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Molecular Cancer Therapeutics Sep 2018The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has been studied for 60 years as a potential anticancer therapeutic. Clinical studies of DON in... (Review)
Review
The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has been studied for 60 years as a potential anticancer therapeutic. Clinical studies of DON in the 1950s using low daily doses suggested antitumor activity, but later phase I and II trials of DON given intermittently at high doses were hampered by dose-limiting nausea and vomiting. Further clinical development of DON was abandoned. Recently, the recognition that multiple tumor types are glutamine-dependent has renewed interest in metabolic inhibitors such as DON. Here, we describe the prior experience with DON in humans. Evaluation of past studies suggests that the major impediments to successful clinical use included unacceptable gastrointestinal (GI) toxicities, inappropriate dosing schedules for a metabolic inhibitor, and lack of targeted patient selection. To circumvent GI toxicity, prodrug strategies for DON have been developed to enhance delivery of active compound to tumor tissues, including the CNS. When these prodrugs are administered in a low daily dosing regimen, appropriate for metabolic inhibition, they are robustly effective without significant toxicity. Patients whose tumors have genetic, metabolic, or imaging biomarker evidence of glutamine dependence should be prioritized as candidates for future clinical evaluations of novel DON prodrugs, given either as monotherapy or in rationally directed pharmacologic combinations. .
Topics: Animals; Antimetabolites, Antineoplastic; Diazooxonorleucine; Glutamine; Humans; Molecular Structure; Nausea; Neoplasms; Prodrugs; Vomiting
PubMed: 30181331
DOI: 10.1158/1535-7163.MCT-17-1148 -
Journal of Medicinal Chemistry Oct 2023The impact of bacteria on cancer progression and treatment is becoming increasingly recognized. Cancer-associated bacteria are linked to metastases, reduced efficacy,...
The impact of bacteria on cancer progression and treatment is becoming increasingly recognized. Cancer-associated bacteria are linked to metastases, reduced efficacy, and survival challenges. In this study, we present a sensitive hypoxia-activated prodrug, , which comprises an antibiotic combined with a chemotherapeutic. This prodrug demonstrates rapid and robust fluorescence enhancement and exhibits potent antibacterial activity against both Gram-positive and Gram-negative bacteria as well as tumor cells. Upon activation, produces a distinct "fluorescence-on" signal, enabling real-time drug release monitoring. By leveraging elevated nitroreductase in cancer cells, gives rise to heightened bacterial cytotoxicity while sparing normal cells. In A549 solid tumor-bearing mice, selectively accumulated at tumor sites, displaying fluorescence signals under hypoxia superior to those of a corresponding prodrug-like control. These findings highlight the potential of as a promising cancer therapy prodrug that benefits from targeted release, antibacterial impact, and imaging-based guidance.
Topics: Mice; Animals; Prodrugs; Precision Medicine; Anti-Bacterial Agents; Nitrogen Dioxide; Gram-Negative Bacteria; Gram-Positive Bacteria; Neoplasms; Hypoxia; Theranostic Nanomedicine; Bacterial Infections; Cell Line, Tumor
PubMed: 37823731
DOI: 10.1021/acs.jmedchem.3c01274 -
Molecules (Basel, Switzerland) Nov 2019Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions,... (Review)
Review
Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the -quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.
Topics: Animals; Central Nervous System; Dose-Response Relationship, Drug; Estrogens; Humans; Kinetics; Oxidative Stress; Prodrugs
PubMed: 31752337
DOI: 10.3390/molecules24224197 -
Theranostics 2023Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an...
Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. PPA-TRPP/Tab reassembled into a micellar structure with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. results indicated that PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.
Topics: Animals; Mice; Prodrugs; Immune Checkpoint Inhibitors; Tumor Microenvironment; Reactive Oxygen Species; Immunogenic Cell Death; Antineoplastic Agents; Immunotherapy; Doxorubicin; Neoplasms; Micelles; Cell Line, Tumor
PubMed: 37064869
DOI: 10.7150/thno.83912 -
Bioorganic & Medicinal Chemistry Oct 2020Phosphoantigens are ligands of BTN3A1 that stimulate anti-cancer functions of γδ T cells, yet the potency of natural phosphoantigens is limited by low cell...
Phosphoantigens are ligands of BTN3A1 that stimulate anti-cancer functions of γδ T cells, yet the potency of natural phosphoantigens is limited by low cell permeability and low metabolic stability. Derivatives of BTN3A1 ligand prodrugs were synthesized that contain an acetate-protected allylic alcohol and act as doubly protected prodrugs. A novel set of phosphonates, phosphoramidates, and phosphonamidates has been prepared through a new route that simplifies synthesis and postpones the point of divergence into different prodrug forms. One of the new prodrugs, compound 11, potently stimulates γδ T cell proliferation (72 h EC = 0.12 nM) and interferon γ response to loaded leukemia cells (4 h EC = 19 nM). This phosphonamidate form was > 900x more potent than the corresponding phosphoramidate, and the phosphonamidate form was also significantly more stable in plasma following acetate hydrolysis. Therefore, prodrug modification of phosphonate butyrophilin ligands at the allylic alcohol can both facilitate chemical synthesis and improve potency of γδ T cell stimulation.
Topics: Antigens, CD; Antineoplastic Agents; Butyrophilins; Cell Line; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Molecular Structure; Organophosphorus Compounds; Prodrugs; Structure-Activity Relationship
PubMed: 32912439
DOI: 10.1016/j.bmc.2020.115666 -
Molecules (Basel, Switzerland) Feb 2020The design and development of prodrugs is the most common and effective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected... (Review)
Review
BACKGROUND
The design and development of prodrugs is the most common and effective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected number of prodrugs have been reached the drugs market throughout history and the recent years have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs for an efficient treatment of various ailment.
METHODS
A Scan conducted to find recent approved prodrugs and prodrugs in development.
RESULTS
Selected prodrugs were reported and categorized in accordance to their target systems.
CONCLUSIONS
the prodrug approach has shown many successes and still remains a viable and effective approach to deliver new active agents. This conclusion is supported by the recent approved prodrugs and the scan of clinical trials conducted between 2013-2018.
Topics: Animals; Drug Development; Humans; Prodrugs
PubMed: 32079289
DOI: 10.3390/molecules25040884 -
Zwitterionic rhodamine-CPT prodrug nanoparticles with GSH/HO responsiveness for cancer theranostics.Theranostics 2023Fluorescently traceable prodrugs, which can monitor their biodistribution and track the kinetics of drug delivery in living cells, are promising for constructing...
Fluorescently traceable prodrugs, which can monitor their biodistribution and track the kinetics of drug delivery in living cells, are promising for constructing theranostic medicines. However, due to their charge and hydrophobicity, most of the fluorescently traceable prodrugs exhibit high protein binding and non-specific tissue retention affecting distribution and toxicity, with high background signals. Herein, the zwitterionic rhodamine (RhB) and camptothecin (CPT) were bridged with a disulfide bond to construct a tumorous heterogeneity-activatable prodrug (RhB-SS-CPT). The interaction of zwitterionic RhB-SS-CPT with proteins was detected by UV and fluorescence spectroscopy, and further demonstrated by molecular docking studies. Then, intracellular tracking and cytotoxicity of RhB-SS-CPT were determined in tumor and normal cells. Finally, the biodistribution, pharmacokinetics, and anticancer efficacy of RhB-SS-CPT were evaluated in a mouse animal model. The tumorous heterogeneity-activatable RhB-SS-CPT prodrug can self-assemble into stable nanoparticles in water based on its amphiphilic structure. Particularly, the zwitterionic prodrug nanoparticles reduce the non-specific binding to generate a low background signal for better identification of cancerous lesions, achieve rapid internalization into cancer cells, selectively release bioactive CPT as a cytotoxic agent in response to high levels of GSH and HO, and exhibit high fluorescence that contributes to the visual chemotherapy modality. In addition, the RhB-SS-CPT prodrug nanoparticles show longer circulation time and better antitumor activity than free CPT . Interestingly, the zwitterionic nature allows RhB-SS-CPT to be excreted through the renal route, with fewer side effects. Zwitterionic features and responsive linkers are important considerations for constructing potent prodrugs, which provide some useful insights to design the next-generation of theranostic prodrugs for cancer.
Topics: Mice; Animals; Prodrugs; Hydrogen Peroxide; Camptothecin; Rhodamines; Tissue Distribution; Molecular Docking Simulation; Precision Medicine; Drug Delivery Systems; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 36593965
DOI: 10.7150/thno.78884 -
Molecules (Basel, Switzerland) Dec 2014The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods.... (Review)
Review
The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods. The development of an efficient means of transdermal delivery can increase drug concentrations, while reducing their systemic distribution, thereby avoiding certain limitations of oral administration. The efficient barrier function of the skin, however, limits the use of most drugs as transdermal agents. This limitation has led to the development of various strategies to enhance drug-skin permeation, including the use of penetration enhancers. This method unfortunately has certain proven disadvantages, such as the increased absorption of unwanted components, besides the drug, which may induce skin damage and irritancy. The prodrug approach to increase the skin's permeability to drugs represents a very promising alternative to penetration enhancers. The concept involves the chemical modification of a drug into a bioreversible entity that changes both its pharmaceutical and pharmacokinetic characteristics to enhance its delivery through the skin. In this review; we report on the in vitro attempts and successes over the last decade by using the prodrug strategy for the percutaneous delivery of pharmacological molecules.
Topics: Administration, Cutaneous; Animals; Dermis; Humans; Permeability; Prodrugs; Solubility
PubMed: 25514222
DOI: 10.3390/molecules191220780 -
BioDrugs : Clinical Immunotherapeutics,... Mar 2024We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the...
We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy. We argue that SG is not an optimal conventional ADC and that the amount of systemic SN-38 spontaneously hydrolyzed from the ADC is so high it must have activity. Then, we describe the concept of time-over-target as related to the pharmacology of SG and PLX038 as SN-38 prodrugs. To be clear, we are not in any way suggesting that PLX038 or any SN-38 prodrug is superior to SG as an anticancer agent. Clearly, SG has the benefit over antigen-independent SN-38 prodrugs in that it targets cells with the TROP2 receptor. However, we surmise that PLX038 should be a more efficacious and less toxic prodrug of systemic SN-38 than SG. Finally, we suggest possible mechanisms of SG resistance and how PLX038 might perform in the context of each. Taken together, we argue that-contrary to many opinions-SG does not exclusively act as a conventional ADC, and propose that PLX038 may be efficacious in some settings of SG-resistance.
Topics: Humans; Irinotecan; Prodrugs; Antigens, Neoplasm; Neoplasms; Immunoconjugates; Camptothecin; Antibodies, Monoclonal, Humanized
PubMed: 38236523
DOI: 10.1007/s40259-024-00643-8 -
Oncogene Mar 2022Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are...
Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.
Topics: Aminopyridines; Carcinogenesis; Histones; Humans; Pancreatic Neoplasms; Phosphogluconate Dehydrogenase; Prodrugs
PubMed: 35031771
DOI: 10.1038/s41388-022-02183-3