-
The Journal of Organic Chemistry Nov 2022A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were...
A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC) 59 ± 17 μM), while the other prodrugs were inactive at 100 μM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays.
Topics: Organophosphonates; Prodrugs; Nucleosides; Esters; Anti-HIV Agents
PubMed: 36283025
DOI: 10.1021/acs.joc.2c02135 -
Molecules (Basel, Switzerland) Dec 2015Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their... (Review)
Review
Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.
Topics: Biological Availability; Drug Delivery Systems; Drug Design; Prodrugs; Solubility
PubMed: 26729077
DOI: 10.3390/molecules21010042 -
Cancer Letters Jul 2023Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe...
Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187-releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies.
Topics: Humans; Prodrugs; ErbB Receptors; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Lung Neoplasms; Cell Proliferation; Hypoxia; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37211067
DOI: 10.1016/j.canlet.2023.216237 -
Bioorganic & Medicinal Chemistry Sep 2021The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for...
The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
Topics: Adenosine; Animals; Antiviral Agents; Chlorocebus aethiops; Male; Mice, Inbred ICR; Microbial Sensitivity Tests; Prodrugs; SARS-CoV-2; Vero Cells; Mice
PubMed: 34450570
DOI: 10.1016/j.bmc.2021.116364 -
Molecules (Basel, Switzerland) Mar 2007Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global... (Review)
Review
Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people,mainly in developing countries, die each year from infectious diseases. From 1975 to 1999,1393 new drugs were approved yet only 1% were for the treatment of neglected diseases[3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas' disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.
Topics: Animals; Antimalarials; Antiparasitic Agents; Antitubercular Agents; Disease; Humans; Prodrugs
PubMed: 18463559
DOI: 10.3390/molecules13030616 -
Current Opinion in HIV and AIDS Nov 2013This review focuses on the chemical and pharmacological rationale behind the development of nucleoside antiviral prodrugs (NAPs). (Review)
Review
PURPOSE OF REVIEW
This review focuses on the chemical and pharmacological rationale behind the development of nucleoside antiviral prodrugs (NAPs).
RECENT FINDINGS
Highly efficacious NAPs have been developed that extend and improve the quality of lives of individuals infected with HIV and hepatitis B virus (HBV), herpes viruses, and adenovirus infection in immunocompromised individuals. A very high rate of hepatitis C virus (HCV) cure is now possible using NAPs combined with other direct acting antiviral agents (DAAs).
SUMMARY
Prodrug strategies can address the issues of poor oral bioavailability and delivery of active metabolites to the targeted cells. Additionally, NAPs demonstrate potential for improving deficiencies in oral absorption, metabolism, tissue distribution, cellular accumulation, phosphorylation, and overall potency, in addition to diminishing potential for in-vivo selection of resistant viruses. NAPs continue to be the backbone for the treatment of HIV and HBV, herpesviruses, and adenovirus infections because their active forms are potent, have long intracellular half-lives and are relatively safe with high barrier to resistance.
Topics: Antiviral Agents; Humans; Nucleosides; Prodrugs; Virus Diseases
PubMed: 24100876
DOI: 10.1097/COH.0000000000000007 -
Molecules (Basel, Switzerland) Mar 2010Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and... (Review)
Review
Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency has been observed in aging and in a wide range of pathologies, including neurodegenerative disorders and cystic fibrosis (CF), as well as in several viral infections. Use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. Several reports have provided evidence for the use of GSH prodrugs able to replenish intracellular GSH levels. This review discusses different strategies for increasing GSH levels by supplying reversible bioconjugates able to cross the cellular membrane more easily than GSH and to provide a source of thiols for GSH synthesis.
Topics: Disease; Glutathione; Humans; Prodrugs
PubMed: 20335977
DOI: 10.3390/molecules15031242 -
Drug Design, Development and Therapy 2022Cisplatin (CDDP) and etoposide (Etp) are recommended first-line therapy for lung cancer. Nanostructured lipid carriers (NLCs) are engineered to deliver drugs for lung...
PURPOSE
Cisplatin (CDDP) and etoposide (Etp) are recommended first-line therapy for lung cancer. Nanostructured lipid carriers (NLCs) are engineered to deliver drugs for lung cancer treatment. In the present study, NLCs were applied to coload an Etp prodrug (EtpP) and CDDP.
METHODS
The Etp prodrug was synthesized by linking the phenolic hydroxyl group of Etp with polyethylene glycol (PEG). EtpP and CDDP coencapsulated NLCs (EtpP-CDDP NLCs) were prepared using film ultrasound. Cytotoxicity of drugs and drug-containing NLCs was assessed by evaluating cell viability using MTT assays. In vivo antitumor efficiency of EtpP-CDDP NLCs was evaluated on lung cancer-bearing xenografts.
RESULTS
EtpP-CDDP NLCs showed a uniformly spherical morphology with a size of 176.8±4.9 nm and -potential of -31.9±3.2 mV. Cellular uptake efficiency of EtpP-CDDP NLCs was 57.4%±3.9% on A549/DDP cells. EtpP-CDDP NLCs exhibited more sustained plasma retention, the highest drug distribution in tumors, and the highest tumor-inhibition rates in lung tumor-bearing mice.
CONCLUSION
EtpP-CDDP NLCs improved tumor-cell uptake, cytotoxicity, and tumor-inhibition efficiency, and could be used as a promising drug-delivery system for lung cancer combination therapy.
Topics: Humans; Mice; Animals; Cisplatin; Etoposide; Prodrugs; Lipids; Cell Line, Tumor; Nanostructures; Drug Carriers; Lung Neoplasms; Particle Size
PubMed: 36506793
DOI: 10.2147/DDDT.S386100 -
Molecules (Basel, Switzerland) Mar 2007While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic... (Review)
Review
While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various ocular structures. The careful consideration of ocular tissue metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and for providing the potential for site-specific bio-activation of certain drug molecules, thus enabling significant improvements in drug efficacy and the minimization of side-effect from either local or systemic drug delivery to the eye. Knowledge of these processes is important to prodrug and codrug development and to researchers involved in the design, delivery and metabolism of ophthalmic drugs. This present article reviews the progress in ocular prodrug and codrug design and delivery in light of ocular metabolic activities.
Topics: Animals; Drug Delivery Systems; Drug Design; Eye; Humans; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Prodrugs
PubMed: 17851396
DOI: 10.3390/12030373 -
Journal of the American Chemical Society Dec 2021The Pt(IV) prodrug -[Pt(pyridine)(N)(OH)] () and its coumarin derivative -[Pt(pyridine)(N)(OH)(coumarin-3-carboxylate)] () are promising agents for photoactivated...
The Pt(IV) prodrug -[Pt(pyridine)(N)(OH)] () and its coumarin derivative -[Pt(pyridine)(N)(OH)(coumarin-3-carboxylate)] () are promising agents for photoactivated chemotherapy. These complexes are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation. We show that photoactivation of induces remarkable cellular damage with extreme alterations to multiple cellular components, including formation of vacuoles, while also significantly increasing the cellular accumulation of Pt species compared to dark conditions. X-ray absorption near-edge structure XANES) measurements in cells treated with indicate only partial reduction of the prodrug upon irradiation, highlighting that phototoxicity in cancer cells may involve not only Pt(II) photoproducts but also photoexcited Pt(IV) species.
Topics: Antineoplastic Agents; Cell Proliferation; Coordination Complexes; Humans; Light; PC-3 Cells; Platinum; Prodrugs; Single-Cell Analysis
PubMed: 34808054
DOI: 10.1021/jacs.1c08630