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ChemMedChem Dec 2022The Bis-T series of compounds comprise some of the most potent inhibitors of dynamin GTPase activity yet reported, e. g.,...
The Bis-T series of compounds comprise some of the most potent inhibitors of dynamin GTPase activity yet reported, e. g., (2E,2'E)-N,N'-(propane-1,3-diyl)bis(2-cyano-3-(3,4-dihydroxyphenyl)acrylamide) (2), Bis-T-22. The catechol moieties are believed to limit cell permeability, rendering these compounds largely inactive in cells. To solve this problem, a prodrug strategy was envisaged and eight ester analogues were synthesised. The shortest and bulkiest esters (acetate and butyl/tert-butyl) were found to be insoluble under physiological conditions, whilst the remaining five were soluble and stable under these conditions. These five were analysed for plasma stability and half-lives ranged from ∼2.3 min (propionic ester 4), increasing with size and bulk, to greater than 24 hr (dimethyl carbamate 10). Similar profiles where observed with the rate of formation of Bis-T-22 with half-lives ranging from ∼25 mins (propionic ester 4). Propionic ester 4 was chosen to undergo further testing and was found to inhibit endocytosis in a dose-dependent manner with IC ∼8 μM, suggesting this compound is able to effectively cross the cell membrane where it is rapidly hydrolysed to the desired Bis-T-22 parent compound.
Topics: Prodrugs; Dynamins; Esters; Endocytosis
PubMed: 36351775
DOI: 10.1002/cmdc.202200400 -
International Journal of Molecular... Jul 2023A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We...
A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We found that subcutaneous injection of acacetin prodrug (5, 10, 20 mg/kg) decreased serum ALT, AST, and ALP, corrected the abnormal MDA and GSH in liver, and improved intrahepatic hemorrhage and destruction of liver structures in APAP (300 mg/kg)-treated mice. Molecular mechanism analysis revealed that the expressions of endoplasmic reticulum (ER) stress markers ATF6, CHOP, and p-PERK, apoptosis-related protein BAX, and cleaved caspase 3 were decreased by acacetin in a dose-dependent manner in vivo and in vitro. Moreover, via the acacetin-upregulated peroxisome-proliferator-activated receptor gamma (PPARγ) of HepG2 cells and liver, the suppressive effect of acacetin on ER stress and apoptosis was abolished by PPARγ inhibitor (GW9662) or PPARγ-siRNA. Molecular docking revealed that acacetin can bind to three active pockets of PPARγ, mainly by hydrogen bond. Our results provide novel evidence that acacetin prodrug exhibits significant protective effect against APAP-induced liver injury by targeting PPARγ, thereby suppressing ER stress and hepatocyte apoptosis. Acacetin prodrug is likely a promising new drug candidate for treating patients with acute liver injury induced by APAP.
Topics: Animals; Mice; Acetaminophen; Chemical and Drug Induced Liver Injury; Liver; Molecular Docking Simulation; Oxidative Stress; PPAR gamma; Prodrugs; Up-Regulation; Flavones
PubMed: 37511082
DOI: 10.3390/ijms241411320 -
European Journal of Pharmaceutics and... Oct 2023The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs)...
The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs) are one of the most important anatomical reservoirs of HIV. Suboptimal levels of antiretroviral (ARVs) drugs in these difficult-to-penetrate viral reservoirs is one of the limitations of current antiretroviral therapy (ART) regimens. This study aimed to design and assess highly lipophilic ester prodrugs of dolutegravir (DTG) formulated with long-chain triglyceride (LCT) for delivery of DTG to the viral reservoir in mesenteric lymph and MLNs. A number of alkyl ester prodrugs of DTG were designed based on the predicted affinity to chylomicrons (CM), and the six most promising prodrugs were selected and synthesised. The synthesised prodrugs were further assessed for their intestinal lymphatic transport potential and biotransformation in biorelevant media in vitro and ex vivo. DTG and the most promising prodrug (prodrug 5) were then assessed in pharmacokinetic and biodistribution studies in rats. Although oral administration of 5 mg/kg of unmodified DTG (an allometrically scaled dose from humans) with or without lipids achieved concentrations above protein binding-adjusted IC (PA-IC) (64 ng/mL) in most tissues, the drug was not selectively targeted to MLNs. The combination of lipophilic ester prodrug and LCT-based formulation approach improved the targeting selectivity of DTG to MLNs 4.8-fold compared to unmodified DTG. However, systemic exposure to DTG was limited, most likely due to poor intestinal absorption of the prodrug following oral administration. In vitro lipolysis showed a good correlation between micellar solubilisation of the prodrug and systemic exposure to DTG in rats in vivo. Thus, it is prudent to include in vitro lipolysis in the early assessment of orally administered drugs and prodrugs in lipidic formulations, even when intestinal lymphatic transport is involved in the absorption pathway. Further studies are needed to clarify the underlying mechanisms of low systemic bioavailability of DTG following oral administration of the prodrug and potential ways to overcome this limitation.
Topics: Humans; Rats; Animals; Prodrugs; Esters; Tissue Distribution; Intestines; Triglycerides; Administration, Oral
PubMed: 37634824
DOI: 10.1016/j.ejpb.2023.08.015 -
British Journal of Cancer May 2016Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic... (Review)
Review
Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic agents to low-oxygen tumour compartments. Despite compelling evidence linking hypoxia with treatment resistance and adverse prognosis, a number of such prodrugs have recently failed to demonstrate efficacy in pivotal clinical trials; an outcome that demands reflection on the discovery and development of these compounds. In this review, we discuss a clear disconnect between the pathobiology of tumour hypoxia, the pharmacology of hypoxia-activated prodrugs and the manner in which they have been taken into clinical development. Hypoxia-activated prodrugs have been evaluated in the manner of broad-spectrum cytotoxic agents, yet a growing body of evidence suggests that their activity is likely to be dependent on the coincidence of tumour hypoxia, expression of specific prodrug-activating reductases and intrinsic sensitivity of malignant clones to the cytotoxic effector. Hypoxia itself is highly variable between and within individual tumours and is not treatment-limiting in all cancer subtypes. Defining predictive biomarkers for hypoxia-activated prodrugs and overcoming the technical challenges of assaying them in clinical settings will be essential to deploying these agents in the era of personalised cancer medicine.
Topics: Antineoplastic Agents; Cell Hypoxia; Humans; Neoplasms; Oxidoreductases; Precision Medicine; Prodrugs
PubMed: 27070712
DOI: 10.1038/bjc.2016.79 -
Molecules (Basel, Switzerland) Sep 2020Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed...
Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free "click" chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability.
Topics: Amino Acid Sequence; Antibiotics, Antineoplastic; Cathepsin B; Cell Line, Tumor; Cell Membrane Permeability; Cell Survival; Click Chemistry; Doxorubicin; G2 Phase Cell Cycle Checkpoints; Humans; Peptides, Cyclic; Polyethylene Glycols; Prodrugs; Solubility
PubMed: 32962018
DOI: 10.3390/molecules25184285 -
Polimery W Medycynie 2014This review deals with the targeting of drugs to the lower gastrointestinal tract i.e. colon. Colonic drug delivery becomes important for localized action as well as for... (Review)
Review
This review deals with the targeting of drugs to the lower gastrointestinal tract i.e. colon. Colonic drug delivery becomes important for localized action as well as for improved systemic availability of peptide and proteins. Drugs which have absorption window in the colonic region have been targeted using different novel technologies. pH sensitive polymers and prodrug based formulation have been used for the delivery of drugs into the colon. Different natural polymers have been used successfully for the delivery of drugs into the colon. Natural polymers are less toxic, biodegradable and easily available with a wide range of molecular weight and varying chemical compositions. One of the supporting properties associated with these polymers is that natural polymers can be used as approved pharmaceutical excipient.
Topics: Absorbable Implants; Administration, Oral; Biological Availability; Chemistry, Pharmaceutical; Coated Materials, Biocompatible; Colon; Drug Carriers; Drug Delivery Systems; Excipients; Hydrogen-Ion Concentration; Molecular Weight; Pharmaceutical Preparations; Polysaccharides; Prodrugs; Pulse Therapy, Drug
PubMed: 24967782
DOI: No ID Found -
Antiviral Chemistry & Chemotherapy Dec 2017In this review, our recent advances in the development of nucleoside di- and nucleoside triphosphate prodrugs is summarized. Previously, we had developed a successful... (Review)
Review
In this review, our recent advances in the development of nucleoside di- and nucleoside triphosphate prodrugs is summarized. Previously, we had developed a successful membrane-permeable pronucleotide system for the intracellular delivery of nucleoside monophosphates as well, the so-called cycloSal-approach. In contrast to that work in which the delivery is initiated by a chemically driven hydrolysis reaction, for the di- and triphosphate delivery, an enzymatic trigger mechanism involving (carboxy)esterases had to be used. The other features of the new pronucleotide approaches are: (i) lipophilic modification was restricted to the terminal phosphate group leaving charges at the internal phosphate moieties and (ii) appropriate lipophilicity is introduced by long aliphatic residues within the bipartite prodrug moiety. The conceptional design of the di- and triphosphate prodrug systems will be described and the chemical synthesis, the hydrolysis properties, a structure-activity relationship and antiviral activity data will be discussed as well. The advantage of these new approaches is that all phosphorylation steps from the nucleoside analogue into the bioactive nucleoside triphosphate form can be bypassed in the case of the triphosphate prodrugs. Moreover, enzymatic processes like the deamination of nucleosides or nucleoside monophosphates which lead to catabolic clearance of the potential antivirally active compound can be avoided by the delivery of the higher phosphorylated nucleotides.
Topics: Antiviral Agents; Diphosphates; Humans; Microbial Sensitivity Tests; Nucleosides; Polyphosphates; Prodrugs; Viruses
PubMed: 29096525
DOI: 10.1177/2040206617738656 -
Advanced Drug Delivery Reviews Apr 2016Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into... (Review)
Review
Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated.
Topics: Animals; Enzymes; Genes, Transgenic, Suicide; Genetic Therapy; Humans; Neoplasms; Prodrugs
PubMed: 26004498
DOI: 10.1016/j.addr.2015.05.009 -
Molecules (Basel, Switzerland) May 2008Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility... (Review)
Review
Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility and non-targeting capabilities. The majority of drugs for cardiovascular diseases undergo first-pass metabolism, resulting in drug inactivation and generation of toxic metabolites, which makes them appealing targets for prodrug design. Since prodrugs undergo a chemical reaction to form the parent drug once inside the body, this makes them very effective in controlling the release of a variety of compounds to the targeted site. This review will provide the reader with an insight on the latest developments of prodrugs that are available for treating a variety of cardiovascular diseases. In addition, we will focus on several drug delivery methodologies that have merged with the prodrug approach to provide enhanced target specificity and controlled drug release with minimal side effects.
Topics: Cardiovascular Diseases; Drug Delivery Systems; Humans; Prodrugs
PubMed: 18560335
DOI: 10.3390/molecules13051156 -
Dalton Transactions (Cambridge, England... Aug 2016Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains... (Review)
Review
Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains the hunt for the "magic bullet" which can satisfy the requirements of an effective chemotherapeutic drug formulation. Pt(iv) complexes are kinetically more inert than the Pt(ii) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting, or drug delivery. The ultimate aim of functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, an increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address the attempts made in our lab to develop Pt(iv) prodrugs that can be activated and delivered using targeted nanotechnology-based delivery platforms.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Organoplatinum Compounds; Platinum Compounds; Prodrugs
PubMed: 27493131
DOI: 10.1039/c6dt01738j