Halogenation at the Phenylalanine Residue of Monomethyl Auristatin F Leads to a Favorable cis/trans Equilibrium and Retained Cytotoxicity
| Autor: | Mirkka Sarparanta, Surachet Imlimthan, Iris Katariina Sokka, Filip S. Ekholm, Mikael P. Johansson, Hannu Maaheimo |
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| Přispěvatelé: | Department of Chemistry, Doctoral Programme in Chemistry and Molecular Sciences, Helsinki Institute of Sustainability Science (HELSUS) |
| Rok vydání: | 2021 |
| Předmět: |
LINKER
Immunoconjugates Magnetic Resonance Spectroscopy Halogenation Molecular Conformation Pharmaceutical Science auristatins Mice 0302 clinical medicine NMR-spectroscopy Neoplasms Drug Discovery Aminobenzoates Antibody-drug conjugates DRUG Cytotoxicity Auristatins 0303 health sciences Cytotoxins Chemistry Biological activity Nuclear magnetic resonance spectroscopy Structural characterization Nmr-spectroscopy Monomethyl auristatin F 317 Pharmacy 030220 oncology & carcinogenesis Molecular Medicine Cancer therapeutics Oligopeptides antibody−drug conjugates medicine.drug Cell Survival Phenylalanine antibody-drug conjugates Antineoplastic Agents Article cancer therapeutics 03 medical and health sciences Isomerism SDG 3 - Good Health and Well-being Cell Line Tumor medicine Animals Humans VEDOTIN 030304 developmental biology Combinatorial chemistry NMR structural characterization PET ANTIBODY DISCOVERY DOLASTATIN-10 Linker Cis–trans isomerism Conjugate |
| Zdroj: | Sokka, I K, Imlimthan, S, Sarparanta, M, Maaheimo, H, Johansson, M P & Ekholm, F S 2021, ' Halogenation at the phenylalanine residue of monomethyl auristatin f leads to a favorable cis/ trans equilibrium and retained cytotoxicity ', Molecular Pharmaceutics, vol. 18, no. 8, pp. 3125-3131 . https://doi.org/10.1021/acs.molpharmaceut.1c00342 Molecular Pharmaceutics |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | Halogenation can be utilized for the purposes of labeling and molecular imaging, providing a means to, e.g., follow drug distribution in an organism through positron emission tomography (PET) or study the molecular recognition events unfolding by nuclear magnetic resonance (NMR) spectroscopy. For cancer therapeutics, where often highly toxic substances are employed, it is of importance to be able to track the distribution of the drugs and their metabolites in order to ensure minimal side effects. Labeling should ideally have a negligible disruptive effect on the efficacy of a given drug. Using a combination of NMR spectroscopy and cytotoxicity assays, we identify a site susceptible to halogenation in monomethyl auristatin F (MMAF), a widely used cytotoxic agent in the antibody-drug conjugate (ADC) family of cancer drugs, and study the effects of fluorination and chlorination on the physiological solution structure of the auristatins and their cytotoxicity. We find that the cytotoxicity of the parent drug is retained, while the conformational equilibrium is shifted significantly toward the biologically active trans isomer, simultaneously decreasing the concentration of the inactive and potentially disruptive cis isomer by up to 50%. Our results may serve as a base for the future assembly of a multifunctional toolkit for the assessment of linker technologies and exploring bystander effects from the warhead perspective in auristatin-derived ADCs. |
| Databáze: | OpenAIRE |
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