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https://www.readbyqxmd.com/read/28647214/development-and-in-vivo-evaluation-of-functionalized-ritonavir-proliposomes-for-lymphatic-targeting
#1
Vasif Ahammed, Reema Narayan, John Paul, Yogendra Nayak, Bisakha Roy, Gopal V Shavi, Usha Y Nayak
AIMS: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. MATERIALS AND METHODS: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies...
June 21, 2017: Life Sciences
https://www.readbyqxmd.com/read/28644183/more-dose-dependent-side-effects-with-mercaptopurine-over-azathioprine-in-ibd-treatment-due-to-relatively-higher-dosing
#2
Mark M T J Broekman, Marieke J H Coenen, Corine J van Marrewijk, Geert J A Wanten, Dennis R Wong, Andre L M Verbeek, Olaf H Klungel, Piet M Hooymans, Henk-Jan Guchelaar, Hans Scheffer, Luc J J Derijks, Dirk J de Jong
BACKGROUND: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. METHODS: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care...
June 20, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28638776/synthetic-approaches-for-the-preparation-of-phosphoramidate-prodrugs-of-2-deoxypseudoisocytidine
#3
Michaela Serpi, Roberto De Biasi, Fabrizio Pertusati, Magdalena Slusarczyk, Christopher McGuigan
A synthetic procedure for the preparation of phosphoramidate prodrugs of C-nucleosides is reported. Different phosphorochloridates were reacted with 3'-O-protected N-acetyl-2'-deoxypseudoisocytidine or 3'-O-protected 2'-deoxypseudoisocytidine, followed by acidic hydrolysis of the protecting group. In the presence of the N-acetyl moiety, the enolisable keto group of the nucleobase was able to react (like the 5'-OH) with the phosphorochloridates to give bisphosphorylated derivatives. Epimerisation (β to α) occurred if the amino group of the nucleobase was unprotected...
June 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28637373/efficacy-pharmacokinetic-and-pharmacodynamic-evaluation-of-apaziquone-in-the-treatment-of-non-muscle-invasive-bladder-cancer
#4
R M Phillips, H R Hendriks, J B Sweeney, G Reddy, G J Peters
Apaziquone (also known as EO9 and Qapzola) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects...
June 21, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28636806/ph-dependent-general-base-catalyzed-activation-rather-than-isocyanate-liberation-may-explain-the-superior-anticancer-efficacy-of-laromustine-compared-to-related-1-2-bis-methylsulfonyl-1-2-chloroethyl-hydrazine-prodrugs
#5
P G Penketh, R A Finch, R Sauro, R P Baumann, E S Ratner, K Shyam
Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) they are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28636344/ruthenium-complexes-are-ph-activated-metallo-prodrugs-phamps-with-light-triggered-selective-toxicity-toward-cancer-cells
#6
Fengrui Qu, Seungjo Park, Kristina Martinez, Jessica L Gray, Fathima Shazna Thowfeik, John A Lundeen, Ashley E Kuhn, David J Charboneau, Deidra L Gerlach, Molly M Lockart, James A Law, Katherine L Jernigan, Nicole Chambers, Matthias Zeller, Nicholas A Piro, W Scott Kassel, Russell H Schmehl, Jared J Paul, Edward J Merino, Yonghyun Kim, Elizabeth T Papish
Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)2Ru(PL)](2+) were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1A: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2A: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4A: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5A: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp)...
June 21, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28636040/tamoxifen-like-metallocifens-target-the-thioredoxin-system-determining-mitochondrial-impairment-leading-to-apoptosis-in-jurkat-cells
#7
Valeria Scalcon, Michèle Salmain, Alessandra Folda, Siden Top, Pascal Pigeon, Hui Zhi Shirley Lee, Gérard Jaouen, Alberto Bindoli, Anne Vessières, Maria Pia Rigobello
Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens...
June 21, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28632406/tailored-pharmacophore-model-to-enhance-virtual-screening-and-drug-discovery-a-case-study-on-the-identification-of-potential-inhibitors-against-drug-resistant-mycobacterium-tuberculosis-3r-hydroxyacyl-acp-dehydratases
#8
Kgothatso E Machaba, Ndumiso N Mhlongo, Yussif M Dokurugu, Mahmoud Es Soliman
AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28630710/hdac-inhibitor-conjugated-polymeric-prodrug-micelles-for-doxorubicin-delivery
#9
Suchithra A Senevirathne, Katherine E Washington, Jason B Miller, Michael C Biewer, David Oupicky, Daniel J Siegwart, Mihaela C Stefan
Amphiphilic diblock copolymers bearing histone deacetylase inhibitors (HDACi) (4-phenyl butyric acid and valproic acid) were synthesized by the ring-opening polymerization of γ-4-phenylbutyrate-ε-caprolactone (PBACL), γ-valproate-ε-caprolactone (VPACL), and ε-caprolactone (CL) from a poly(ethylene glycol) macroinitiator (PEG). These amphiphilic diblock copolymers self-assembled into stable pro-drug micelles and demonstrated excellent biocompatibility. High loading of doxorubicin (DOX) up to 5.1 wt% was achieved...
March 21, 2017: Journal of Materials Chemistry. B, Materials for Biology and Medicine
https://www.readbyqxmd.com/read/28628771/lentinan-diminishes-apoptotic-bodies-in-the-ileal-crypts-associated-with-s-1-administration
#10
Yasuyo Suga, Kenji Takehana
S-1 is an oral agent containing tegafur (a prodrug of 5-fluorouracil) that is used to treat various cancers, but adverse effects are frequent. Two pilot clinical studies have suggested that lentinan (LNT; β-1,3-glucan) may reduce the incidence of adverse effects caused by S-1 therapy. In this study, we established a murine model for assessment of gastrointestinal toxicity associated with S-1 and studied the effect of LNT. S-1 was administered orally to BALB/c mice at the effective dose (8.3mg/kg, as tegafur equivalent) once daily (5days per week) for 3weeks...
June 16, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28628279/acyclic-nucleoside-phosphonates-containing-9-deazahypoxanthine-and-a-5-membered-heterocycle-as-selective-inhibitors-of-plasmodial-6-oxopurine-phosphoribosyltransferases
#11
Martin Maxmilian Kaiser, Ondřej Baszczyňski, Dana Hocková, Lenka Poštová-Slavětínská, Martin Dračínský, Dianne T Keough, Luke W Guddat, Zlatko Janeba
Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine instead of 6-aminopurine or pyrimidine bases are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs has been synthesized and tested as inhibitors of human HGPRT, PfHGXPRT and Plasmodium vivax (Pv) HGPRT...
June 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28628181/synthesis-and-antiviral-evaluation-of-base-modified-deoxythreosyl-nucleoside-phosphonates
#12
Chao Liu, Shrinivas G Dumbre, Christophe Pannecouque, Brent Korba, Steven De Jonghe, Piet Herdewijn
l-α-2'-Deoxythreosyl nucleoside phosphonates and their phosphonodiamidate prodrugs with a hypoxanthine, 2,6-diaminopurine, 2-amino-6-cyclopropylaminopurine, 7-deazaadenine, 5-fluorouracil and 5-methylcytosine heterocycle as a nucleobase were synthesized and evaluated for their inhibitory activity against HIV and HBV. The 2,6-diaminopurine modified analogue 23a displayed the most potent activity against HIV, with an EC50 value of 11.17 μM against HIV-1 (IIIB) and an EC50 value of 8.15 μM against HIV-2 (ROD)...
June 19, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28627471/phospholipid-drug-conjugates-as-a-novel-oral-drug-targeting-approach-for-the-treatment-of-inflammatory-bowel-disease
#13
Arik Dahan, Milica Markovic, Svetlana Epstein, Noa Cohen, Ellen M Zimmermann, Aaron Aponick, Shimon Ben-Shabat
The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied...
June 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28626570/riboflavin-as-a-bioorthogonal-photocatalyst-for-the-activation-of-a-pt-iv-prodrug
#14
Silvia Alonso-de Castro, Emmanuel Ruggiero, Ane Ruiz-de-Angulo, Elixabete Rezabal, Juan C Mareque-Rivas, Xabier Lopez, Fernando López-Gallego, Luca Salassa
Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst...
June 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28626533/synthesis-and-anti-hcv-activity-of-a-novel-2-3-dideoxy-2-%C3%AE-fluoro-2-%C3%AE-c-methyl-guanosine-phosphoramidate-prodrug
#15
Wenquan Yu, Ertong Li, Zhigang Lv, Ke Liu, Xiaohe Guo, Yuan Liu, Junbiao Chang
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28623355/epigenetic-and-antitumor-effects-of-platinum-iv-octanoato-conjugates
#16
Vojtech Novohradsky, Ilaria Zanellato, Cristina Marzano, Jitka Pracharova, Jana Kasparkova, Dan Gibson, Valentina Gandin, Domenico Osella, Viktor Brabec
We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28622881/discovery-of-%C3%AE-d-2-deoxy-2-dichlorouridine-nucleotide-prodrugs-as-potent-inhibitors-of-hepatitis-c-virus-replication
#17
Pedro Pinho, Genadiy Kalayanov, Hans Westerlind, Åsa Rosenquist, Horst Wähling, Christian Sund, Maria Almeida, Susana Ayesa, Jan Tejbrant, Paul Targett-Adams, Anders Eneroth, Annelie Lindqvist
Discovery of sofosbuvir has radically changed hepatitis C treatment and nucleoside/tide NS5B inhibitors are now viewed as one of the key components in combination therapies with other direct-acting antiviral agents. As part of our program to identify new nucleoside inhibitors of HCV replication, we now wish to report on the discovery of β-d-2'-deoxy-2'-dichlorouridine nucleotide prodrugs as potent inhibitors of HCV replication. Although, cytidine analogues have long been recognized to be metabolized to both cytidine and uridine triphosphates through the action of cytidine deaminase, uridine analogues are generally believed to produce exclusively uridine triphosphate...
May 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28621793/kinetics-and-mechanism-of-oxidation-of-the-anti-tubercular-prodrug-isoniazid-and-its-analog-by-iridium-iv-as-models-for-biological-redox-systems
#18
Jingran Dong, Yanli Ren, Sufang Sun, Jiao Yang, Chunxia Nan, Hongmei Shi, Jianzhong Xu, Jie Duan, Tiesheng Shi, Lars I Elding
A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6](2-) as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6](2-) and hydrazide, and the observed second-order rate constants k' have been determined as a function of pH...
June 16, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28620994/amphiphilic-naproxen-prodrugs-differential-scanning-calorimetry-study-on-their-interaction-with-phospholipid-bilayers
#19
Maria Chiara Giuffrida, Rosario Pignatello, Francesco Castelli, Maria Grazia Sarpietro
OBJECTIVES: Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. METHODS: The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied...
June 16, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28620913/efficacy-of-oral-lipid-based-formulations-of-apomorphine-and-its-diester-in-a-parkinson-s-disease-rat-model
#20
Nrupa Borkar, Daniel R Andersson, Mingshi Yang, Anette Müllertz, René Holm, Huiling Mu
OBJECTIVES: Apomorphine is used to symptomatically treat Parkinson's disease (PD). Oral delivery of apomorphine is generally limited by its short plasma half-life and a hepatic first-pass metabolism. This study was aimed at evaluating the behavioural response of apomorphine and its prodrug administered in oral lipid-based formulations. METHODS: The behavioural response of apomorphine and its prodrug administered in oral lipid-based formulations was evaluated using a 6-hydroxydopamine-lesioned rat model simulating PD symptomatology...
June 16, 2017: Journal of Pharmacy and Pharmacology
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