rich analogue 2 showed even lower activity compared to 1, while electron-deficient derivatives 3-5 decreased the EC50 by 2 orders of magnitude. This enhancement in potency by electron-withdrawing groups was also evident when comparing the naphthalene derivatives 6 and 7, as well as the amide derivatives 8 and 9.

Scheme 2 Potency of Diazonium Compounds for DNA Cleavage

1.5 h, irradiation (525 nm), water (pH = 7.0), 22 °C. Values were obtained from duplicate experiments.

To mimic the benzenoid diradical intermediate that arises from calicheamicin γ1, we explored bis-diazonium salts. Benzene-1,4-bisdiazonium 10 displayed improved potency compared to monodiazonium 1. Similarly, naphthalene-1,5-bisdiazonium 11 outperformed 6. In analogues 12-16, where the two diazonium groups are distributed across two different arene rings, connected via ketone, amide, ester, and ether linkages, there was a notable improvement in potency, with EC50 values ranging from 18 nM to 74 nM. Notably, 13 was more effective than 12, indicating that the orientation and distance between the two radicals play a crucial role in their activity. (S) and (R) 1,1′-binaphthyl derivatives 17 and 18 showed different potencies, suggesting that enantiomers are distinguished through molecular recognition via their interaction with DNA. The diazonium derivatives of acridine, known DNA intercalators,34,3519 and 20 exhibited only modest potency, which are attributed to the misaligned orientation of the SOMOs (singly occupied molecular orbitals) relative to the C–H bond at C5′ of the nucleotides.36

Subsequently, we increased the number of diazo units in the molecule. Tridiazonium compound 21 showed no notable improvement, possibly due to the extended distance between the diazo units. Tetra-diazonium salts 22 and 23 displayed excellent potencies. Specifically, 23 exhibited an EC50 of 2.76 nM (2.14 ng/mL). In a preliminary cell viability study, we tested the antiproliferation activity of 23 on HeLa cells. Compound 23 proved to be cytotoxic with an IC50 of 6.71 μM (Figure S45). Additionally, we employed monosaccharides as scaffolds to host multiple diazonium moieties. Both 24 and 25 demonstrated very good potencies. The anomeric position in the carbohydrate framework serves as a handle for potentially linking to a minor-groove binder to enhance molecular recognition and achieve specificity.37 Moreover, this handle opens avenues for connecting the diazonium compounds as a payload to an antibody in further development of ADCs.

Control experiments shed light on the MoA (Figure 2A). We first evaluated the effect of light irradiation. In darkness, the EC50 value for DNA cleavage by 23 increased to 1 μM, substantiating the necessity of light for its activation. While a shorter wavelength of 467 nm provided activity comparable to that of 525 nm, a longer wavelength (660 nm) led to a slight decrease in reactivity. Performing the reaction with a degassed solution led to a significant 2-log scale decrease in activity (Figures 2B and S10), consistent with the participation of O2 in the cleavage process.

Figure 2 (A) Effect of light irradiation for 23-mediated DNA cleavage; (B) DNA cleavage in a degassed solution; (C) Cleavage of linear pBR322 (form III) by 23; (D) UV–vis spectroscopic study of the interaction between DNA and 23.

Subjecting prelinearized DNA pBR322 (form III) to 23 resulted in noticeable cleavage into low molecular weight fragments at concentrations of 100 nM (Figures 2C and S11). The need for higher concentrations of 23 to cleave linear DNA, compared to supercoiled DNA, may be attributed to certain molecular recognition with supercoiled DNA. Alternatively, the inherent strain in supercoiled DNA makes it more susceptible to cleavage than its linear form.

We conducted UV–vis experiments to probe the interaction between diazonium compounds and DNA (Figure 2D). Neither form of pBR322 nor 23 alone absorbed above 350 nm. Mixing supercoiled or linear DNA pBR322 with 23 led to an increase in absorption between 200 and 300 nm and a redshift in absorption bands, extending up to 500 nm. Incubating this mixture in darkness for 20 min did not alter the absorption spectra. In contrast, exposure to 525 nm light for 20 min significantly changed the spectrum. The increase in absorption intensity upon mixing DNA with 23 suggests that intercalation is unlikely, as intercalation typically results in decreased absorption due to quenching effects caused by DNA.38 The redshift in the absorption bands supports an association between DNA and diazonium compounds, potentially explaining green light-promoted activation. Nonetheless, the activity of 23 triggered by red light irradiation remains unexplained by the UV–vis data, indicating the need for further investigation.

While the MoA for diazonium-mediated photoredox DNA cleavage remains elusive, we hypothesize that the ground-state association between supercoiled DNA and diazonium compounds facilitates inner-sphere charge transfer upon irradiation. This could lead to the reduction of diazonium salts by reductive components in DNA, such as guanine or adenine (Eox ∼ 1 V vs NHE),39 although such charge transfer is typically unfavorable in an outer-sphere context determined by their redox potentials. Upon the extrusion of an N2 molecule, the diazonium compounds generate aryl radicals that initiate HAT on nucleic acids. The resulting radical intermediates generated on polynucleic acids are subsequently trapped by O2, leading to the oxidative cleavage of the DNA chain.

In summary, we explored diazonium compounds as simple molecule mimics for complex enediyne natural products, capable of generating aryl radicals under green or red-light irradiation for DNA cleavage. The straightforward synthesis and modular structures enabled SAR studies of over 30 analogues. Formation of benzenoid diradicals appears to be unnecessary to achieve potent DNA cleavage. Instead, radicals can be distributed among different arenes, provided they are connected through suitable linkages. The potency of these diazonium compounds depends on several factors: electronic effect, the distance and the arrangement of radicals, stereochemistry, and steric hindrances. This diverse array of diazonium compounds demonstrates a wide range of EC50 values, from 2.76 nM to μM levels, highlighting their potential as economical, potent, photoresponsive, tunable, and modular warheads for cancer and antibiotic therapies. Moreover, the high potency of multidiazonium compounds demonstrates that the biological activities of natural products may be replicated by synthetic mimics that target only the reactive intermediate. These mimics can achieve this through a different mechanism of activation from a simplified precursor.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c07754.All experimental procedures, gel images, and characterization spectra (PDF)

Supplementary Material

ja4c07754_si_001.pdf

Author Contributions

C.L. and M.F.B. contributed equally.

The authors declare the following competing financial interest(s): A provisional patent, titled "Diazonium compounds and methods of use for DNA cleavage" has been filed on November 29, 2023.

Acknowledgments

B.B.-Z. is grateful for the scientific advice and technical support received from the Lupoli, Traseeth, and Arora groups. T.D. thanks Prof. Tomanik for helpful discussions. This work was supported by the National Institute of Health (R01 GM-127778) and the NYU Discovery Research Fund for Human Health. B.B.-Z. thanks the NSF Graduate Fellowship. C.L. is a recipient of the Société de Chimie Industrielle Fellowship. C.L. and M.F.B. acknowledge the Dean’s Undergraduate Research Fellowship.
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Additional diazonium compounds and their activities are detailed in Scheme S1, which displays consistent trends.

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