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Molecules (Basel, Switzerland) Apr 2020Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including... (Review)
Review
Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.
Topics: Adenosine; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Furans; Humans; K562 Cells; Mice; Molecular Structure; Nucleosides; Oxygen; Prodrugs; Purine Nucleosides; Pyrimidinones; Thionucleosides; Vitamin E
PubMed: 32354007
DOI: 10.3390/molecules25092050 -
Molecular Pharmaceutics Jan 2020Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains...
Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.
Topics: Animals; CD4-Positive T-Lymphocytes; Cell Survival; Chromatography, Liquid; Darunavir; Drug Resistance, Viral; HIV Protease Inhibitors; HIV-1; Humans; Macrophages; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron; Prodrugs; Rats; Tandem Mass Spectrometry
PubMed: 31742407
DOI: 10.1021/acs.molpharmaceut.9b00871 -
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 -
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 -
International Journal of Molecular... Nov 2022Pt(IV) prodrugs remain one of the most promising alternatives to conventional Pt(II) therapy due to their versatility in axial ligand choice and delayed mode of action.... (Review)
Review
Pt(IV) prodrugs remain one of the most promising alternatives to conventional Pt(II) therapy due to their versatility in axial ligand choice and delayed mode of action. Selective activation from an external source is especially attractive due to the opportunity to control the activity of an antitumor drug in space and time and avoid damage to normal tissues. In this review, we discuss recent advances in photoabsorber-mediated photocontrollable activation of Pt(IV) prodrugs. Two main approaches developed are the focus of the review. The first one is the photocatalytic strategy based on the flavin derivatives that are not covalently bound to the Pt(IV) substrate. The second one is the conjugation of photoactive molecules with the Pt(II) drug via axial position, yielding dual-action Pt(IV) molecules capable of the controllable release of Pt(II) cytotoxic agents. Thus, Pt(IV) prodrugs with a light-controlled mode of activation are non-toxic in the absence of light, but show high antiproliferative activity when irradiated. The susceptibility of Pt(IV) prodrugs to photoreduction, photoactivation mechanisms, and biological activity is considered in this review.
Topics: Prodrugs; Cell Line, Tumor; Antineoplastic Agents; Ligands
PubMed: 36498837
DOI: 10.3390/ijms232314511 -
Journal of Medicinal Chemistry Feb 2024We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the...
We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two alkyl residues and ; (ii) the δ-phosph(on)ate is esterified covalently by one acyloxybenzyl moiety and a moiety and ; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two prodrug groups and . We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates ( and , (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of Tetraro-prodrug was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.
Topics: Anti-HIV Agents; Nucleosides; Stavudine; HIV-1; Nucleotides; Prodrugs
PubMed: 38345794
DOI: 10.1021/acs.jmedchem.3c02022 -
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 -
Drug Delivery Dec 2021Multidrug resistance (MDR) is one of the main reasons for tumor chemotherapy failure. Podophyllotoxin (PPT) has been reported that can suppress MDR cancer cell growth;...
pH and ROS sequentially responsive podophyllotoxin prodrug micelles with surface charge-switchable and self-amplification drug release for combating multidrug resistance cancer.
Multidrug resistance (MDR) is one of the main reasons for tumor chemotherapy failure. Podophyllotoxin (PPT) has been reported that can suppress MDR cancer cell growth; however, effective delivery of PPT to MDR cancer cells is challenged by cascaded bio-barriers. To effectively deliver PPT to MDR cancer cells, a PPT polymeric prodrug micelle (PCDMA) with the charge-conversion capability and self-acceleration drug release function are fabricated, which is composed of a pH and reactive oxygen species (ROS) sequentially responsive PPT-polymeric prodrug and an ROS generation agent, cucurbitacin B (CuB). After reach to tumor tissue, the surface charge of PCDMA could rapidly reverse to positive in the tumor extracellular environment to promote cellular uptake. Subsequently, the PCDMA could be degraded to release PPT and CuB in response to an intracellular high ROS condition. The released CuB is competent for generating ROS, which in turn accelerates the release of PPT and CuB. Eventually, the released PPT could kill MDR cancer cells. The and studies demonstrated that PCDMA was effectively internalized by cancer cells and produces massive ROS intracellular, rapid release drug, and effectively overcame MDR compared with the control cells, due to the tumor-specific weakly acidic and ROS-rich environment. Our results suggest that the pH/ROS dual-responsive PCDMA micelles with surface charge-reversal and self-amplifying ROS-response drug release provide an excellent platform for potential MDR cancer treatment.
Topics: A549 Cells; Animals; Cell Survival; Chemistry, Pharmaceutical; Drug Carriers; Drug Liberation; Drug Resistance, Neoplasm; Humans; Hydrogen-Ion Concentration; Mice; Micelles; Podophyllotoxin; Polymers; Prodrugs; Reactive Oxygen Species; Surface Properties; Triterpenes
PubMed: 33818237
DOI: 10.1080/10717544.2021.1905750 -
Advanced Science (Weinheim,... Jan 2023Camptothecin (CPT) is a potent chemotherapeutic agent for various cancers, but the broader application of CPT is still hindered by its poor bioavailability and systemic...
Camptothecin (CPT) is a potent chemotherapeutic agent for various cancers, but the broader application of CPT is still hindered by its poor bioavailability and systemic toxicity. Here, a prodrug that releases CPT in response to glutathione (GSH), which is commonly overexpressed by cancer cells is reported. Through assembling with PEGylated lipids, the prodrug is incorporated within as-assembled nanoparticles, affording CPT with a prolonged half-life in blood circulation, enhanced tumor targetingability, and improved therapeutic efficacy. Furthermore, such prodrug nanoparticles can also promote dendritic cell maturation and tumor infiltration of CD8 T cells, providing a novel strategy to improve the therapeutic efficacy of CPT.
Topics: Humans; Prodrugs; Camptothecin; CD8-Positive T-Lymphocytes; Nanoparticles; Neoplasms; Glutathione
PubMed: 36442854
DOI: 10.1002/advs.202205246