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1.
Targeting a Targeted Drug: An Approach Toward Hypoxia‐Activatable Tyrosine Kinase Inhibitor Prodrugs 下载免费PDF全文
Claudia Karnthaler‐Benbakka Diana Groza Bettina Koblmüller Dr. Alessio Terenzi Katharina Holste Melanie Haider Dina Baier Prof. Dr. Walter Berger Dr. Petra Heffeter Dr. Christian R. Kowol Prof. Dr. Dr. Bernhard K. Keppler 《ChemMedChem》2016,11(21):2410-2421
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2‐nitroimidazole‐based hypoxia‐activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of structural modifications on drug binding to the enzymes: whereas the catalytic pocket of the epidermal growth factor receptor (EGFR) accepted all new erlotinib derivatives, the vascular endothelial growth factor receptor (VEGFR)‐inhibitory potential in the case of the sunitinib prodrugs was dramatically diminished by derivatization. In line, hypoxia dependency of ERK signaling inhibition was observed with the sunitinib prodrugs, while oxygen levels had no impact on the activity of the erlotinib derivatives. Overall, proof of principle could be shown for this concept, and the results obtained are an important basis for the future development of tyrosine kinase inhibitor prodrugs. 相似文献
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Kenji Matsumoto Kosuke Hayashi Kaoru Murata‐Hirai Masashi Iwasaki Prof. Haruki Okamura Prof. Nagahiro Minato Prof. Craig T. Morita Prof. Yoshimasa Tanaka 《ChemMedChem》2016,11(24):2656-2663
Nitrogen‐containing bisphosphonates have antitumor activity in certain breast cancer and myeloma patients. However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy “bone hook” on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2‐(thiazole‐2‐ylamino)ethylidene‐1,1‐bisphosphonate ( 7 ), was found to potently inhibit the in vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound 7 inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1–10 nm . In preclinical studies, 7 slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, 7 is significantly more active than zoledronic acid, the most active FDA‐approved BP, and a potential anticancer therapeutic. 相似文献
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Tercel M Lee HH Yang S Liyanage HD Mehta SY Boyd PD Jaiswal JK Tan KL Pruijn FB 《ChemMedChem》2011,6(10):1860-1871
Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An intermediate in the synthesis of this prodrug was resolved by chiral HPLC and the absolute configuration assigned by X-ray crystallography. The intermediate was used to prepare the prodrug's enantiomers, and also the enantiomers of the active nitro and amino metabolites. In vitro analysis in the human cervical carcinoma cell line SiHa showed that both nitro enantiomers are hypoxia-selective cytotoxins, but the "natural" S enantiomer is at least 20-fold more potent. Examination of extracellular amino metabolite concentrations demonstrated no enantioselectivity in the hypoxia-selective reduction of nitro to amino. Low levels of amino derivative were also found in aerobic cell suspensions, sufficient to account for the observed oxic toxicity of the nitro form. At an equimolar dose in SiHa-tumour bearing animals, the (-)-R enantiomer of the prodrug was inactive, while the (+)-S enantiomer caused significantly more hypoxic tumour cell kill than the racemate. At this dose, the combination of (+)-S-prodrug and radiation eliminated detectable colony-forming cells in four out of five treated tumour-bearing animals. 相似文献
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Katsunori Matsushita Takumi Okuda Dr. Shohei Mori Dr. Masamitsu Konno Dr. Hidetoshi Eguchi Dr. Ayumu Asai Dr. Jun Koseki Dr. Yoshifumi Iwagami Dr. Daisaku Yamada Dr. Hirofumi Akita Dr. Tadafumi Asaoka Dr. Takehiro Noda Dr. Koichi Kawamoto Dr. Kunihito Gotoh Dr. Shogo Kobayashi Dr. Yuuya Kasahara Dr. Kunihiko Morihiro Prof. Dr. Taroh Satoh Prof. Dr. Yuichiro Doki Prof. Dr. Masaki Mori Prof. Dr. Hideshi Ishii Prof. Dr. Satoshi Obika 《ChemMedChem》2019,14(15):1384-1391
The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment. 相似文献
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NIR Fluorogenic Dye as a Modular Platform for Prodrug Assembly: Real‐Time in vivo Monitoring of Drug Release 下载免费PDF全文
Orit Redy‐Keisar Shiran Ferber Prof. Ronit Satchi‐Fainaro Prof. Doron Shabat 《ChemMedChem》2015,10(6):999-1007
The ability to monitor drug release in vivo provides essential pharmacological information. We developed a new modular approach for the preparation of theranostic prodrugs with a turn‐ON near‐infrared (NIR) fluorescence mode of action. The prodrugs release their chemotherapeutic cargo and an active cyanine fluorophore upon reaction with a specific analyte. The prodrug platform is based on the fluorogenic dye QCy7; upon removal of a triggering substrate, the dye fluoresces, and the free drug is released. The evaluated camptothecin prodrug was activated by endogenous hydrogen peroxide produced in tumor cells in vitro and in vivo. Drug release and in vitro cytotoxicity were correlated with the emitted fluorescence. The prodrug activation was effectively imaged in real time in mice bearing tumors. The modular design of the QCy7 fluorogenic platform should allow the preparation of numerous other prodrugs with various triggering substrates and chemotherapeutic agents. We anticipate that the development of real‐time in vivo monitoring tools such as that described herein will pave the way for personalized therapy. 相似文献
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Dr. Cristina Maccallini Dr. Lisa Marinelli Dr. Patrick Indorf Prof. Ivana Cacciatore Dr. Marialuigia Fantacuzzi Prof. Bernd Clement Prof. Antonio Di Stefano Prof. Rosa Amoroso 《ChemMedChem》2020,15(22):2157-2163
Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood-brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated. 相似文献
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Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase‐triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug‐like properties such as lipophilicity. Herein we detail a comprehensive assessment for strategies that effectively release hydroxy and phenolic moieties in the presence of an esterase. Matrix metalloproteinases (MMPs) serve as our proof‐of‐concept target. Three distinct ester‐responsive protecting groups are incorporated into MMP proinhibitors containing hydroxy moieties. Analytical evaluation of the proinhibitors demonstrates that the use of a benzyl ether group appended to the esterase trigger leads to considerably faster kinetics of conversion and enhanced aqueous stability when compared with more conventional approaches where the trigger is directly attached to the inhibitor. Biological assays confirm that all protecting groups effectively cleave in the presence of esterase to generate the active inhibitor. The superior reaction‐based prodrug strategies presented here should serve as a platform for esterase‐responsive prodrug design in the future. 相似文献
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A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer 下载免费PDF全文
Dr. Hiromi Ii Dr. Taku Yoshiya Dr. Susumu Nakata Keiko Taniguchi Dr. Koushi Hidaka Dr. Shugo Tsuda Dr. Masayoshi Mochizuki Dr. Yuji Nishiuchi Prof. Dr. Yuko Tsuda Prof. Dr. Kosei Ito Dr. Susumu Kageyama Prof. Dr. Tatsuhiro Yoshiki 《ChemMedChem》2018,13(2):155-163
γ‐Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester‐type cell‐permeable prodrug, pro‐GA, was developed based on the structure of N‐glutaryl‐l ‐alanine (GA), by structure optimization using temporary fluorophore‐tagged prodrug candidates. The antiproliferative activity of pro‐GA was demonstrated using GGCT‐overexpressing NIH‐3T3 cells and human cancer cells including MCF7, HL‐60, and PC3 cells. By contrast, normal cells were not significantly affected by pro‐GA treatment. Moreover, pro‐GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT‐overexpressing tumors. 相似文献
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Dr. Melanie Zindler Boris Pinchuk Christian Renn Rebecca Horbert Alexander Döbber Prof. Dr. Christian Peifer 《ChemMedChem》2015,10(8):1335-1338
Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail. 相似文献
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Design,Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach 下载免费PDF全文
Dr. Ru‐Bing Wang Dr. Wen Zhou Dr. Qing‐Qing Meng Dr. Xu Zhang Jing Ding Yan Xu Hua‐Long Song Dr. Kai Yang Dr. Jia‐Hua Cui Prof. Shao‐Shun Li 《ChemMedChem》2014,9(12):2798-2808
To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core‐scaffold‐modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R‐, S‐, and 2‐ and 6‐isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor‐inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells. 相似文献
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Dr. Melrose Mailig Dr. Fa Liu 《Chembiochem : a European journal of chemical biology》2019,20(16):2017-2031
Intramolecular N-to-O and O-to-N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl-mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide-bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic. 相似文献
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Brooklynn Venteicher Kasey Merklin Dr. Huy X. Ngo Dr. Huan-Chieh Chien Keino Hutchinson Jerome Campbell Hannah Way Joseph Griffith Cesar Alvarado Prof. Surabhi Chandra Prof. Evan Hill Prof. Avner Schlessinger Prof. Allen A. Thomas 《ChemMedChem》2021,16(5):869-880
The l -type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l -DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1-targeted amino acid-drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti-inflammatory drug ketoprofen to l -tyrosine and l -phenylalanine. We found that esters of meta-carboxyl l -phenylalanine had better LAT1 transport rates than the corresponding acylated l -tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood-brain barrier or on cancer cells. 相似文献
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Jean Leandro dos Santos Vanessa Moreira Michel Leandro Campos Rafael Consolin Chelucci Karina Pereira Barbieri Pollyana Cristina Maggio de Castro Souto Márcio Hideki Matsubara Catarina Teixeira Priscila Longhin Bosquesi Rosangela Gon?alves Peccinini Chung Man Chin 《International journal of molecular sciences》2012,13(11):15305-15320
Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE2 levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy. 相似文献
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A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide 下载免费PDF全文
The clinical use of N,N′‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N′‐bis(2‐boronic pinacol ester benzyl)ethylenediamine‐N,N′‐diacetic acid methyl, ethyl, and isopropyl esters 7 a – c , respectively, and their dimesylate salts 8 a – c , are double prodrugs that mask the two phenolate and two carboxylate donors of HBED as boronic esters and carboxylate esters, respectively. Their activation by chemical hydrolysis and oxidation, their passive diffusivity, and their cytoprotective capabilities have been investigated here. 8 a – c hydrolyzed in minimum essential medium at 37 °C with half‐lives of 0.69, 0.81, and 2.28 h, respectively. The intermediate formed, 9 [N,N′‐bis(2‐boronic acid benzyl)ethylenediamine‐N,N′‐diacetic acid], then underwent oxidative deboronation by H2O2 to give HBED (k=1.82 m ?1 min?1). Solubility measurements in mineral oil and in phosphate buffer indicated that 7 a had a better balance between lipid and aqueous solubilities than did HBED. 7 a was also able to passively diffuse across a lipid‐like silicone membrane (log flux=?0.36), whereas HBED‐HCl was not. 8 c provided better protection to retinal cells than did HBED against a lethal dose of H2O2 (84 % vs. 28 % protection, respectively, at 44 μm ). These results suggest that the double prodrugs have better membrane permeability than does HBED, and therefore could be therapeutically useful for improving the delivery of HBED. 相似文献
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Prodrugs of Nucleoside Triphosphates as a Sound and Challenging Approach: A Pioneering Work That Opens a New Era in the Direct Intracellular Delivery of Nucleoside Triphosphates 下载免费PDF全文
Prof. María‐José Camarasa 《ChemMedChem》2018,13(18):1885-1889
Synthetic nucleosides, designed to mimic naturally occurring nucleosides, are important antiviral and anticancer chemotherapeutic agents. However, nucleosides are not active as such and need to be metabolized, step by step, to their corresponding active nucleoside triphosphates (NTPs). This is mediated by phosphorylating enzymes, mainly host cellular kinases with strong specificity for their substrates; in many cases, this specificity prevents efficient conversion into the NTPs. To circumvent this metabolic handicap, successful nucleo(s/t)ide prodrugs have been developed as a valuable concept in the design of effective drugs. The unique concept of the TriPPPro approach, developed by Chris Meier and colleagues, is a powerful tool for the intracellular delivery of active NTPs, bypassing all the phosphorylation steps required by nucleosides to yield the active NTP metabolites. This concept is illustrated herein with general examples. 相似文献
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Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas 下载免费PDF全文
Prof. Dr. Martyn A. Sharpe Dr. Junyan Han Alexandra M. Baskin Prof. Dr. David S. Baskin 《ChemMedChem》2015,10(4):621-628
Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO‐B‐selectively activated prodrug, N,N‐bis(2‐chloroethyl)‐2‐(1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)propanamide (MP‐MUS), for the treatment of gliomas based on 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). The design of neutral MP‐MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO‐B, which is up‐regulated ≥fourfold in glioma cells. Once the binding occurs, MP‐MUS is converted into a positively charged moiety, P+‐MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP‐MUS against glioma cells is 75 μM , which is two‐ to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP‐MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150–180 μM MP‐MUS killed 90–95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP‐MUS is highly dependent on MAO‐B, and inhibition of MAO‐B activity with selegiline protected human glioma cells from apoptosis. 相似文献
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《国际聚合物材料杂志》2012,61(6):283-292
Present research has been made to reduce frequency of administration and increase therapeutic efficacy by developing sustained release of diclofenac sodium. In this regard, prodrugs have been synthesized by using eco-friendly “green” materials such as cellulose and xylan by activation of carboxylic acid via N,N′-carbonyldiimidazole. The polymer–drug interactions were evaluated by means of FT-IR, powder X-ray diffraction, and thermal analysis techniques. In vitro release study of synthesized prodrugs might be suggested regarding protection of drug in the upper gastrointestinal tract, and, thereby, it is expected to reach the targeted site specifically to colon. 相似文献