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https://www.readbyqxmd.com/read/28545088/transcriptional-activation-of-hif-1-by-a-ros-erk-axis-underlies-the-resistance-to-photodynamic-therapy
#1
María Julia Lamberti, María Florencia Pansa, Renzo Emanuel Vera, Martín Ernesto Fernández-Zapico, Natalia Belén Rumie Vittar, Viviana Alicia Rivarola
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT...
2017: PloS One
https://www.readbyqxmd.com/read/28544290/organic-co-prodrugs-structure-co-release-rate-relationship-studies
#2
Binghe Wang, Zhixiang Pan, Xingyue Ji, Vayou Chittavong, Wei Li, Kaili Ji, Mengyuan Zhu, Jun Zhang
Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals, and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Herein, we describe the structure-release rate studies of the first class of organic CO-prodrugs that release CO in aqueous solution at neutral pH.
May 25, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28539659/involvement-of-the-bed-nucleus-of-the-stria-terminalis-in-l-dopa-induced-dyskinesia
#3
Matthieu F Bastide, Christelle Glangetas, Evelyne Doudnikoff, Qin Li, Mathieu Bourdenx, Pierre-Olivier Fernagut, Éric C Dumont, François Georges, Erwan Bézard
A whole brain immediate early gene mapping highlighted the dorsolateral bed nucleus of the stria terminalis (dlBST) as a structure putatively involved in L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesia (LID), the debilitating side-effects of chronic dopamine replacement therapy in Parkinson's disease (PD). dlBST indeed displayed an overexpression of ∆FosB, ARC, Zif268 and FRA2 only in dyskinetic rats. We thus hypothesized that dlBST could play a role in LID hyperkinetic manifestations. To assess the causal role of the dlBST in LID, we used Daun02 inactivation to selectively inhibit the electrical activity of dlBST ΔFosB-expressing neurons...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28535350/activation-of-phenyl-4-2-oxo-3-alkylimidazolidin-1-yl-benzenesulfonates-prodrugs-by-cyp1a1-as-new-antimitotics-targeting-breast-cancer-cells
#4
Sébastien Fortin, Xavier Charest-Morin, Vanessa Turcotte, Coraline Lauvaux, Jacques Lacroix, Marie-France Côté, Stéphane Gobeil, Rene C-Gaudreault
Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs), that are antimicrotubule prodrugs activated by CYP1A1. Although PAIB-SOs are inert in most cells tested, they are highly cytocidal towards several human breast cancer cells, including hormone-independent and chemoresistant types...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28532670/syntheses-of-prodrug-type-phosphotriester-oligonucleotides-responsive-to-intracellular-reducing-environment-for-improvement-of-cell-membrane-permeability-and-nuclease-resistance
#5
Junsuke Hayashi, Yusuke Samezawa, Yosuke Ochi, Shun-Ichi Wada, Hidehito Urata
We synthesized prodrug-type phosphotriester (PTE) oligonucleotides containing the six-membered cyclic disulfide moiety by using phosphoramidite chemistry. Prodrug-type oligonucleotides named "Reducing-Environment-Dependent Uncatalyzed Chemical Transforming (REDUCT) PTE oligonucleotides" were converted into natural oligonucleotides under cytosol-mimetic reductive condition. Furthermore, the REDUCT PTE oligonucleotides were robust to nuclease digestion and exhibited good cell membrane permeability.
May 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28532154/injectable-nir-ph-responsive-nanocomposite-hydrogel-as-long-acting-implant-for-chemo-photothermal-synergistic-cancer-therapy
#6
Xiaoyu Xu, Ziyuan Huang, Zeqian Huang, Xuefei Zhang, Siyu He, Xiaoqi Sun, Yifeng Shen, Mina Yan, Chunshun Zhao
In this study, Gold nanorods (GNRs) were incorporated into the hydrogel networks formed by the copolymerization of N-isopropylacrylamide (NIPAm) and methacrylated β-cyclodextrin-based macromer (MPCD) to fabricate an injectable and NIR/pH-responsive poly(NIPAm-co-MPCD)/GNRs nanocomposite hydrogel, which could serve as a long-acting implant for chemo-photothermal synergistic cancer therapy. The nanocomposite hydrogel showed superior mechanical and swelling properties, gelation characteristic and excellent NIR-responsive property...
May 23, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28531881/first-in-man-dose-escalation-and-pharmacokinetic-study-of-cap7-1-a-novel-prodrug-of-etoposide-in-adults-with-refractory-solid-tumours
#7
U Keilholz, L Rohde, P Mehlitz, M Knoedler, A Schmittel, V Kümmerlen, K Klinghammer, P Treasure, M Lassus, G Steventon, M Machacek, N Utku
AIM: An open-label, phase I dose-escalation trial was performed in adult patients with various solid cancers to identify the maximum tolerated dose (MTD), to assess the safety, pharmacokinetic profile and anti-tumour activity of the new prodrug CAP7.1. The prodrug is converted to its active moiety etoposide via carboxylesterases in selective cells leading to a better tolerability and higher efficacy in therapeutic resistance cells and children with refractory neuroblastoma. PATIENTS AND METHODS: Eligible adult patients with advanced, refractory, solid malignancies received CAP7...
May 19, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28530711/a-combinatorial-screen-of-the-cloud-uncovers-a-synergy-targeting-the-androgen-receptor
#8
Marco P Licciardello, Anna Ringler, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Sara Sdelci, Erika Schirghuber, André C Müller, Michael Caldera, Anja Wagner, Rebecca Herzog, Thomas Penz, Michael Schuster, Bernd Boidol, Gerhard Dürnberger, Yasin Folkvaljon, Pär Stattin, Vladimir Ivanov, Jacques Colinge, Christoph Bock, Klaus Kratochwill, Jörg Menche, Keiryn L Bennett, Stefan Kubicek
Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC)...
May 22, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28529549/abiraterone-acetate-and-prednisone-in-chemotherapy-na%C3%A3-ve-prostate-cancer-patients-rationale-evidence-and-clinical-utility
#9
REVIEW
E David Crawford, Neal D Shore, Daniel P Petrylak, Celestia S Higano, Charles J Ryan
Abiraterone acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate is the oral prodrug of abiraterone, a specific CYP17 inhibitor that blocks androgen biosynthesis within the adrenal glands, testes and tumor microenvironment. In a phase III trial of men with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC, treatment with oral abiraterone acetate plus prednisone led to a statistically significant improvement in the co-primary endpoints of overall survival and radiographic progression-free survival when compared with placebo plus prednisone...
May 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28527109/erratum-to-clinical-pharmacokinetics-of-sacubitril-valsartan-lcz696-a-novel-angiotensin-receptor-neprilysin-inhibitor
#10
Surya Ayalasomayajula, Thomas Langenickel, Parasar Pal, Sreedevi Boggarapu, Gangadhar Sunkara
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1...
May 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28526350/designing-novel-bioconjugates-of-hydroxyethylcellulose-and-salicylates-for-potential-pharmaceutical-and-pharmacological-applications
#11
Khawar Abbas, Muhammad Amin, Muhammad Ajaz Hussain, Muhammad Sher, Syed Nasir Abbas Bukhari, Ibrahim Jantan, Kevin J Edgar
The present study deals with fabrication of macromolecular prodrugs (MPDs) of salicylic acid (SA) and aspirin (ASP) based on a hydrophilic cellulose ether, hydroxyethylcellulose (HEC). Degrees of substitution (DS) of SA and ASP per HEC repeating unit (HEC-RU) were achieved ranging from 0.60-2.18 and 0.53-1.50, respectively. The amphiphilic HEC-SA conjugate 2 assembled into nanowire-like structures, while HEC-ASP conjugate 6 formed nanoparticles (diameter 300-700nm) at a water/DMSO interface. After oral administration in rabbit models, conjugates 2 and 6 showed plasma half-life of 6...
May 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28523102/design-and-synthesis-of-mercaptoacetamides-as-potent-selective-and-brain-permeable-histone-deacetylase-6-inhibitors
#12
Wei Lv, Guangming Zhang, Cyril Barinka, James H Eubanks, Alan P Kozikowski
A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#13
John J Krais, Needa Virani, Partick H McKernan, Quang Nguyen, Kar-Ming Fung, Vassilios I Sikavitsas, Carla D Kurkjian, Roger G Harrison
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5.  Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine.  The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28521372/synthesis-and-characterization-of-new-azecine-derivatives-as-potential-neuroleptics
#14
Stephanie Zergiebel, Christian Fleck, Hans-Dieter Arndt, Christoph Enzensperger, Andreas Seeling
Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT2A-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs...
May 18, 2017: Drug Research
https://www.readbyqxmd.com/read/28513140/hybrid-prodrug-nanoparticles-with-tumor-penetration-and-programmed-drug-activation-for-enhanced-chemo-resistant-cancer-therapy
#15
Caiyan Zhao, Leihou Shao, Jianqing Lu, Xiongwei Deng, Yujia Tong, Yan Wu
Despite nanomedicine has shown great potential for reverse cancer cells resistance, the suboptimal transport across multiple biological obstacles seriously impedes its reaching targets at an efficacious level, which remains the challenging hurdle for clinical success in resistant cancer therapy. Here, a lipid-based hybrid nanoparticle was designed to efficiently deliver the therapeutics to resistant cells and treat resistant cancer in vivo. The hybrid nanoparticles (D-NPs/TET) are composed of a pH-responsive prodrug 1,2-distearoyl-snglycero-3-phosphoethanolamine (DSPE)-doxorubicin (DOX), a efflux inhibitor tetrandrine (TET) and a surfactant 1,2-distearoyl-snglycero-3-phosphoethanolamine-[methoxy (polyethylene glycol)-2000] (DSPE-mPEG2000), which hierarchically combatted the sequential physiological and pathological barriers of drug resistance, exhibited prolonged blood circulation, high tumor accumulation, and deep tumor parenchyma penetration...
May 17, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28509442/self-assembled-nanoparticles-from-phenolic-derivatives-for-cancer-therapy
#16
Yunlu Dai, Junling Guo, Ting-Yi Wang, Yi Ju, Andrew J Mitchell, Thomas Bonnard, Jiwei Cui, Joseph J Richardson, Christoph E Hagemeyer, Karen Alt, Frank Caruso
Therapeutic nanoparticles hold clinical promise for cancer treatment by avoiding limitations of conventional pharmaceuticals. Herein, a facile and rapid method is introduced to assemble poly(ethylene glycol) (PEG)-modified Pt prodrug nanocomplexes through metal-polyphenol complexation and combined with emulsification, which results in ≈100 nm diameter nanoparticles (PtP NPs) that exhibit high drug loading (0.15 fg Pt per nanoparticle) and low fouling properties. The PtP NPs are characterized for potential use as cancer therapeutics...
May 16, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28508653/synthesis-and-reactivity-of-5-substituted-furfuryl-carbamates-via-oxanorbornadienes
#17
Srinivas Tekkam, M G Finn
Furfuryl carbamates are labile and require care to be accessed by activating furfuryl alcohols. An alternative oxanorbornadiene (OND)-based strategy is presented for the preparation of 5-R-substituted furfuryl carbamates via the reactions of amines with intermediate OND carbonates. The resulting OND carbamates, which are stable for several months, undergo thiol mediated retro-Diels-Alder reaction to deliver the desired furfuryl carbamates in a single flask. Conditions for the selective hydrolysis of furfuryl carbamates in the presence of tert-butyloxycarbonyl (Boc) groups were identified, and it was shown that furfuryl carbamates can be used as a prodrug handle...
May 16, 2017: Organic Letters
https://www.readbyqxmd.com/read/28507680/an-albumin-based-tumor-targeted-oxaliplatin-prodrug-with-distinctly-improved-anticancer-activity-in-vivo
#18
Josef Mayr, Petra Heffeter, Diana Groza, Luis Galvez, Gunda Koellensperger, Alexander Roller, Beatrix Alte, Melanie Haider, Walter Berger, Christian R Kowol, Bernhard K Keppler
The design of targeted platinum(iv) prodrugs is a very promising approach to enhance the low selectivity of platinum(ii) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(iv) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect...
March 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28505195/dose-escalation-study-to-evaluate-safety-tolerability-and-efficacy-of-intravenous-etoposide-phosphate-administration-in-27-dogs-with-multicentric-lymphoma
#19
Pierre Boyé, François Serres, Laurent Marescaux, Juliette Hordeaux, Emmanuel Bouchaert, Bruno Gomes, Dominique Tierny
Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs...
2017: PloS One
https://www.readbyqxmd.com/read/28504251/programmable-co-delivery-of-the-immune-checkpoint-inhibitor-nlg919-and-chemotherapeutic-doxorubicin-via-a-redox-responsive-immunostimulatory-polymeric-prodrug-carrier
#20
Jing-Jing Sun, Yi-Chao Chen, Yi-Xian Huang, Wen-Chen Zhao, Yan-Hua Liu, Raman Venkataramanan, Bin-Feng Lu, Song Li
To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles)...
May 8, 2017: Acta Pharmacologica Sinica
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