Diazaborines Are a Versatile Platform to Develop ROS‐Responsive Antibody Drug Conjugates**

António, João P. M.; Carvalho, Joana Inês; André, A; Dias, Joana; Aguiar, Sandra I.; Faustino, Hélio; Lopes, Ricardo; Veiros, Luı́s F.; Bernardes, Gonçalo J. L.; Silva, Frederico A da; Góis, Pedro M. P.

doi:10.1002/anie.202109835

Cited by 23 publications

(20 citation statements)

References 32 publications

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“…An exchange experiment with particular α-N nucleophiles or ortho-carbonyl phenylboronic acid can measure their thermodynamic stability 28,29 . Notably, most DAB derivatives are thermodynamically stable under physiological conditions 23,26 . DAB derivatives were first reported in 1962 30 .…”

Section: Resultsmentioning

confidence: 99%

“…However, pTSHz degraded slightly (~8%) after 10 hrs. The Gois group has recently demonstrated the oxidation of diazaborine can be achieved at a millimolar concentration of H2O2 26 , and the reaction is sluggish even at millimolar concentration 42 .…”

Section: Stability and Bioorthogonality Studiesmentioning

confidence: 99%

“…Utmost alkyl and aryl hydrazine compounds show liabilities to their registered toxicological profile 24,25 . In addition, diazaborine conjugate of PHz has recently been reported as unstable 26 . Contrarily, despite the stability and biocompatibility of Scz, the reaction between Scz and 2APBA suffers from a moderate conversion at a low micromolar concentration, 60% at 50 µM.…”

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confidence: 99%

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Employing the suitable diazaborine chemistry in bioorthogonal applications

Chowdhury

Chatterjee

Kushwaha

et al. 2022

Preprint

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Finding an ideal biorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho-carbonyl phenylboronic acid with α-nucleophiles is an attractive conjugation module. Yet such reactions demand stringent criteria to satisfy biorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho-carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. The reaction conversion is quantitative and rapid (k2 >103 M-1s-1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. Further, DFT calculations support that SHz facilitated DAB formation runs via the lowest energy transition state and provides the most stable conjugate product while considering other biocompatible α-nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.

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Section: Resultsmentioning

confidence: 99%

Section: Stability and Bioorthogonality Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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Employing the suitable diazaborine chemistry in bioorthogonal applications

Chowdhury

Chatterjee

Kushwaha

et al. 2022

Preprint

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“…This approach allows not only sequential targeting and release but in addition spatial release at a certain location in the body. Furthermore, the presence of reactive oxygen species in the tumor environment has been utilized for triggered release and may prove suitable for ADC drug release [128][129][130].…”

Section: Linking Up: Advances In Site-directed Conjugation and Linker...mentioning

confidence: 99%

More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates

Schwach¹,

Abdellatif²,

Stengl³

2022

Front. Biosci. (Landmark Ed)

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Antibody drug conjugates (ADCs) are rapidly becoming a cornerstone in targeted therapies, especially for the treatment of cancer. Currently, there are 12 FDA-approved ADCs, eight of which have been approved within the last five years, with numerous candidates in clinical trials. The promising clinical perspective of ADCs has led to the development of not only novel conjugation techniques, but also antibody formats, linkers, and payloads. While the majority of currently approved ADCs relies on cytotoxic small molecule warheads, alternative modes of action imparted by novel payloads and non-classical antibody formats are gaining attention. In this review, we summarize the current state of the art of ADC technologies, as well as comprehensively examine alternative payloads, such as toxic proteins, cytokines, PROTACs and oligonucleotides, and highlight the potential of multi-specific antibody formats for the next generation of therapeutic antibody conjugates.

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“…Recently, we showed that boronic acids (BAs) enable the modular assembly of cleavable drug conjugates . In addition to this, we also demonstrated that BAs can be used as a configurational lock for the construction of fluorescent boronic acid derived salicylidenehydrazone complexes (BASHY), which exhibit suitable properties to be used in bioimaging applications .…”

mentioning

confidence: 94%

The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib–GV1001 Conjugate

Baldo

Antunes

Felicidade

et al. 2021

ACS Med. Chem. Lett.

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In this study, we show that fluorescent boronic-acid derived salicylidenehydrazone complexes (BASHY) can function as fluorescent linkers for bioconjugates that were used to monitor the delivery of the proteasome inhibitor bortezomib (Btz) to HT-29 cancer cells. BASHY complexes were structurally optimized to improve the stability of the complex in buffered conditions (ammonium acetate, pH 7 up to t 1/2 = 40 h), photophysically characterized regarding their fluorescence properties and used in confocal microscopy colocalization studies that revealed their intracellular sequestration by lipid droplets. The accumulation in these hydrophobic organelles limited the hydrolysis of the complex and consequently the drug release, a problem that was circumvented by the conjugation of the BASHY-Btz complex with a cell-penetrating peptide GV1001-C. The conjugate exhibited an improved cytoplasmic availability as confirmed by confocal fluorescence microscopy studies and an improved potency against HT-29 cancer cells (IC50 = 100 nM) as compared to the nontargeted complex (IC50 = 450 nM).

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Diazaborines Are a Versatile Platform to Develop ROS‐Responsive Antibody Drug Conjugates**

Cited by 23 publications

References 32 publications

Employing the suitable diazaborine chemistry in bioorthogonal applications

Employing the suitable diazaborine chemistry in bioorthogonal applications

More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates

The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib–GV1001 Conjugate

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