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Bioorganic & Medicinal Chemistry Letters Jun 2020A prodrug based on a known antibacterial compound is reported to target Staphylococcus aureus and Escherichia coli under reductive conditions. The prodrug was prepared...
A prodrug based on a known antibacterial compound is reported to target Staphylococcus aureus and Escherichia coli under reductive conditions. The prodrug was prepared by masking the N-terminus and side chain amines of a component lysine residue as 4-nitrobenzyl carbamates. Activation to liberate the antibacterial was demonstrated on treatment with a model reductant, tin(II) chloride. The bioactivity of 1 was confirmed in antibacterial susceptibility assays whereas prodrug 2 was inactive.
Topics: Anti-Bacterial Agents; Escherichia coli; Microbial Sensitivity Tests; Prodrugs; Staphylococcus aureus; Tin Compounds
PubMed: 32247730
DOI: 10.1016/j.bmcl.2020.127140 -
Journal of Drug Targeting Jan 2022Hyaluronic acid (HA), an important component of the extracellular matrix, has high water solubility and biocompatibility, and good application prospects in biomedicine....
Hyaluronic acid (HA), an important component of the extracellular matrix, has high water solubility and biocompatibility, and good application prospects in biomedicine. Especially in tumour treatment, prodrug polymer micelles prepared from HA and chemotherapeutics can increase water solubility, prolong drug release time, improve organ distribution and therapeutic effects, and show good tumour targeting and biocompatibility. Therefore, this study introduces strategies for using HA to prepare prodrug polymer micelles and discusses recent research on HA prodrug micelles for antitumor applications.
Topics: Drug Liberation; Humans; Hyaluronic Acid; Micelles; Neoplasms; Prodrugs
PubMed: 33913791
DOI: 10.1080/1061186X.2021.1919125 -
Bioconjugate Chemistry Dec 2023Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current...
Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.
Topics: Humans; Prodrugs; Doxorubicin; Neoplasms; Albumins; Cell Line, Tumor
PubMed: 37955377
DOI: 10.1021/acs.bioconjchem.3c00404 -
International Journal of Molecular... May 2020Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step... (Review)
Review
Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step in successful prodrug is its activation, which releases the active parent drug, exerting a therapeutic effect. Prodrug activation can be based on oxidation/reduction processes, or through enzyme-mediated hydrolysis, from oxidoreductases (i.e., Cytochrome P450) to hydrolytic enzymes (i.e., carboxylesterase). This study provides an overview of the novel in silico methods for the optimization of enzyme-mediated prodrug activation. Computational methods simulating enzyme-substrate binding can be simpler like molecular docking, or more complex, such as quantum mechanics (QM), molecular mechanics (MM), and free energy perturbation (FEP) methods such as molecular dynamics (MD). Examples for MD simulations used for elucidating the mechanism of prodrug (losartan, paclitaxel derivatives) metabolism via CYP450 enzyme are presented, as well as an MD simulation for optimizing linker length in phospholipid-based prodrugs. Molecular docking investigating quinazolinone prodrugs as substrates for alkaline phosphatase is also presented, as well as QM and MD simulations used for optimal fit of different prodrugs within the human carboxylesterase 1 catalytical site. Overall, high quality computational simulations may show good agreement with experimental results, and should be used early in the prodrug development process.
Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Molecular Docking Simulation; Molecular Dynamics Simulation; Prodrugs; Protein Binding
PubMed: 32443905
DOI: 10.3390/ijms21103621 -
Journal of Labelled Compounds &... May 2024Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has...
Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.
Topics: Quinolones; Deuterium; Chemistry Techniques, Synthetic; Prodrugs; Antimalarials
PubMed: 38661253
DOI: 10.1002/jlcr.4092 -
ACS Nano Sep 2022Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted to parent drugs and induce the... (Review)
Review
Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted to parent drugs and induce the mechanism of action. The development of prodrugs has upgraded conventional drug treatments in terms of bioavailability, targeting, and reduced side effects. Especially in cancer therapy, the application of prodrugs has achieved substantial therapeutic effects. From serendipitous discovery in the early stage to functional design with pertinence nowadays, the importance of prodrugs in drug design is self-evident. At present, studying stimuli-responsive activation mechanisms, regulating the stimuli intensity , and designing nanoscale prodrug formulations are the major strategies to promote the development of prodrugs. In this review, we provide an outlook of recent cutting-edge studies on stimuli-responsive prodrug nanosystems from these three aspects. We also discuss prospects and challenges in the future development of such prodrugs.
Topics: Biological Availability; Drug Delivery Systems; Drug Design; Humans; Neoplasms; Prodrugs
PubMed: 36048467
DOI: 10.1021/acsnano.2c05379 -
ChemMedChem May 2021This paper describes a comparative analysis of the physicochemical and structural properties of prodrugs and their corresponding drugs with regard to drug-likeness...
This paper describes a comparative analysis of the physicochemical and structural properties of prodrugs and their corresponding drugs with regard to drug-likeness rules. The dataset used in this work was obtained from the DrugBank. Sixty-five pairs of prodrugs/drugs were retrieved and divided into the following categories: carrier-linked to increase hydrophilic character, carrier-linked to increase absorption, and bioprecursors. We compared the physicochemical properties related to drug-likeness between prodrugs and drugs. Our results show that prodrugs do not always follow Lipinski's Rule of 5, especially as we observed 15 prodrugs with more than 10 hydrogen bond acceptors and 18 with a molecular weight greater than 500 Da. This fact highlights the importance of extending Lipinski's rules to encompass other parameters as both strategies (filtering of drug-like chemical libraries and prodrug design) aim to improve the bioavailability of compounds. Therefore, critical reasoning is fundamental to determine whether a structure has drug-like properties or could be considered a potential orally active compound in the drug-design pipeline.
Topics: Administration, Oral; Biological Availability; Databases, Chemical; Drug Design; Hydrogen Bonding; Molecular Weight; Pharmaceutical Preparations; Prodrugs
PubMed: 33471444
DOI: 10.1002/cmdc.202000805 -
ACS Nano Apr 2023Prodrug nanoassemblies combine the advantages of prodrug and nanomedicines, offering great potential in targeting the lesion sites and specific on-demand drug release,...
Prodrug nanoassemblies combine the advantages of prodrug and nanomedicines, offering great potential in targeting the lesion sites and specific on-demand drug release, maximizing the therapeutic performance while minimizing their side effects. However, there is still lacking a facile pathway to prepare the lipid prodrug nanoassemblies (LPNAs). Herein, we report the LPNAs via the dynamic covalent boronate between catechol and boronic acid. The resulting LPNAs possess properties like drug loading in a dynamic covalent manner, charge reversal in an acidic microenvironment, and specific drug release at an acidic and/or oxidative microenvironment. Our methodology enables the encapsulation and delivery of three model drugs: ciprofloxacin, bortezomib, and miconazole. Moreover, the LPNAs are often more efficient in eradicating pathogens or cancer cells than their free counterparts, both and . Together, our LPNAs with intriguing properties may boost the development of drug delivery and facilitate their clinical applications.
Topics: Prodrugs; Drug Delivery Systems; Bortezomib; Boronic Acids; Lipids; Nanoparticles; Drug Liberation
PubMed: 36999933
DOI: 10.1021/acsnano.2c12233 -
Advanced Healthcare Materials May 2022Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of...
Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune-suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand-tagged polymeric prodrugs, termed "drugamers." The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide-3-kinase inhibitor, PI-103. The extended release of PI-103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein-drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron-tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene-activating small molecule prodrugs.
Topics: Fluoresceins; Humans; Ligands; Neoplasms; Polymers; Prodrugs
PubMed: 34889072
DOI: 10.1002/adhm.202101944 -
Future Medicinal Chemistry Feb 2023Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving... (Review)
Review
Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving drug defects and optimizing the physical and chemical properties of a drug, such as lipophilicity and water solubility, changing the way of administration can be achieved through specific structural modification. Designing prodrugs by linking microenvironment-responsive groups to the prototype drugs is of great help in enhancing drug targeting. In the meantime, making connections between prodrugs and suitable drug delivery systems could realize drug loading increases, greater stability, bioavailability and drug release control. In this paper, lipidic, water-soluble, pH-responsive, redox-sensitive and enzyme-activatable prodrugs are reviewed on the basis of structural modification.
Topics: Prodrugs; Drug Delivery Systems; Solubility; Drug Liberation; Water
PubMed: 36946236
DOI: 10.4155/fmc-2022-0309