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1.
Bioconjug Chem ; 31(5): 1392-1399, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32208715

RESUMO

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.


Assuntos
Portadores de Fármacos/química , Mesilatos/química , Animais , Ciclização , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Mesilatos/sangue , Camundongos , Proibitinas
2.
Bioconjug Chem ; 30(7): 1969-1978, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31251559

RESUMO

The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar-OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.


Assuntos
Aminas/química , Compostos de Benzil/química , Compostos Heterocíclicos/química , Fenol/química , Sulfatos/química , Álcoois/síntese química , Álcoois/química , Aminas/síntese química , Compostos de Benzil/síntese química , Ciclização , DNA/síntese química , DNA/química , Compostos Heterocíclicos/síntese química , Fenol/síntese química , RNA/síntese química , RNA/química , Sulfatos/síntese química
3.
Bioconjug Chem ; 30(7): 1957-1968, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31251583

RESUMO

A new self-immolative linker motif, Ortho Hydroxy-Protected Aryl Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates (ADC) were tested in vitro and in vivo. Conveniently synthesized using Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally on diaryl sulfate, with one aryl acting as a payload and the other as a self-immolative sulfate unit having a latent phenol function at the ortho position. The chemically stable OHPAS linker was stable in plasma samples from 5 different species, yet it can release the payload molecule smoothly upon chemical or biological triggering. The payload release proceeds via intramolecular cyclization, producing a cyclic sulfate coproduct that eventually hydrolyzes to a catechol monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were prepared with a drug to antibody ratio of ∼2, and were shown to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude that OHPAS conjugates will be of considerable use for delivering phenol-containing payloads to tissues targeted for medical intervention.


Assuntos
Antineoplásicos Imunológicos/química , Imunoconjugados/química , Sulfatos/química , Trastuzumab/química , Animais , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Química Click , Humanos , Imunoconjugados/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Fenóis , Trastuzumab/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
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