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https://www.readbyqxmd.com/read/28229357/experimental-determination-and-theoretical-calculation-of-the-eutectic-composition-of-cefuroxime-axetil-diastereomers
#1
Namita Dalal, Ira S Buckner, Peter L D Wildfong
Cefuroxime axetil (CFA), an ester prodrug of cefuroxime exists as a pair of diastereoemers, namely isomer A and isomer B. To enable phase diagram construction, crystallization of the diastereomers of CFA from the commercially available amorphous drug substance was carried out. Isomer A was separated with a purity approaching 100% whereas the maximum purity of isomer B was 85% as confirmed by solution state proton NMR spectroscopy. The crystalline forms of isomer A and isomer B were confirmed as forms AI and BI, respectively, based on differential scanning calorimetry (DSC) analysis and powder X-ray diffraction...
February 22, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28223020/synthesis-and-evaluation-of-prodrugs-of-corticotropin-releasing-factor-1-crf1-receptor-antagonist-bms-665053-leading-to-improved-oral-bioavailability
#2
Richard A Hartz, Vivekananda M Vrudhula, Vijay T Ahuja, James E Grace, Nicholas J Lodge, Joanne J Bronson, John E Macor
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies...
February 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28220535/interaction-of-approved-drugs-with-synaptic-vesicle-protein-2a
#3
Azeem Danish, Vigneshwaran Namasivayam, Anke C Schiedel, Christa E Müller
Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [(3) H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM...
February 21, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28219253/in-vitro-and-in-vivo-evaluation-of-macromolecular-prodrug-gc-fua-based-nanoparticle-for-hepatocellular-carcinoma-chemotherapy
#4
Can Huang, Na-Mei Li, Pei Gao, Sa Yang, Qian Ning, Wen Huang, Zhi-Ping Li, Peng-Ju Ye, Li Xiang, Dong-Xiu He, Xiang-Wen Tan, Cui-Yun Yu
A novel type of macromolecular prodrug delivery system is reported in this research. The N-galactosylated-chitosan-5-fluorouracil acetic acid conjugate (GC-FUA) based nanoparticle delivery system was evaluated in vitro and in vivo. Biocompatibility of GC-FUA-NPs was screened by BSA adsorption test and hemolysis activity examination in vitro. Cytotoxicity and cellular uptake study in HepG2 and A549 cells demonstrated that compared to free 5-Fu, the GC-FUA-NPs play great function in killing cancer cells for the cell endocytosis mediated by asialoglycoprotein receptor (ASGPR), which overexpresses on the cell surface...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28219047/strategies-in-the-designing-of-prodrugs-taking-into-account-the-antiviral-and-anticancer-compounds
#5
REVIEW
Monika A Lesniewska-Kowiel, Izabela Muszalska
Prodrugs are a wide group of substances of low or no pharmacological activity. The search for prodrugs is aimed at obtaining drugs characterized by better pharmacokinetic properties, pharmaceutical availability and selective activity of the active substance. Prodrug strategies involve chemical modifications and syntheses of new structures as well as the establishment of systems that deliver active substances for therapeutic aims that is prodrug-based treatments. The paper describes decisive factors in prodrug designing, such as enzymes participating in their activation, concepts of chemical modifications in the group of antiviral drugs and new anticancer treatments based on prodrugs (ADEPT, GDEPT, LEAPT)...
February 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28218845/phosphinophosphonates-and-their-tris-pivaloyloxymethyl-prodrugs-reveal-a-negatively-cooperative-butyrophilin-activation-mechanism
#6
Rebekah R Shippy, Xiaochen Lin, Sherry S Agabiti, Jin Li, Brendan M Zangari, Benjamin J Foust, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, David F Wiemer, Andrew Joseph Wiemer
Butyrophilin 3A1 (BTN3A1) binds small phosphorous-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone...
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28217276/synthesis-and-biological-evaluation-of-benzocyclooctene-based-and-indene-based-anticancer-agents-that-function-as-inhibitors-of-tubulin-polymerization
#7
Christine A Herdman, Tracy E Strecker, Rajendra P Tanpure, Zhi Chen, Alex Winters, Jeni Gerberich, Li Liu, Ernest Hamel, Ralph P Mason, David J Chaplin, Mary Lynn Trawick, Kevin G Pinney
The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs)...
December 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28216581/biopharmaceutical-characterization-and-bioavailability-study-of-a-tetrazole-analog-of-clofibric-acid-in-rat
#8
Nancy Vara-Gama, Adriana Valladares-Méndez, Gabriel Navarrete-Vazquez, Samuel Estrada-Soto, Luis Manuel Orozco-Castellanos, Julio César Rivera-Leyva
In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10(-6) cm/s in duodenum and 1...
February 14, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28215600/synthesis-of-dual-action-parthenolide-prodrugs-as-potent-anticancer-agents
#9
Akram Taleghani, Mohammad Ali Nasseri, Mehrdad Iranshahi
Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency...
February 1, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28215138/amino-acid-ester-prodrugs-of-nucleoside-and-nucleotide-antivirals
#10
Marcela Krečmerová
The review covers basic principles of the prodrug strategy applied to antiviral nucleoside drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the most important representatives (compounds under clinical investigations or available on the market) are described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine, valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides...
February 16, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28205649/comparative-studies-of-oxaliplatin-based-platinum-iv-complexes-in-different-in-vitro-and-in-vivo-tumor-models
#11
Simone Göschl, Ekaterina Schreiber-Brynzak, Verena Pichler, Klaudia Cseh, Petra Heffeter, Ute Jungwirth, Michael A Jakupec, Walter Berger, Bernhard K Keppler
Using platinum(iv) prodrugs of clinically established platinum(ii) compounds is a strategy to overcome side effects and acquired resistances. We studied four oxaliplatin-derived platinum(iv) complexes with varying axial ligands in various in vitro and in vivo settings. The ability to interfere with DNA (pUC19) in the presence and absence of a reducing agent (ascorbic acid) was investigated in cell-free experiments. Cytotoxicity was compared under normoxic and hypoxic conditions in monolayer cultures and multicellular spheroids of colon carcinoma cell lines...
February 16, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28203075/co-delivery-of-paclitaxel-and-tos-cisplatin-via-tat-targeted-solid-lipid-nanoparticles-with-synergistic-antitumor-activity-against-cervical-cancer
#12
Bo Liu, Li Han, Junyan Liu, Shumei Han, Zhen Chen, Lixi Jiang
BACKGROUND: Cervical cancer is a major world health problem for women. Currently, cancer research focuses on improving therapy for cervical cancer using various treatment options such as co-delivery of chemotherapeutic agents by nanocarriers. PURPOSE: The aim of this study was to develop trans-activating transcriptional activator (TAT)-modified solid lipid nanoparticles (SLNs) for co-delivery of paclitaxel (PTX) and α-tocopherol succinate-cisplatin prodrug (TOS-CDDP) (TAT PTX/TOS-CDDP SLNs) in order to achieve synergistic antitumor activity against cervical cancer...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28201966/synthesis-and-biological-evaluation-of-mutual-prodrugs-of-carboxylic-group-containing-some-non-steroidal-anti-inflammatory-drugs-and-propyphenazone
#13
Sucheta Ohlan, Meenu Paliwal, Ruchita Ruchita, Shilpa Jain, Monika Monika, Himanshu Himanshu
Non-steroidal anti-inflammatory drugs (NSAIDs); ketorolac (KA), niflumic acid (NA), tolfenamic acid (TA) were conjugated with propyphenazone derivative 3-Hydroxymethyl propyphenazone (HMP) by direct coupling and by using spacer technique with the objective of obtaining gastro-sparing NSAIDs prodrugs devoid of ulcerogenic side effects. Mutual prodrugs were synthesized and their structures were confirmed and characterized using IR, 1H NMR, 13C NMR, mass spectroscopy and their purity was established by elemental analysis...
February 13, 2017: Current Drug Delivery
https://www.readbyqxmd.com/read/28201868/enzyme-responsive-liposomes-for-the-delivery-of-anticancer-drugs
#14
Farnaz Fouladi, Kristine J Steffen, Sanku Mallik
Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while, the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site...
February 16, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28198007/modulating-tumor-hypoxia-by-nanomedicine-for-effective-cancer-therapy
#15
REVIEW
Rana Jahanban-Esfahlan, Miguel de la Guardia, Delshad Ahmadi, Bahman Yousefi
Hypoxia, a characteristic feature of tumors, is indispensable to tumor angiogenesis, metastasis, and multi drug resistance. Hypoxic avascular regions, deeply embedded inside the tumors significantly hinder delivery of therapeutic agents. The low oxygen tension results in resistance to the current applied anti-cancer therapeutics including radiotherapy, chemotherapy and photodynamic therapy, the efficacy of which is firmly tied to the level of tumor oxygen supply. However, emerging data indicate that nanocarriers/nanodrugs can offer substantial benefits to improve the efficacy of current therapeutics, through modulation of tumor hypoxia...
February 15, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28197314/combretastatin-a4-%C3%AE-galactosyl-conjugates-for-ovarian-cancer-prodrug-monotherapy
#16
Tomohiro Doura, Kazuaki Takahashi, Yasumitsu Ogra, Noriyuki Suzuki
Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-βGal-1 without a linker...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197307/synthesis-and-antitumor-activity-evaluation-of-a-novel-combi-nitrosourea-prodrug-bgcnu
#17
Yameng Wang, Ting Ren, Xinxin Lai, Guohui Sun, Lijiao Zhao, Na Zhang, Rugang Zhong
Chloroethylnitrosoureas (CENUs) are an important type of alkylating agent employed in the clinical treatment of cancer. However, the anticancer efficacy of CENUs is greatly decreased by a DNA repairing enzyme, O(6)-alkylguanine-DNA alkyltransferase (AGT), by preventing the formation of interstrand cross-links (ICLs). In this study, a combi-nitrosourea prodrug, namely, N-(2-chloroethyl)-N'-2-(O(6)-benzyl-9-guanine)ethyl-N-nitrosourea (BGCNU), which possesses an O(6)-benzylguanine (O(6)-BG) derivative and CENU pharmacophores simultaneously, was synthesized and evaluated for its ability to induce ICLs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197304/ester-prodrugs-of-ihvr-19029-with-enhanced-oral-exposure-and-prevention-of-gastrointestinal-glucosidase-interaction
#18
Julia Ma, Shuo Wu, Xuexiang Zhang, Fang Guo, Katherine Yang, Jia Guo, Qing Su, Huagang Lu, Patrick Lam, Yuhuan Li, Zhengyin Yan, William Kinney, Ju-Tao Guo, Timothy M Block, Jinhong Chang, Yanming Du
IHVR-19029 (6) is a lead endoplasmic reticulum α-glucosidases I and II inhibitor, which efficiently protected mice from lethal Ebola and Marburg virus infections via injection route, but suffered from low bioavailability and off-target interactions with gut glucosidases when administered orally. In an effort to improve efficacious exposure levels and avoid side effects, we designed and synthesized ester prodrugs. Not only were the prodrugs stable in simulated gastric and intestinal fluids and were inactive against glucosidases but they also exhibited antiviral activities against dengue virus infection in a cell based assay...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28196799/a-phase-2-trial-of-long-acting-transcon-growth-hormone-in-adult-gh-deficiency
#19
Charlotte Höybye, Andreas F H Pfeiffer, Diego Ferone, Jens S Christiansen, David Gilfoyle, Eva Dam Christoffersen, Eva Mortensen, Jonathan A Leff, Michael Beckert
TransCon growth hormone is a sustained release human growth hormone prodrug in development in which unmodified growth hormone is transiently linked to a carrier molecule. It is intended as an alternative to daily growth hormone in the treatment of growth hormone deficiency. This was a multi-center, randomized, open-label, active-controlled trial designed to compare the safety (including tolerability and immunogenicity), pharmacokinetics, and pharmacodynamics of three doses of weekly TransCon GH to daily growth hormone (Omnitrope)...
February 14, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/28195491/prodrug-like-pegylated-protein-toxin-trichosanthin-for-reversal-of-chemoresistance
#20
Yingzhi Chen, Meng Zhang, Hongyue Jin, Yisi Tang, Aihua Wu, Qin Xu, Yongzhuo Huang
Multidrug resistance (MDR) is a main obstacle in cancer chemotherapy. The MDR mechanisms involve P-glycoprotein (P-gp) overexpression, abnormality of apoptosis-related protein, and altered expression of drug-targeting proteins. Therapeutic proteins are emerging as candidates for overcoming cancer MDR because of not only their large molecular size that potentially circumvents the P-gp-mediated drug efflux but also their distinctive bioactivity distinguished from small-molecular drugs. Herein we report trichosanthin, a plant protein toxin, possesses synergistic effect with paclitaxel (PTX) in the PTX-resistance A549/T nonsmall cell lung cancer (NSCLC) cells, by reversing PTX-caused caspase 9 phosphorylation and inducing caspase 3-dependent apoptosis...
February 14, 2017: Molecular Pharmaceutics
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