Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
| العنوان: | Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates |
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| المؤلفون: | Jeremy F. Vaughn, Joseph A. Reddy, Hari Krishna Santhapuram, Fei You, Hanna F. Klein, Melissa Nelson, Albert Felten, Longwu Qi, Paul J. Kleindl, Christopher P. Leamon, Iontcho Radoslavov Vlahov, Jeff Nicoson, Spencer Hahn, Marilynn Vetzel, Kevin Wang, Garth L. Parham |
| المصدر: | Bioconjugate Chemistry. 28:2921-2931 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Oxazolidine, Imine, Reactive intermediate, Biomedical Engineering, Pharmaceutical Science, Antineoplastic Agents, Bioengineering, Chemistry Techniques, Synthetic, 01 natural sciences, KB Cells, Benzodiazepines, 03 medical and health sciences, chemistry.chemical_compound, Neoplasms, Humans, Moiety, Prodrugs, Pyrroles, Molecular Targeted Therapy, Pharmacology, chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, Aromatic amine, Prodrug, Combinatorial chemistry, 0104 chemical sciences, 030104 developmental biology, Diazepine, chemistry, Drug Design, Linker, Biotechnology |
| الوصف: | Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed excellent biological activity and specificity. |
| تدمد: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.7b00476 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd57ff3b52bd26b3369c3eab77a7d8b3 https://doi.org/10.1021/acs.bioconjchem.7b00476 |
| رقم الانضمام: | edsair.doi.dedup.....dd57ff3b52bd26b3369c3eab77a7d8b3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204812 10431802 |
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| DOI: | 10.1021/acs.bioconjchem.7b00476 |