Aryl Sulfate is a Useful Motif for Conjugating and Releasing Phenolic Molecules: Sulfur Fluorine Exchange Click Chemistry Enables Discovery of Ortho-Hydroxy-Protected Aryl Sulfate Linker

Park, Suho; Kim, Sun Young; Cho, Jongun; Jung, Doohwan; Seo, Donghoon; Lee, Jae-Ho; Lee, Sangkwang; Yun, Sanghyeon; Lee, Hyangsook; Park, Okku; Seo, Beomseok; Woo, Seung Hyo; Park, Tae Kyo

doi:10.1021/acs.bioconjchem.9b00340

Cited by 18 publications

(21 citation statements)

References 49 publications

(66 reference statements)

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“…Again, a very fast payload release rate was observed (t 1/2 of 8a and 8b, <5 min) under our standard conditions. 1 During our study, Pardeshi et al reported similar findings with para-acyloxybenzyl sulfonate. 4 While they were exploring the system with totally different objectives in mind (exploited as sulfur dioxide donor), apparent operation of a 1,6-elimination mechanism has now been observed by at least two different groups.…”

Section: ■ Benzylsulfonate Versions Of Ohpas Linker Break Down Via Tw...supporting

confidence: 84%

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group

Park¹,

Kim²,

Cho³

et al. 2020

Bioconjugate Chem.

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Recently we have reported that the ortho-hydroxy-protected aryl sulfate (OHPAS) system can be exploited as a new self-immolative group (SIG) for phenolic payloads. We extended the system to nonphenolic payloads by simply introducing a para-hydroxy benzyl (PHB) spacer. As an additional variation of the system, we explored a benzylsulfonate version of the OHPAS system and found that it has two distinct breakdown pathways, cyclization and 1,4-elimination, the latter of which implies that para-hydroxy-protected (PHP) benzylsulfonate (BS) can also be used as an alternative SIG. The PHP-BS system was found to be stable chemically and in mouse and human plasma, having payload release rates comparable to those of the original OHPAS conjugates.

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Section: ■ Benzylsulfonate Versions Of Ohpas Linker Break Down Via Tw...supporting

confidence: 84%

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group

Park¹,

Kim²,

Cho³

et al. 2020

Bioconjugate Chem.

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“…In 2019, Park et al. 82 developed an ortho-hydroxy-protected aryl sulfate (OHPAS) attachment for payloads containing an aromatic-OH based on highly stable diaryl sulfate structures ( Fig. 13 B).…”

Section: Linker‒payload Attachments Of the Linkermentioning

confidence: 99%

Antibody–drug conjugates: Recent advances in linker chemistry

Xiao²,

Xie³

et al. 2021

Acta Pharmaceutica Sinica B

133

114

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Antibody–drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody–drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.

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“…Recently Park and collaborators devised a new self-immolative linker motif (OHPAS) for phenol containing payloads ( Figure 39 ) [ 59 ]. It is a diaryl sulfate, with one aryl moiety coming from the payload and the other from a latent phenol function at the ortho position of a self-immolative unit.…”

Section: Adc Payloads and Their Attachment To The Linkermentioning

confidence: 99%

The Chemistry Behind ADCs

et al. 2021

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Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.

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Aryl Sulfate is a Useful Motif for Conjugating and Releasing Phenolic Molecules: Sulfur Fluorine Exchange Click Chemistry Enables Discovery of Ortho-Hydroxy-Protected Aryl Sulfate Linker

Cited by 18 publications

References 49 publications

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group

Antibody–drug conjugates: Recent advances in linker chemistry

The Chemistry Behind ADCs

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