Abstract
A self-immolative bioorthogonal conditionally cleavable linker based on Grob fragmentation is described. It is derived from 1,3-aminocyclohexanols and allows the release of sulfonate-containing compounds in aqueous media. Modulation of the amine pKa promotes fragmentation even at slightly acidic pH, a common feature of several tumor environments. The Grob fragmentation can also occur under physiological conditions in living cells, highlighting the potential bioorthogonal applicability of this reaction.
Highlights
A self-immolative bioorthogonal conditionally cleavable linker based on Grob fragmentation is described
Antibody−drug conjugates (ADCs) combine the high selectivity of a monoclonal antibody for a specific target on cancer cells with the toxicity of a drug attached through a linker
The most validated self-immolative linker uses a p-amino benzyl carbamate either coupled to a valine-citrulline (Val-CitPAB) or β-glucuronide, which release the cytotoxic payload upon cathepsin B or β-glucuronidase cleavage, respectively.[12]. These linkers have been successfully translated into the clinic; for example, Adcetris has been approved for the treatment of refractory Hodgkin’s lymphoma.[13]
Summary
Pablo Garrido − Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain; orcid.org/0000-0002-5960-8569. Josune García-Sanmartín − Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain; orcid.org/0000-0003-4391-5537. Busto − Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain; orcid.org/0000-00034403-4790. Peregrina − Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain; orcid.org/0000-00033778-7065. Alfredo Martínez − Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain; orcid.org/0000-0003-4882-4044.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
