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ACS Medicinal Chemistry Letters Feb 2024Cannabidiol (CBD ) is a nonpsychotic cannabinoid-based drug approved by the U.S. FDA for treating refractory epilepsy, namely, Lennox-Gastaut and Dravet syndrome....
Cannabidiol (CBD ) is a nonpsychotic cannabinoid-based drug approved by the U.S. FDA for treating refractory epilepsy, namely, Lennox-Gastaut and Dravet syndrome. However, its low aqueous solubility and oral bioavailability are compensated by administering high doses, and there is an increased demand for conjugates with improved properties. In this direction, the present work is focused on synthesizing CBD-based prodrugs to address the issue of poor solubility and oral bioavailability. Several CBD-based prodrugs were synthesized and studied in a battery of assays: viz, release kinetic (), solubility (), chemical stability (), plasma stability (), pharmacokinetics (), and efficacy studies (). Among the synthesized prodrugs, the morpholinyl CBD-based prodrugs and showed good release behavior, stability, better solubility, and a plasma profile. Moreover, prodrug candidate showed better therapeutic efficacy. The present study identifies CBD-based prodrugs with improved physiochemical properties and oral exposure.
PubMed: 38352838
DOI: 10.1021/acsmedchemlett.3c00461 -
Angewandte Chemie (International Ed. in... Dec 2023Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control...
Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.
Topics: Humans; Prodrugs; NADP; Antineoplastic Agents; Dacarbazine; Cytochrome P-450 Enzyme System; Neoplasms
PubMed: 37881154
DOI: 10.1002/anie.202314025 -
Science (New York, N.Y.) Mar 2024Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In...
Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.
Topics: Animals; Administration, Oral; Ebolavirus; Hemorrhagic Fever, Ebola; Macaca fascicularis; Nucleosides; Adenosine Monophosphate; Alanine; Prodrugs; Antiviral Agents
PubMed: 38484056
DOI: 10.1126/science.adk6176 -
Current Drug Discovery Technologies May 2024One lucrative method for overcoming challenges in drug discovery or for enhancing undesirable properties of already-approved medications is prodrug design. The goal of...
One lucrative method for overcoming challenges in drug discovery or for enhancing undesirable properties of already-approved medications is prodrug design. The goal of this review is to present researchers with a profile of naturally occurring Phytophenols as carriers that would be used for prodrug synthesis as well as their advantages. Phytophenols offer several advantages when used as promoieties as they also possess antioxidant and analgesic properties, they are obtained naturally and their safety profile is well established. Several phytophenols like menthol, thymol, eugenol, guaiacol, sesamol, vanillin, and umbelliferone are some of the phytophenols that have several beneficial properties and are extensively employed in the field of food processing and medicine. In the current review, we have listed all types of promoieties that are used for prodrug synthesis and phytophenols are reviewed in detail, which may help researchers to select phytophenols based on their need and suitability for drug candidates.
PubMed: 38818921
DOI: 10.2174/0115701638282895240523091552 -
Carbohydrate Polymers Nov 2023Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier...
Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (HO) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (O) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.
Topics: Micelles; Photochemotherapy; Dextrans; Prodrugs; Luminescence; Hydrogen Peroxide; Luminol; Cell Line, Tumor; Photosensitizing Agents; Paclitaxel; Nanoparticles
PubMed: 37567697
DOI: 10.1016/j.carbpol.2023.121192 -
Biotechnology Progress 2023Today, biologic prodrugs have led to targeting specific tumor markers and have increased specificity and selectivity in cancer therapy. Various studies have shown the... (Review)
Review
Today, biologic prodrugs have led to targeting specific tumor markers and have increased specificity and selectivity in cancer therapy. Various studies have shown the role of ncRNAs in cancer pathology and tumorigenesis and have suggested that ncRNAs, especially miRNAs, are valuable molecules in understanding cancer biology and therapeutic processes. Most miRNAs-based research and treatment are limited to chemically synthesized miRNAs. Synthetic alterations in these miRNA mimics may affect their folding, safety profile, and even biological activity. However, despite synthetic miRNA mimics produced by automated systems, various carriers could be used to achieve efficient production of bioengineered miRNAs through economical microbial fermentation. These bioengineered miRNAs as biological prodrugs could provide a new approach for safe therapeutic methods and drug production. In this regard, bioengineered chimeric miRNAs could be selectively processed to mature miRNAs in different types of cancer cells by targeting the desired gene and regulating cancer progression. In this article, we aim to review bioengineered miRNAs and their use in cancer therapy, as well as offering advances in this area, including the use of chimeric tRNA/pre-miRNAs.
Topics: Humans; MicroRNAs; Prodrugs; Neoplasms; RNA, Transfer
PubMed: 37608520
DOI: 10.1002/btpr.3387 -
Biochemical Pharmacology Dec 2023Butyrylcholinesterase (BChE) is present in plasma and numerous cells and organs. Its physiological function(s) is(are) still unclear. However, this enzyme is of... (Review)
Review
Butyrylcholinesterase (BChE) is present in plasma and numerous cells and organs. Its physiological function(s) is(are) still unclear. However, this enzyme is of pharmacological and toxicological importance. It displays a broad specificity and is capable of hydrolyzing a wide range of substrates with turnovers differing by several orders of magnitude. Nowaday, these substrates include more than two dozen carboxyl-ester drugs, numerous acetylated prodrugs, and transition state analogues of acetylcholine. In addition, BChE displays a promiscuous hydrolytic activity toward amide bonds of arylacylamides, and slowly hydrolyzes carbamyl- and phosphoryl-esters. Certain pseudo-substrates like carbamates and organophosphates are major drugs of potential medical interest. The existence of a large genetic poly-allelism, affecting the catalytic properties of BChE is at the origin of clinical complications in the use of certain drugs catabolized by BChE. The number of drugs and prodrugs hydrolyzed by BChE is expected to increase in the future. However, very few quantitative data (K, k) are available for most marketed drugs, and except for myorelaxants like succinylcholine and mivacurium, the impact of BChE genetic mutations on catalytic parameters has not been evaluated for most of these drugs.
Topics: Humans; Butyrylcholinesterase; Prodrugs; Succinylcholine; Hydrolysis; Mutation
PubMed: 37972875
DOI: 10.1016/j.bcp.2023.115910 -
Chemical Communications (Cambridge,... Oct 2023Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native... (Review)
Review
Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native biochemical reactions, has gained ever-increasing momentum in prodrug delivery over the past few decades. Albeit great progress has been attained in developing new bioorthogonal catalytic reactions and optimizing the catalytic performance of transition metal catalysts (TMCs), the use of TMCs to activate chemotherapeutics at the site of interest remains a challenging endeavor. To translate the bioorthogonal catalysis-mediated prodrug activation paradigm from flasks to animals, TMCs with targeting capability and stimulus-responsive behavior have been well-designed to perform chemical transformations in a controlled manner within highly complex biochemical systems, rendering on-demand drug activation to mitigate off-target toxicity. Here, we review the recent advances in the development of controllable bioorthogonal catalysis systems, with an emphasis on different strategies for engineering TMCs to achieve precise control over prodrug activation. Furthermore, we outline the envisaged challenges and discuss future directions of controllable bioorthogonal catalysis for disease therapy.
Topics: Animals; Prodrugs; Transition Elements; Metals; Catalysis; Activation, Metabolic
PubMed: 37791560
DOI: 10.1039/d3cc04286c -
Small Methods Dec 2023Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by... (Review)
Review
Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug-based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus-responsive CPT nano-prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus-responsive CPT nano-prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus-responsive CPT nano-prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano-prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected.
PubMed: 38085682
DOI: 10.1002/smtd.202301271 -
Advanced Healthcare Materials Nov 2023It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result...
It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result of their lack of selectivity, poor stability, and low solubility. Herein, it reports the development of a novel nanoparticle system, called ROS-CA-NPs, which is formed using polymer-cinnamaldehyde (CA) conjugates and is responsive to reactive oxygen species (ROS). ROS-CA-NPs exhibit excellent drug stability, tissue selectivity, and controlled drug release upon oxidative stress activation. Using mouse models of chronic rheumatoid arthritis and acute ulcerative colitis, this study demonstrates that the systemic administration of ROS-CA-NPs results in their accumulation at inflamed lesions and leads to greater therapeutic efficacy compared to traditional drugs. Furthermore, ROS-CA-NPs present excellent biocompatibility. The findings suggest that ROS-CA-NPs have the potential to be developed as safe and effective nanotherapeutic agents for a broad range of inflammatory diseases.
Topics: Animals; Mice; Prodrugs; Reactive Oxygen Species; Polymers; Anti-Inflammatory Agents; Nanoparticles
PubMed: 37540810
DOI: 10.1002/adhm.202301394