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https://www.readbyqxmd.com/read/28748212/genetically-engineered-multilineage-differentiating-stress-enduring-cells-as-cellular-vehicles-against-malignant-gliomas
#1
Tomohiro Yamasaki, Shohei Wakao, Hiroshi Kawaji, Shinichiro Koizumi, Tetsuro Sameshima, Mari Dezawa, Hiroki Namba
Malignant glioma, the most common malignant brain tumor in adults, is difficult to treat due to its aggressive invasive nature. Enzyme/prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, which are endogenous non-tumorigenic pluripotent-like stem cells that are easily collectable from the bone marrow as SSEA-3(+) cells, as carriers of the HSVtk gene...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28741675/pharmacokinetics-of-dinalbuphine-sebacate-and-nalbuphine-in-human-after-intramuscular-injection-of-dinalbuphine-sebacate-in-an-extended-release-formulation
#2
Yu En Tien, Wen-Chuan Huang, Hui-Yuan Kuo, Lily Tai, Yow-Shieng Uang, Wendy H Chern, Jin-Ding Huang
Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practices, resulting in greater incidences of adverse events. We have developed a prodrug of nalbuphine, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain effective blood nalbuphine level. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine...
July 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28741467/status-quo-in-antibody-drug-conjugates-can-glyco-enzymes-solve-the-current-challenges
#3
Florentina Kubizek, Britta Eggenreich, Oliver Spadiut
Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others in clinical trials...
July 24, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28741367/radiotherapy-synergizes-with-the-hypoxia-activated-prodrug-evofosfamide-in-vitro-and-in-vivo-studies
#4
Yoichi Takakusagi, Shun Kishimoto, Naz Sarwat, Shingo Matsumoto, Keita Saito, Charles Hart, James B Mitchell, Murali K Cherukuri
AIMS: Evofosfamide (TH-302) is a hypoxia-activated prodrug (HAP) which releases the DNA damaging bromo-isophosphoramide (Br-IPM) moiety selectively under hypoxic conditions. Since solid tumors are known to have hypoxic regions, HAPs in combination with chemotherapy or radiotherapy will be beneficial. We tested the oxygen dependence of the release kinetics of Br-IPM using Electron Paramagnetic Resonance (EPR) with spin trapping by monitoring the redox-cycling the nitroimidazole moiety of TH-302 and oxygen dependence of TH-302 on in vitro cytotoxicity at different levels of hypoxia was also examined...
July 25, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28740613/synthesis-and-biological-evaluation-of-paclitaxel-and-camptothecin-prodrugs-on-the-basis-of-2-nitroimidazole
#5
Chen Jin, Shuai Wen, Qiumeng Zhang, Qiwen Zhu, Jiahui Yu, Wei Lu
Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28740124/evaluation-of-sofosbuvir-%C3%AE-d-2-deoxy-2-%C3%AE-fluoro-2-%C3%AE-c-methyluridine-as-an-inhibitor-of-dengue-virus-replication
#6
Hong-Tao Xu, Susan P Colby-Germinario, Said A Hassounah, Clare Fogarty, Nathan Osman, Navaneethan Palanisamy, Yingshan Han, Maureen Oliveira, Yudong Quan, Mark A Wainberg
We evaluated Sofosbuvir (SOF), the anti-hepatitis C virus prodrug of β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine-5'-monophosphate, for potential inhibitory activity against DENV replication. Both cell-based and biochemical assays, based on use of purified DENV full-length NS5 enzyme, were studied. Cytopathic effect protection and virus yield reduction assays confirmed that SOF possessed anti-DENV activity in cell culture with a 50% effective concentration (EC50) of 4.9 µM and 1.4 µM respectively...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739166/characterizing-activation-mechanisms-and-binding-preferences-of-ruthenium-metallo-prodrugs-by-a-competitive-binding-assay
#7
Christian Artner, Hannah U Holtkamp, Christian G Hartinger, Samuel M Meier-Menches
The activation mechanisms and reactivity of ruthenium metallo-prodrug lead structures were investigated in detail using capillary zone electrophoresis mass spectrometry (CZE-MS) in a time-dependent manner and by exposing to a protein/oligonucleotide mixture. The competitive assays were performed with sodium trans-[RuCl4(HInd)2] where Hind=indazole (NKP-1339), [(η(6)-p-cymene)RuCl2(pta)], where pta=1,3,5-triaza-7-phosphaadamantane (RAPTA-C) and [(η(6)-biphenyl)RuCl(1,2-ethylenediamine)]PF6 (RM175). Molecular and quantitative information on binding preferences was obtained by coupling CZE to electrospray ionization MS (ESI-MS) and inductively coupled plasma MS (ICP-MS), respectively...
July 16, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28738357/biphasically-modulating-the-activity-of-carboxypeptidase-g2-with-ultrasound
#8
Wanying Ma, Ying Zhang, Xueling Zheng, Tinghe Yu
BACKGROUND/AIMS: Carboxypeptidase G2 (CPG2) has been used for cancer prodrug therapy to realize the targeted release of active drugs, but there yet lacks a means to modulate the CPG2 activity. Here ultrasound was used to modulate the CPG2 activity. METHODS: The activity of insonated CPG2 was determined, and then underlying biochemical (i.e., monomer, dimer and conformation) and ultrasonic (i.e., heat and cavitation) mechanisms were explored. RESULTS: Ultrasound (1...
July 24, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28737832/self-assembled-polyprodrug-amphiphile-for-subcutaneous-xenograft-tumor-inhibition-with-prolonged-acting-time-in-vivo
#9
Dong Chen, Yu Huang, Shuting Xu, Huangyong Jiang, Jieli Wu, Xin Jin, Xinyuan Zhu
Polymeric drug delivery system termed as "polyprodrug amphiphile" poly(2-methylacryloyloxyethyl phosphorylcholine)-b-poly(10-hydroxy-camptothecin methacrylate (pMPC-b-pHCPT) is developed for the prolonged-acting cancer therapy. It is obtained by two-step reversible addition-fragmentation chain transfer polymerization of zwitterionic monomer MPC and an esterase-responsive polymerizable prodrug methacrylic anhydride-CPT, respectively. This diblock polymer is composed of both antifouling (pMPC) and bioactive (pHCPT) segments and the drug is designed as a building block to construct the polymer skeleton directly...
July 24, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28737785/how-to-obtain-pt-iv-complexes-suitable-for-conjugation-to-nanovectors-from-the-oxidation-of-ptcl-terpyridine
#10
E Gabano, E Perin, C Fielden, J A Platts, A Gallina, B Rangone, M Ravera
Oxidation of [Pt((II))Cl(terpy)](+) (terpy = 2,2':6',2''-terpyridine) has been attempted with several oxidizing agents and under different experimental conditions in order to obtain a Pt(iv) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 °C in 50% aqueous H2O2 for 2 h. Under these conditions the quantitative formation of [Pt((IV))Cl(OH)2(terpy)](+) was observed...
July 24, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28729550/anti-tumor-activity-and-immunotherapeutic-potential-of-a-bisphosphonate-prodrug
#11
Yoshimasa Tanaka, Masashi Iwasaki, Kaoru Murata-Hirai, Kenji Matsumoto, Kosuke Hayashi, Haruki Okamura, Tomoharu Sugie, Nagahiro Minato, Craig T Morita, Masakazu Toi
Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28728896/platinum-iv-complexes-conjugated-with-phenstatin-analogue-as-inhibitors-of-microtubule-polymerization-and-reverser-of-multidrug-resistance
#12
Xiaochao Huang, Rizhen Huang, Shaohua Gou, Zhimei Wang, Zhixin Liao, Hengshan Wang
Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28728523/structural-insights-into-the-binding-of-small-ligand-molecules-to-a-g-quadruplex-dna-located-in-the-hiv-1-promoter
#13
Petar M Mitrasinovic
Targeting guanine (G)-rich DNA sequences, folded into non-canonical G-quadruplex (G4) structures, by small ligand molecules is a promising strategy for gene therapy of various diseases. There is experimental proposal that, among eight studied ligands, nitidine chloride - NC and a benzo phenanthridine derivative - BPD have the highest binding affinities for such a sequence (5'-T(1)G(2)G(3)C(4)C(5)T(6)G(7)G(8)G(9)C(10)G(11)G(12)G(13)A(14)C(15)T(16)G(17)G(18)G(19)-3') in the HIV-1 promoter, indicating that an anti-HIV-1 prodrug may regulate the expression of the promoter...
July 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28727740/genetically-engineered-suicide-gene-in-mesenchymal-stem-cells-using-a-tet-on-system-for-anaplastic-thyroid-cancer
#14
Senthilkumar Kalimuthu, Ji Min Oh, Prakash Gangadaran, Liya Zhu, Ho Won Lee, Yong Hyun Jeon, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene-based therapies...
2017: PloS One
https://www.readbyqxmd.com/read/28725053/cyclic-di-gmp-regulates-mycobacterium-tuberculosis-resistance-to-ethionamide
#15
Hai-Nan Zhang, Zhao-Wei Xu, He-Wei Jiang, Fan-Lin Wu, Xiang He, Yin Liu, Shu-Juan Guo, Yang Li, Li-Jun Bi, Jiao-Yu Deng, Xian-En Zhang, Sheng-Ce Tao
Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally, with existing severe problem of ETH resistance. ETH is a prodrug, which is activated by Etha inside M.tb, and etha is transcriptionally repressed by Ethr. We found that c-di-GMP could bind Ethr, enhanced the binding of Ethr to the promoter of etha, and then repressed the transcription of etha, thus caused resistance of M...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723407/nano-lipid-drug-conjugate-an-integrated-review
#16
REVIEW
Piya Adhikari, Paulami Pal, Anup Kr Das, Subhabrata Ray, Arpita Bhattacharjee, Bhaskar Mazumder
Lipid-drug conjugates (LDC), which may also be addressed as lipoidal prodrug, have the therapeutic actives chemically bound to a lipid moiety like fatty acids or phospholipids. Fabricated in nano-size, lipid-drug conjugate forms another breed of lipid nanoparticles. LDCs are prepared in order to increase the drug loading and hence prevent leakage of a highly polar drug from a lipophilic matrix. In turn, it assists to achieve active targeting of therapeutics with reduced side effect by altering the pharmacokinetic profile of the drug...
July 16, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28721903/clinical-advances-of-hypoxia-activated-prodrugs-in-combination-with-radiation-therapy
#17
REVIEW
Ishna N Mistry, Matthew Thomas, Ewen D D Calder, Stuart J Conway, Ester M Hammond
With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy...
August 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28721301/synthesis-and-characterization-of-n-mannich-based-prodrugs-of-ciprofloxacin-and-norfloxacin-in-vitro-anthelmintic-and-cytotoxic-evaluation
#18
Mona Piplani, Harish Rajak, Prabodh Chander Sharma
Prodrugs, the inert derivatives of existing drugs have successfully contributed to the modification of their physicochemical properties. The improved antimicrobial potential due to enhanced lipophilicity of some of the synthesized prodrugs of antibacterial agents by various schemes has already been reported. In the current study, synthesis, characterization, and biological evaluation of some more lipid based prodrugs/compounds of ciprofloxacin and norfloxacin has been carried out. The synthesized prodrugs/compounds have been screened for anthelmintic activity using Indian earthworms and cytotoxic activity against human lung cancer cell lines A-549 employing sulforhodamine B (SRB) assay method...
July 2017: Journal of Advanced Research
https://www.readbyqxmd.com/read/28719222/how-drug-life-cycle-management-patent-strategies-may-impact-formulary-management
#19
Jan Berger, Jeffrey D Dunn, Margaret M Johnson, Kurt R Karst, W Chad Shear
Drug manufacturers may employ various life-cycle management patent strategies, which may impact managed care decision making regarding formulary planning and management strategies when single-source, branded oral pharmaceutical products move to generic status. Passage of the Hatch-Waxman Act enabled more rapid access to generic medications through the abbreviated new drug application process. Patent expirations of small-molecule medications and approvals of generic versions have led to substantial cost savings for health plans, government programs, insurers, pharmacy benefits managers, and their customers...
October 2016: American Journal of Managed Care
https://www.readbyqxmd.com/read/28719094/discovery-and-characterization-of-a-novel-tryptophan-hydroxylase-1-inhibitor-as-a-prodrug
#20
Hailong Shi, Yaya Cui, Yifei Qin
Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2 are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH...
July 18, 2017: Chemical Biology & Drug Design
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