Converting bleomycin into a prodrug that undergoes spontaneous reactivation under physiological conditions
| Autor: | Dana Atrakchi, Michael D. Walker, Itzik Cooper, Yoram Shechter, Mati Fridkin, Amnon Horovitz |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cations Divalent medicine.drug_class Antibiotics Microbial Sensitivity Tests Pharmacology Toxicology Bleomycin Models Biological Inhibitory Concentration 50 Mice 03 medical and health sciences Hydrolysis chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Escherichia coli medicine Animals Potency Computer Simulation Prodrugs Fluorenes Mice Inbred ICR Antibiotics Antineoplastic Chemistry respiratory system Prodrug In vitro respiratory tract diseases carbohydrates (lipids) Zinc 030104 developmental biology 030220 oncology & carcinogenesis Conjugate |
| Zdroj: | Toxicology and Applied Pharmacology. 384:114782 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2019.114782 |
| Popis: | Bleomycin is an anticancer antibiotic effective against a range of human malignancies. Yet its usefulness is limited by serious side effects. In this study, we converted bleomycin into a prodrug by covalently linking 2-sulfo, 9 fluorenylmethoxycarbonyl (FMS) to the primary amino side chain of bleomycin. FMS—bleomycin lost its efficacy to bind transition metal ions and therefore was converted into an inactive derivative. Upon incubation in vitro under physiological conditions, the FMS-moiety undergoes spontaneous hydrolysis, generating native bleomycin possessing full anti-bacterial potency. FMS hydrolysis and reactivation takes place with a t1/2 value of 17 ± 1 h. In silico simulation predicts a narrow therapeutic window in human patients of seven hours, starting 40 min after administration. In mice, close agreement was obtained between the experimental and the simulated pharmacokinetic profiles for FMS-bleomycin. FMS-bleomycin is thus shown to be a classical prodrug: it is inactive at the time of administration and the non-modified (active) bleomycin is released with a desirable pharmacokinetic profile following administration, suggesting it may have therapeutic value in the clinic. |
| Databáze: | OpenAIRE |
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