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41.
Shashank Shukla Joseph Favata Vikas Srivastava Sina Shahbazmohamadi Anubhav Tripathi Anita Shukla 《Journal of polymer science. Part A, Polymer chemistry》2020,58(10):1365-1379
Developing optimized hydrogel products requires an in-depth understanding of the mechanisms that drive hydrogel tunability. Here, we performed a full 4 × 4 factorial design study investigating the impact of gellan, a naturally derived polysaccharide (1%, 2%, 3%, or 4% w/v) and CaCl2 concentration (1, 3, 7, or 10 mM) on the viscoelastic, swelling, and drug release behavior of gellan hydrogels containing a model drug, vancomycin. These concentrations were chosen to specifically provide insight into gellan hydrogel behavior for formulations utilizing polymer and salt concentrations expanding beyond those commonly reported by previous studies exploring gellan. With increasing gellan and CaCl2 concentration, the hydrogel storage moduli (0.1–100 kPa) followed a power-law relationship and on average these hydrogels had higher liquid absorption capability and greater total drug release over 6 days. We suggest that the effects of gellan and CaCl2 concentration and their interactions on hydrogel properties can be explained by various phenomena that lead to increased swelling and increased resistance to network expansion. 相似文献
42.
Rongzhen Wu Hongyu Chen Dr. Ninghui Chang Yuzhi Xu Prof. Dr. Jiao Jiao Prof. Dr. Hailong Zhang 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(6):1166-1195
Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014–present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1 , the most-studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development. 相似文献
43.
Dr. Andrew Ballard Dr. Stefania Narduolo Dr. Hiwa O. Ahmed Nathaniel I. Keymer Dr. Nabil Asaad Dr. David A. Cosgrove Dr. Niklaas J. Buurma Dr. Andrew G. Leach 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(17):3661-3687
The two enantiomers of a compound often have profoundly different biological properties and thus their liability to racemisation in aqueous solutions is an important piece of information. The authors reviewed the available data concerning the process of racemisation in vivo, in the presence of biological molecules (e.g., racemase enzymes, serum albumin, cofactors and derivatives) and under purely chemical but aqueous conditions (acid, base and other aqueous systems). Mechanistic studies are described critically in light of reported kinetic data. The types of experimental measurement that can be used to effectively determine rate constants of racemisation in various conditions are discussed and the data they provide is summarised. The proposed origins of enzymatic racemisation are presented and suggest ways to promote the process that are different from processes taking place in bulk water. Experimental and computational studies that provide understanding and quantitative predictions of racemisation risk are also presented. 相似文献
44.
Jason P. Holland Melanie Gut Simon Klingler Rachael Fay Amaury Guillou 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(1):33-48
The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre-association (non-covalent ligand-protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed. 相似文献
45.
Kanna Adachi Tomoshi Yamada Hayate Ishizuka Mana Oki Shunsuke Tsunogae Noriko Shimada Osamu Chiba Tatsuya Orihara Prof. Dr. Masafumi Hidaka Prof. Dr. Takatsugu Hirokawa Dr. Minami Odagi Prof. Dr. Keiichi Konoki Prof. Dr. Mari Yotsu-Yamashita Prof. Dr. Kazuo Nagasawa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):2025-2033
A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717. 相似文献
46.
Ariadna Lázaro Cristina Balcells Dr. Josefina Quirante Prof. Josefa Badia Prof. Laura Baldomà Dr. Jas S. Ward Prof. Kari Rissanen Dr. Mercè Font-Bardia Prof. Laura Rodríguez Dr. Margarita Crespo Prof. Marta Cascante 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):1947-1952
Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)PtIV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs. 相似文献
47.
Emilie Boulard Vivien Zibulski Luisa Oertel Dr. Philip Lienau Dr. Martina Schäfer Dr. Ursula Ganzer Dr. Ulrich Lücking 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(19):4378-4388
A short synthetic approach with broad scope to access five- to seven-membered cyclic sulfoximines in only two to three steps from readily available thiophenols is reported. Thus, simple building blocks were converted to complex molecular structures by a sequence of S-alkylation and one-pot sulfoximine formation, followed by intramolecular cyclization. Seventeen structurally diverse cyclic sulfoximines were prepared in high overall yields. In vitro evaluation of these underrepresented, three-dimensional, cyclic sulfoximines with respect to properties relevant to medicinal chemistry did not reveal any intrinsic flaw for application in drug discovery. 相似文献
48.
Manman Liu Yang Zhu Tiantian Wu Dr. Junjie Cheng Prof. Yangzhong Liu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(33):7442-7450
Ferritin is an iron-storage protein nanocage that is assembled from 24 subunits. The hollow cavity of ferritin enables its encapsulation of various therapeutic agents; therefore, ferritin has been intensively investigated for drug delivery. The use of antibody-ferritin conjugates provides an effective approach for targeted drug delivery. However, the complicated preparation and limited protein stability hamper wide applications of this system. Herein, we designed a novel nanobody-ferritin platform (Nb-Ftn) for targeted drug delivery. The site-specific conjugation between nanobody and ferritin is achieved by transglutaminase-catalyzed protein ligation. This ligation strategy allows the Nb conjugation after drug loading in ferritin, which avoids deactivation of the nanobody under the harsh pH environment required for drug encapsulation. To verify the tumor targeting of this Nb-Ftn platform, a photodynamic reagent, manganese phthalocyanine (MnPc), was loaded into the ferritin cavity, and an anti-EGFR nanobody was conjugated to the surface of the ferritin. The ferritin nanocage can encapsulate about 82 MnPc molecules. This MnPc@Nb-Ftn conjugate can be efficiently internalized by EGFR positive A431 cancer cells, but not by EGFR negative MCF-7 cells. Upon 730 nm laser irradiation, MnPc@Nb-Ftn selectively killed EGFR positive A431 cells by generating reactive oxygen species (ROS), whereas no obvious damage was observed on MCF-7 cells. Given that ferritin can be used for encapsulation of various therapeutic agents, this work provides a strategy for facile construction of nanobody-ferritin for targeted drug delivery. 相似文献
49.
Prof. Dr. Frank Heinrich Aria Salyapongse Akari Kumagai Dr. Fernando G. Dupuy Karpur Shukla Dr. Anja Penk Prof. Dr. Daniel Huster Prof. Dr. Robert K. Ernst Dr. Anna Pavlova Prof. Dr. James C. Gumbart Prof. Dr. Berthony Deslouches Prof. Dr. Y. Peter Di Prof. Dr. Stephanie Tristram-Nagle 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(28):6247-6256
In the quest for new antibiotics, two novel engineered cationic antimicrobial peptides (eCAPs) have been rationally designed. WLBU2 and D8 (all 8 valines are the d -enantiomer) efficiently kill both Gram-negative and -positive bacteria, but WLBU2 is toxic and D8 nontoxic to eukaryotic cells. We explore protein secondary structure, location of peptides in six lipid model membranes, changes in membrane structure and pore evidence. We suggest that protein secondary structure is not a critical determinant of bactericidal activity, but that membrane thinning and dual location of WLBU2 and D8 in the membrane headgroup and hydrocarbon region may be important. While neither peptide thins the Gram-negative lipopolysaccharide outer membrane model, both locate deep into its hydrocarbon region where they are primed for self-promoted uptake into the periplasm. The partially α-helical secondary structure of WLBU2 in a red blood cell (RBC) membrane model containing 50 % cholesterol, could play a role in destabilizing this RBC membrane model causing pore formation that is not observed with the D8 random coil, which correlates with RBC hemolysis caused by WLBU2 but not by D8. 相似文献
50.
Gema Vivo-Llorca Vicente Candela-Noguera Dr. María Alfonso Dr. Alba García-Fernández Prof. Mar Orzáez Dr. Félix Sancenón Prof. Ramón Martínez-Máñez 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(69):16318-16327
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. In the last years, navitoclax has emerged as a possible treatment for TNBC. Nevertheless, rapid navitoclax resistance onset has been observed thorough Mcl-1 overexpression. As a strategy to overcome Mcl-1-mediated resistance, herein we present a controlled drug co-delivery system based on mesoporous silica nanoparticles (MSNs) targeted to TNBC cells. The nanocarrier is loaded with navitoclax and the Mcl-1 inhibitor S63845 and capped with a MUC1-targeting aptamer ( apMUC1-MSNs(Nav/S63845) ). The apMUC1-capped nanoparticles effectively target TNBC cell lines and successfully induce apoptosis, overcoming navitoclax resistance. Moreover, navitoclax encapsulation protects platelets against apoptosis. These results point apMUC1-gated MSNs as suitable BH3 mimetics nanocarriers in the targeted treatment of MUC1-expressing TNBC. 相似文献