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https://www.readbyqxmd.com/read/28108625/combined-parthenolide-and-balsalazide-have-enhanced-antitumor-efficacy-through-blockade-of-nf-%C3%AE%C2%BAb-activation
#1
Se-Lim Kim, Seong Hun Kim, Young Ran Park, Yu-Chuan Liu, Eun-Mi Kim, Hwan-Jeong Jeong, Yo Na Kim, Seung Young Seo, In Hee Kim, Seung Ok Lee, Soo Teik Lee, Sang-Wook Kim
: Balsalazide is a colon-specific prodrug of 5-aminosalicylate that is associated with a reduced risk of colon cancer in patients with ulcerative colitis. Parthenolide, a strong NF-κB inhibitor, has recently been demonstrated to be a promising therapeutic agent, promoting apoptosis of cancer cells. In the current study, the antitumor effect of balsalazide combined with parthenolide in human colorectal cancer cells and colitis-associated colon cancers (CAC) was investigated. The results demonstrate that the combination of balsalazide and parthenolide markedly suppress proliferation, nuclear translocation of NF-κB, IκB-α phosphorylation, NF-κB DNA binding, and expression of NF-κB targets...
November 14, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28106035/esterase-mutation-is-a-mechanism-of-resistance-to-antimalarial-compounds
#2
Eva S Istvan, Jeremy P Mallari, Victoria C Corey, Neekesh V Dharia, Garland R Marshall, Elizabeth A Winzeler, Daniel E Goldberg
Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P...
January 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28105390/reactive-oxygen-species-responsive-drug-delivery-systems-promises-and-challenges
#3
REVIEW
Gurusamy Saravanakumar, Jihoon Kim, Won Jong Kim
Given the increasing evidence indicates that many pathological conditions are associated with elevated reactive oxygen species (ROS) levels, there have been growing research efforts focused on the development of ROS-responsive carrier systems because of their promising potential to realize more specific diagnosis and effective therapy. By judicious utilization of ROS-responsive functional moieties, a wide range of carrier systems has been designed for ROS-mediated drug delivery. In this review article, insights into design principle and recent advances on the development of ROS-responsive carrier systems for drug delivery applications are provided alongside discussion of their in vitro and in vivo evaluation...
January 2017: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
https://www.readbyqxmd.com/read/28105276/covalent-guanosine-mimetic-inhibitors-of-g12c-kras
#4
Yuan Xiong, Jia Lu, John Hunter, Lianbo Li, David Scott, Hwan Geun Choi, Sang Min Lim, Anuj Manandhar, Sudershan Gondi, Taebo Sim, Kenneth D Westover, Nathanael S Gray
Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28103684/activation-pathway-of-a-nucleoside-analog-inhibiting-respiratory-syncytial-virus-polymerase
#5
Paul C Jordan, Sarah K Stevens, Yuen Tam, Ryan P Pemberton, Shuvam Chaudhuri, Antitsa D Stoycheva, Natalia Dyatkina, Guangyi Wang, Julian A Symons, Jerome Deval, Leo Beigelman
Human respiratory syncytial virus (RSV) is a negative-sense RNA virus and a significant cause of respiratory infection in infants and the elderly. No effective vaccines or antiviral therapies are available for the treatment of RSV. ALS-8176 is a first-in-class nucleoside prodrug inhibitor of RSV replication currently under clinical evaluation. ALS-8112, the parent molecule of ALS-8176, undergoes intracellular phosphorylation, yielding the active 5'-triphosphate metabolite. The host kinases responsible for this conversion are not known...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28099809/a-gemcitabine-based-peptide-conjugate-with-improved-metabolic-properties-and-dual-mode-of-efficacy
#6
Theodoros Karampelas, Eleni Skavatsou, Orestis Argyros, Demosthenes Fokas, Constantin Tamvakopoulos
Gemcitabine is a clinically established anticancer agent potent in various solid tumors but limited by its rapid metabolic inactivation and off-target toxicity. We have previously generated a metabolically superior to gemcitabine molecule (GSG) by conjugating gemcitabine to a gonadotropin releasing hormone receptor (GnRH-R) ligand peptide, and showed that GSG was efficacious in a castration resistant prostate cancer (CRPC) animal model. The current manuscript provides an in-depth metabolic and mechanistic study of GSG, coupled with toxicity assays that strengthen the potential role of GSG in the clinic...
January 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28099191/long-acting-combination-anti-hiv-drug-suspension-enhances-and-sustains-higher-drug-levels-in-lymph-node-cells-than-in-blood-cells-and-plasma
#7
John C Kraft, Lisa A McConnachie, Josefin Koehn, Loren Kinman, Carol Collins, Danny D Shen, Ann C Collier, Rodney J Y Ho
OBJECTIVE: To determine if a combination of anti-HIV drugs-tenofovir (TFV), lopinavir (LPV), and ritonavir (RTV)-in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma. DESIGN: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analyzed using a validated combination LC-MS/MS assay...
January 17, 2017: AIDS
https://www.readbyqxmd.com/read/28091654/cisplatin-and-valproate-released-from-the-bifunctional-pt-iv-cl2-nh3-2-valproato-2-antitumor-prodrug-or-from-liposome-formulations-who-does-what
#8
M Ravera, E Gabano, I Zanellato, A Gallina, E Perin, A Arrais, S Cantamessa, D Osella
The cisplatin-sensitive human ovarian cancer cells A2780 have been challenged with cationic liposomes containing the single drug cisplatin or valproate or their combination with an approximate 1 : 2 molar ratio, i.e. the same ratio present in preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv), that releases such metabolites by intracellular Pt(iv) → Pt(ii) reduction. The results of this comparison confirm that valproate barely penetrates cells unless it is transported by liposomes or it is coordinated to a lipophilic Pt(iv) assembly...
January 16, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28088890/nanoparticles-as-a-carrier-system-for-drug-delivery-across-blood-brain-barrier
#9
Alika Sarkar, Ismat Fatima, Qazi Mohammad Sajid Jamal, Usman Sayeed, M Kalim A Khan, Salman Akhtar, Mohammad Amjad Kamal, Alvina Farooqui, Mohammad Haris Siddiqui
Brain, the center of the nervous system and an integral part the body, is protected by two anatomical and biochemical dynamic barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a highly complex multi-cellular organized structure that protects the brain from harmful substances and invading organisms from the bloodstream and thus protecting it from diseases and injuries. However, it also significantly precludes the delivery of drug to the brain, thus, preventing treatment of a number of neurological disorders...
January 13, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28088486/pharmacological-targeting-of-adenosine-receptor-signaling
#10
REVIEW
Maria Peleli, Bertil Fredholm, Luis Sobrevia, Mattias Carlström
Adenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo...
January 11, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28088075/development-of-a-hypoxia-triggered-and-hypoxic-radiosensitized-liposome-as-a-doxorubicin-carrier-to-promote-synergetic-chemo-radio-therapy-for-glioma
#11
Hongmei Liu, Yandong Xie, Yafei Zhang, Yifan Cai, Baiyang Li, Honglin Mao, Yingguo Liu, Jun Lu, Longzhen Zhang, Rutong Yu
The treatment of malignant primary brain tumors is challenging. Concomitant radiochemotherapy has become the standard clinical treatment for malignant glioma, but there are two critical challenges to overcome in order to increase efficacy. First, glioma is known to have increased resistant to radiation due to its intra-tumoral hypoxia. In addition, the blood-brain barrier (BBB) restricts the distribution of the chemotherapeutic agent to the brain. Therefore, we developed a hypoxic radiosensitizer-prodrug liposome (MLP), in order to deliver DOX to the tumor and to overcome the above challenges, achieving a synergistic chemo-/radiotherapy treatment of malignant glioma...
January 3, 2017: Biomaterials
https://www.readbyqxmd.com/read/28080031/a-new-approach-to-sensitize-antitumor-monofunctional-platinum-ii-complexes-via-short-time-photo-irradiation
#12
Xuling Xue, Chengcheng Zhu, Huachao Chen, Yang Bai, Xiangchao Shi, Yang Jiao, Zhongyan Chen, Yupeng Miao, Weijiang He, Zijian Guo
Sensitizing the antitumor activity of monofunctional Pt(II) complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional Pt(II) complexes, in this study, the photosensitizing monofunctional Pt(II) complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation...
December 6, 2016: Inorganic Chemistry
https://www.readbyqxmd.com/read/28079299/a-platinum-blue-complex-exerts-its-cytotoxic-activity-via-dna-damage-and-induces-apoptosis-in-cancer-cells
#13
Zelal Adiguzel, Seniz Ozalp-Yaman, Gokalp Celik, Safia Salem, Tugba Bagci-Onder, Filiz Senbabaoglu, Yüksel Cetin, Ceyda Acilan
Here, we describe the characteristics of a Pt-blue complex [Pt4 (2-atp)8 (H2 O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single and double stranded breaks (DBS) on DNA in vitro, but no DSBs in cells...
January 12, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28079213/a-computational-mechanistic-investigation-into-the-reduction-of-pt-iv-prodrugs-with-two-axial-chlorides-by-biological-reductants
#14
Zeinab Ejehi, Alireza Ariafard
It is widely reported that the Pt(iv) prodrugs with two axial chlorido ligands are reduced by biological reductants via a chloride-bridged inner-sphere mechanism. By contrast, in this contribution, we demonstrate that although this approach might be true for the reductants with sulphur donors, the reduction by ascorbates preferentially occurs via an outer sphere mechanism.
January 12, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28079003/colorectal-cancer-chemotherapy-the-evolution-of-treatment-and-new-approaches
#15
Rachel M McQuade, Vanesa Stojanovska, Joel C Bornstein, Kulmira Nurgali
Colorectal cancer (CRC) is one the greatest contributors to cancer related mortality. Although 5 year survival rate for patients at the early stage of CRC (stages I and II) is above 60%, more than 50% of patients are diagnosed at or beyond stage III when distant metastasis has already occurred, in which case 5 year survival rate drops to 10%. Chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival. For decades following its discovery, an antimetabolite 5-fluorouracil (5-FU) was the only chemotherapeutic agent available to successfully improve 12 month survival in CRC patients...
January 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28076335/infrequent-development-of-drug-resistance-in-hiv-1-infected-treatment-naive-subjects-after-96-weeks-of-treatment-with-elvitegravir-cobicistat-emtricitabine-tenofovir-alafenamide-or-elvitegravir-cobicistat-emtricitabine-tenofovir-disoproxil-fumarate
#16
Nicolas Margot, Stephanie Cox, Moupali Das, Scott McCallister, Michael D Miller, Christian Callebaut
BACKGROUND: Tenofovir alafenamide (TAF) is a novel prodrug of the nucleotide RT inhibitor (NtRTI) tenofovir (TFV) that loads lymphocytes with TFV-diphosphate more efficiently than tenofovir disoproxil fumarate (TDF). The single-tablet regimen (STR) composed of elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) has demonstrated non-inferiority to the STR of E/C/F/TDF in clinical studies, with high proportions of subjects achieving HIV-1 RNA <50 copies/mL at week 48, and maintained through week 96...
January 11, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/28075466/co-delivery-of-doxorubicin-and-ph-sensitive-curcumin-prodrug-by-transferrin-targeted-nanoparticles-for-breast-cancer-treatment
#17
Tongxing Cui, Sihao Zhang, Hong Sun
The natural product curcumin and the chemotherapeutic agent doxorubicin have been used in the treatment of many cancers, including breast cancer. However, fast clearance and unspecific distribution in the body after intravenous injection are still challenges to be overcome by an ideal nano-sized drug delivery system in cancer treatment. In this study we design transferrin (Tf) decorated nanoparticles (NPs) to co-deliver CUR and DOX for breast cancer treatment. A pH-sensitive prodrug, transferrin-poly(ethylene glycol)-curcumin (Tf-PEG-CUR), was synthesized and used for the self‑assembling of NPs (Tf-PEG-CUR NPs)...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/28071889/enzyme-and-redox-dual-triggered-intracellular-release-from-actively-targeted-polymeric-micelles
#18
Lei Zhang, Yi Wang, Xiaobin Zhang, Xiao Wei, Xiang Xiong, Shaobing Zhou
Highly effective delivery of therapeutic agents into target cells using nanocarriers and subsequently rapid intracellular release are of great importance in cancer treatment. Here, we developed an enzyme and redox dual-responsive polymeric micelle with active targeting abilities to achieve rapid intracellular drug release. To overcome both its poor solubility in water and instability in the blood circulation, camptothecin (CPT) was chemically conjugated to monomethyl poly(ethylene glycol) (mPEG) via a redox-responsive linker to form polymeric prodrugs...
January 20, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28070974/stimulus-responsive-short-peptide-nanogels-for-controlled-intracellular-drug-release-and-overcome-tumor-resistance
#19
Bengang Xing, Linna Lyu, Fang Liu, Xiaoyong Wang, Ming Hu, Jing Mu, Haolun Cheong, Gang Liu
Multidrug resistance (MDR) places a major burden against cancer treatment. As one important factor contributing to MDR, over-expression of P-glycoprotein (P-gp), results in the reduced intracellular drug accumulation. Hence, the ability to effectively block the efflux protein and accumulate the therapeutics in cancer cells is of great significance in clinical practice. In this work, we successfully developed a smart stimulus-responsive short peptide assembled system, termed as PD/VER nanogels, which synergistically combined the acid activatable Doxorubicin (Dox) antitumor prodrug with the P-gp inhibitor (Verapamil, VER) for reversing MDR...
January 9, 2017: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/28070879/a-review-of-pharmacogenetics-of-antimalarials-and-associated-clinical-implications
#20
REVIEW
Hazem Elewa, Kyle John Wilby
Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter...
January 9, 2017: European Journal of Drug Metabolism and Pharmacokinetics
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