共查询到20条相似文献,搜索用时 15 毫秒
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Alberto Dal Corso Valentina Borlandelli Cristina Corno Paola Perego Laura Belvisi Luca Pignataro Cesare Gennari 《Angewandte Chemie (International ed. in English)》2020,59(10):4176-4181
Self‐immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)‐2‐(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease‐sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms. 相似文献
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Morten T. Jarlstad Olesen Raoul Walther Pier Paolo Poier Frederik Dagns‐Hansen Alexander N. Zelikin 《Angewandte Chemie (International ed. in English)》2020,59(19):7390-7396
In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor‐targeted glucuronides attractive for translational medicine. 相似文献
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Weston J. Smith Nathan P. Oien Dr. Robert M. Hughes Christina M. Marvin Zachary L. Rodgers Junghyun Lee Prof. David S. Lawrence 《Angewandte Chemie (International ed. in English)》2014,53(41):10945-10948
Light‐activatable drugs offer the promise of controlled release with exquisite temporal and spatial resolution. However, light‐sensitive prodrugs are typically converted to their active forms using short‐wavelength irradiation, which displays poor tissue penetrance. We report herein erythrocyte‐mediated assembly of long‐wavelength‐sensitive phototherapeutics. The activating wavelength of the constructs is readily preassigned by using fluorophores with the desired excitation wavelength λex. Drug release from the erythrocyte carrier was confirmed by standard analytical tools and by the expected biological consequences of the liberated drugs in cell culture: methotrexate, binding to intracellular dihydrofolate reductase; colchicine, inhibition of microtubule polymerization; dexamethasone, induced nuclear migration of the glucocorticoid receptor. 相似文献
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Dr. Lara Cala Dr. Iván Rivilla Prof. Dr. Fernando P. Cossío Prof. Dr. Francisco J. Fañanás Prof. Dr. Félix Rodríguez 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(57):13083-13087
Chlorosulfate derivatives are interesting reagents that have been traditionally used to get other sulfur-containing compounds by formal nucleophilic substitution of the chlorine atom. This work describes a different mode of reactivity of alkyne-containing chlorosulfates to get sultones, the sulfur analogues of lactones. The complex skeletal rearrangement observed in this transformation is comparable to those intricate processes promoted or catalyzed by organometallic compounds. However, the reaction here described does not require any reagent or additive, being just a thermal process. Computational calculations support a mechanism based on a series of cascade reactions where almost every step is counterintuitive. Some of these steps include original processes related to classical reactions, thus adding complementary views to traditional organic chemistry. 相似文献
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Hydroxyapatite (HAp) nanorods possess vast potential applications in various fields, and here HAp nanorods with high aspect ratio were synthesized via a convenient two‐stage precipitation‐hydrolysis process at 60°C under atmospheric pressure. The precursor of CaHPO4 at precipitation stage is well crystallized as nubby morphology with CTAB as surfactant, while CaHPO4 was dissolved and CTA+ stabilized the HAp nuclei during the hydrolysis stage. OH? ions were absorbed onto the active crystal surface, where Ca2+ and PO43+ reacted with OH? to make the nuclei grow into larger crystals, and highly crystalline HAp nanorods were obtained by Ostwald ripening. The loaded drug of IBU on the HAp crystals can be 100% released in 24 h. PVP modified HAp nanorods can increase the drug‐loading capacity and release drug faster than pure HAp nanorods. The results indicate that HAp nanorods modified with suitable surfactants are of great use in drug delivery system. 相似文献
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Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport,Avoid First‐Pass Metabolism,and Enhance Oral Bioavailability 下载免费PDF全文
Dr. Luojuan Hu Dr. Tim Quach Dr. Sifei Han Dr. Shea F. Lim Preeti Yadav Danielle Senyschyn Dr. Natalie L. Trevaskis Dr. Jamie S. Simpson Prof. Christopher J. H. Porter 《Angewandte Chemie (International ed. in English)》2016,55(44):13700-13705
First‐pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first‐pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first‐pass drug, glyceride‐mimetic prodrugs incorporating self‐immolative (SI) spacers, resulted in remarkable increases (up to 90‐fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first‐pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue. 相似文献
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Photoinduced Dynamics and Toxicity of a Cancer Drug in Proximity of Inorganic Nanoparticles under Visible Light 下载免费PDF全文
Siddhi Chaudhuri Samim Sardar Damayanti Bagchi Dr. Shreyasi Dutta Dr. Sushanta Debnath Prof. Partha Saha Prof. Peter Lemmens Prof. Samir Kumar Pal 《Chemphyschem》2016,17(2):270-277
Drug sensitization with various inorganic nanoparticles (NPs) has proved to be a promising and an emergent concept in the field of nanomedicine. Rose bengal (RB), a notable photosensitizer, triggers the formation of reactive oxygen species under green‐light irradiation, and consequently, it induces cytotoxicity and cell death. In the present study, the effect of photoinduced dynamics of RB upon complexation with semiconductor zinc oxide NPs is explored. To accomplish this, we successfully synthesized nanohybrids of RB with ZnO NPs with a particle size of 24 nm and optically characterized them. The uniform size and integrity of the particles were confirmed by high‐resolution transmission electron microscopy. UV/Vis absorption and steady‐state fluorescence studies reveal the formation of the nanohybrids. ultrafast picosecond‐resolved fluorescence studies of RB–ZnO nanohybrids demonstrate an efficient electron transfer from the photoexcited drug to the semiconductor NPs. Picosecond‐resolved Förster resonance energy transfer from ZnO NPs to RB unravel the proximity of the drug to the semiconductor at the molecular level. The photoinduced ROS formation was monitored using a dichlorofluorescin oxidation assay, which is a conventional oxidative stress indicator. It is observed that the ROS generation under green light illumination is greater at low concentrations of RB–ZnO nanohybrids compared with free RB. Substantial photodynamic activity of the nanohybrids in bacterial and fungal cell lines validated the in vitro toxicity results. Furthermore, the cytotoxic effect of the nanohybrids in HeLa cells, which was monitored by MTT assay, is also noteworthy. 相似文献
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Antiviral drug is a powerful weapon for humans to defeat the virus. The spread of 2019 novel coronavirus pneumonia (COVID-19) outbreak has a serious impact on the world. At the same time, it also makes people aware of the importance of antiviral drug development. This article reviews the application of the phosphoramidate prodrug strategy and the application of ProTide technology in the development of antiviral drugs. The synthesis methods of nucleoside-phosphoramidate prodrugs are introduced. The application of nucleoside-phosphoramidate in different antiviral drugs is also summarized. This review can provide a reference for the development of new antiviral drugs in the future. 相似文献
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Elena Calatrava-Pérez Luke A. Marchetti Gavin J. McManus Dylan M. Lynch Robert B. P. Elmes D. Clive Williams Thorfinnur Gunnlaugsson Eoin M. Scanlan 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(3):e202103858
Real-time tracking of prodrug uptake, delivery and activation in vivo represents a major challenge for prodrug development. Herein, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimaging, offering unique insight into the prodrug pharmacokinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach. 相似文献
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Alexander Kastner Isabella Poetsch Josef Mayr Jaroslav V. Burda Alexander Roller Petra Heffeter Bernhard K. Keppler Christian R. Kowol 《Angewandte Chemie (International ed. in English)》2019,58(22):7464-7469
Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, PtIV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato PtIV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of PtIV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact PtIV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of PtIV compounds and needs to be considered in the screening and design for novel platinum‐based anticancer drugs. 相似文献
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Tunable Visible and Near‐IR Photoactivation of Light‐Responsive Compounds by Using Fluorophores as Light‐Capturing Antennas 下载免费PDF全文
Prof. Thomas A. Shell Prof. Jennifer R. Shell Zachary L. Rodgers Prof. David S. Lawrence 《Angewandte Chemie (International ed. in English)》2014,53(3):875-878
Although the corrin ring of vitamin B12 is unable to efficiently absorb light beyond 550 nm, it is shown that commercially available fluorophores can be used as antennas to capture long‐wavelength light to promote scission of the Co? C bond at wavelengths up to 800 nm. The ability to control the molecular properties of bioactive species with long visible and near‐IR light has implications for drug delivery, nanotechnology, and the spatiotemporal control of cellular behavior. 相似文献
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Esterase‐Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide
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Yueqin Zheng Bingchen Yu Dr. Kaili Ji Zhixiang Pan Vayou Chittavong Prof. Binghe Wang 《Angewandte Chemie (International ed. in English)》2016,55(14):4514-4518
Prodrugs that release hydrogen sulfide upon esterase‐mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2S donors. Additionally, such prodrugs can easily be conjugated to another non‐steroidal anti‐inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2S prodrugs, the anti‐inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS‐induced TNF‐α production in RAW 264.7 cells. This type of H2S prodrugs shows great potential as both research tools and therapeutic agents. 相似文献