The pyridoindole derivative stobadin, [(-)-cis-2,8-dimetyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3b]-indole] is a perspective antiarrhythmic, antihistamine, anaesthetic, antiulcerous drug capable of extinguishing free oxygen radical. Its prodrug forms--N(5)- acyl-substituted stobadine--of the active substance--stobadine--have been prepared and it is assumed that the will be hydrolyzed in the organism and the active substance will be released in higher concentrations in different biological tissues. The present paper is concerned with the investigation of the kinetics of the hydrolysis of 13 acyl derivatives of stobadine in the medium of a buffer solution of pH 7 at temperatures of 70 degrees C and 75 degrees C spectrophotometrically in the UV region of the spectrum. The determined rate constants were correlated with the length of the side acyl chain and the pKa values of the drugs under study. The profile of log k--pH of substances was determined.

• MeSH
• hydrolýza MeSH
• karboliny chemie   MeSH
• koncentrace vodíkových iontů MeSH
• prekurzory léčiv chemie   MeSH
• scavengery volných radikálů chemie   MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dicarbine MeSH Prohlížeč
• karboliny MeSH
• prekurzory léčiv MeSH
• scavengery volných radikálů MeSH

Stobadin, (-)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyridol[4,3b]- indol is a compound with a potential antiarrhythmic, antihistamine, anaesthetic, antiulcerous, and marked antioxidative effect. N5-acylsubstitution of stobadin yielded derivatives, which represent prodrug forms of the active principle--stobadin, and it is assumed that they will be hydrolysed in the organism and the active principle will be released in higher concentrations in various biological tissues. The present paper deals with the investigation of the kinetics of hydrolysis of 13 stobadin acylderivatives in a medium of 0.1 mol/l of sodium hydroxide at 70 degrees C, employing spectrophotometry in the UV region of the spectrum. The determined rate constants were correlated with the length of the side acyl chain and the pKa values of the compounds under study.

• MeSH
• hydrolýza MeSH
• karboliny chemie   MeSH
• koncentrace vodíkových iontů MeSH
• prekurzory léčiv chemie   MeSH
• scavengery volných radikálů chemie   MeSH
• spektrofotometrie ultrafialová MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dicarbine MeSH Prohlížeč
• karboliny MeSH
• prekurzory léčiv MeSH
• scavengery volných radikálů MeSH

Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochemical properties─lipid bilayer permeability and water-lipid equilibrium partitioning coefficient. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biological barriers. There are several options for solving this issue: (i) change of the lipid bilayer composition, (ii) addition of a permeability enhancer, or (iii) modification of the chemical structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the molecular structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodology for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addition of aliphatic hydrocarbon chains via ester or amide bonds can render the molecule more lipophilic and increase its permeability by approximately 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the molecule and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coefficient can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible.

• Klíčová slova
• COSMOperm, lipid bilayer, partitioning coefficient, permeability, prodrug,
• MeSH
• fluorouracil MeSH
• lipidové dvojvrstvy chemie   MeSH
• liposomy * chemie   MeSH
• permeabilita MeSH
• prekurzory léčiv * chemie   MeSH
• tkáňová distribuce MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorouracil MeSH
• lipidové dvojvrstvy MeSH
• liposomy * MeSH
• prekurzory léčiv * MeSH

Phenolic group in therapeutic drugs can be used for a prodrug modification to overcome various undesirable drug properties that may become pharmacological, pharmaceutical or pharmacokinetic barriers for application. Several strategies have been used in order to overcome the limited bioavailability of phenolic drugs. Classical design represents a nonspecific chemical approach to mask undesirable drug properties, limited bioavailability or chemical instability. Targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrug to specific enzyme or specific membrane transporter has potential as selective drug delivery system mainly in cancer therapy. The article brings examples of ester, sulphate, carbamate, carbonate, phosphate and ether prodrugs as well as the limitations of these prodrug strategies. Some specific enzyme targets are also presented.

• MeSH
• antitumorózní látky aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• biologická dostupnost MeSH
• fenoly chemie   MeSH
• léčivé přípravky aplikace a dávkování   metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   patofyziologie   MeSH
• prekurzory léčiv MeSH
• racionální návrh léčiv * MeSH
• systémy cílené aplikace léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• fenoly MeSH
• léčivé přípravky MeSH
• prekurzory léčiv MeSH

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

• MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• diazooxonorleucin farmakologie   terapeutické užití   MeSH
• glutamin metabolismus   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• prekurzory léčiv * farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diazooxonorleucin MeSH
• glutamin MeSH
• inhibitory enzymů MeSH
• prekurzory léčiv * MeSH

This work studied the mechanism of action of a Pt(IV) complex 2 bearing two axial lonidamine ligands, which are selective inhibitors of aerobic glycolysis. The presence of two lonidamine ligands in 2 compared to the parent Pt(II) complex increased its antiproliferative activity, cellular accumulation, and changed its cell cycle profile and mechanism of cell death. In 3D cell culture, 2 showed exceptional antiproliferative activity with IC50 values as low as 1.6 μM in MCF7 cells. The study on the influence of the lonidamine ligands in the Pt complex on glycolysis showed only low potency of ligands to affect metabolic processes in cancer cells, making the investigated complex, not a dual- or multi-action prodrug. However, the Pt(IV) prodrug effectively delivers the cytotoxic Pt(II) complex into cancer cells.

• Klíčová slova
• bioinorganic chemistry, lonidamine, medicinal inorganic chemistry, metals in medicine, Pt(IV) complexes,
• MeSH
• antitumorózní látky * farmakologie   MeSH
• indazoly MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky * MeSH
• indazoly MeSH
• ligandy MeSH
• lonidamine MeSH Prohlížeč
• prekurzory léčiv * MeSH

The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.

• Klíčová slova
• Gene directed enzyme prodrug therapy, MSC suicide gene exosomes, mesenchymal stem cells, suicide gene,
• MeSH
• antimetabolity antitumorózní metabolismus   farmakologie   MeSH
• cytosindeaminasa genetika   metabolismus   MeSH
• exozómy genetika   metabolismus   MeSH
• flucytosin metabolismus   MeSH
• fluorouracil metabolismus   farmakologie   MeSH
• fungální proteiny genetika   metabolismus   MeSH
• genetická terapie metody   MeSH
• kvasinky genetika   metabolismus   MeSH
• lidé MeSH
• mezenchymální kmenové buňky metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• pentosyltransferasy genetika   metabolismus   MeSH
• prekurzory léčiv metabolismus   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• transgeny sebevražedné genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antimetabolity antitumorózní MeSH
• cytosindeaminasa MeSH
• flucytosin MeSH
• fluorouracil MeSH
• fungální proteiny MeSH
• pentosyltransferasy MeSH
• prekurzory léčiv MeSH
• uracil phosphoribosyltransferase MeSH Prohlížeč

AIMS: Neuroinflammation is a prominent hallmark in several neurodegenerative diseases (NDs). Halting neuroinflammation can slow down the progression of NDs. Improving the efficacy of clinically available non-steroidal anti-inflammatory drugs (NSAIDs) is a promising approach that may lead to fast-track and effective disease-modifying therapies for NDs. Here, we aimed to utilize the L-type amino acid transporter 1 (LAT1) to improve the efficacy of salicylic acid as an example of an NSAID prodrug, for which brain uptake and intracellular localization have been reported earlier. MAIN METHODS: Firstly, we confirmed the improved LAT1 utilization of the salicylic acid prodrug (SA-AA) in freshly isolated primary mouse microglial cells. Secondly, we performed behavioural rotarod, open field, and four-limb hanging tests in mice, and a whole-brain proteome analysis. KEY FINDINGS: The SA-AA prodrug alleviated the lipopolysaccharide (LPS)-induced inflammation in the rotarod and hanging tests. The proteome analysis indicated decreased neuroinflammation at the molecular level. We identified 399 proteins linked to neuroinflammation out of 7416 proteins detected in the mouse brain. Among them, Gps2, Vamp8, Slc6a3, Slc18a2, Slc5a7, Rgs9, Lrrc1, Ppp1r1b, Gnal, and Adcy5/6 were associated with the drug's effects. The SA-AA prodrug attenuated the LPS-induced neuroinflammation through the regulation of critical pathways of neuroinflammation such as the cellular response to stress and transmission across chemical synapses. SIGNIFICANCE: The efficacy of NSAIDs can be improved via the utilization of LAT1 and repurposed for the treatment of neuroinflammation. This improved brain delivery and microglia localisation can be applied to other inflammatory modulators to achieve effective and targeted CNS therapies.

• Klíčová slova
• Grid-hanging test, LAT1, LPS-induced neuroinflammation, Mouse brain proteome, Mouse membrane transporters, Rotarod,
• MeSH
• antiflogistika nesteroidní * farmakologie   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• kyselina salicylová farmakologie   MeSH
• lipopolysacharidy MeSH
• mikroglie metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurodegenerativní nemoci * metabolismus   MeSH
• neurozánětlivé nemoci * farmakoterapie   MeSH
• prekurzory léčiv * farmakologie   MeSH
• proteom metabolismus   MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika nesteroidní * MeSH
• GPS2 protein, mouse MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• kyselina salicylová MeSH
• lipopolysacharidy MeSH
• prekurzory léčiv * MeSH
• proteom MeSH

Gene-directed enzyme/prodrug therapy (GDEPT) mediated by mesenchymal stromal cells (MSC) was already approved for clinical study on a progressive disease refractory to standard therapy. In this work, we examined the effect of several GDEPT approaches on chemoresistant cells. First, we derived 5-fluorouracil (5-FU)-resistant variant of human colorectal adenocarcinoma cells HT-29 designated HT-29/EGFP/FUR. Our data show that the upregulation of thymidylate synthase (TS) and downregulation of thymidine phosphorylase (TP), orotate phosphoribosyl transferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) contributed to the 5-FU resistance in cancer cells. Next, we combined the MSC expressing either yeast cytosine deaminase (CD-MSC) or fusion yeast CD::uracil phosphoribosyl transferase (CD::UPRT-MSC) and prodrug 5-fluorocytosine (5-FC) in a cell-mediated GDEPT approach. Bystander cytotoxic effect in the direct co-cultures of the tumor and therapeutic cells mixed in a 5:1 ratio resulted in 55% and 70% inhibition of proliferation, respectively. However, the acquired chemoresistance to 5-FU can be overcome by introducing the prodrug-converting transgene into the tumor cells. When the transgene CD::UPRT was expressed in the chemoresistant cells (CD::UPRT-FUR), substantial suicide effect and a 90% decrease in viability was observed using non-toxic concentration of 62.5 µg/ml 5-FC. In summary, we demonstrate here that the transgene introduction circumvented 5-FU resistance in the tumor cells.

• MeSH
• fluorouracil farmakologie   terapeutické užití   MeSH
• genetická terapie metody   MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorouracil MeSH
• prekurzory léčiv MeSH

The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared with Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over 2-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope-labeled flux analyses in tumors identified multiple glutamine-dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.

• MeSH
• glutamin antagonisté a inhibitory   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory nervové pochvy farmakoterapie   MeSH
• prekurzory léčiv farmakologie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• glutamin MeSH
• prekurzory léčiv MeSH