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排序方式: 共有160条查询结果,搜索用时 15 毫秒
71.
Lars Hemmersbach Ruth Adam Christina Plevnali Xinmiao Zhang Prof. Dr. Benito Yard Prof. Dr. Hans-Günther Schmalz 《European journal of organic chemistry》2023,26(9):e202201424
In an attempt to develop new anti-inflammatory agents which act by co-release of carbon monoxide (CO) and a specialized pro-resolving mediator, we designed conjugates of a lipoxin A4 analogue and an acyloxycyclohexadiene-Fe(CO)3 complex as an esterase-triggered CO-releasing molecule (ET-CORM). After adjustment of the protecting group strategy, two of such compounds were successfully prepared by total synthesis (12 steps; 4–5 % overall yield) starting from deoxy-d -ribose and exploiting a Wittig olefination and an intermolecular Heck reaction as key C−C bond-forming steps. A crucial late reduction of an aryl-ketone moiety in the presence of a highly sensitive dienol ester functionality was achieved with BH3-SMe2 in the presence of catalytic amounts of NaBH4. Both target compounds were dose-dependently toxic towards cultured human umbilical vein endothelial cells (HUVEC), with LipET-CORM 1-A being slightly more toxic. While induction of heme oxygenase 1 (HO-1) in HUVEC was observed for both compounds, they did not inhibit TNF-α-mediated VCAM-1 expression in these cells. In M2 polarized macrophages HO-1 expression was more pronounced as compared to M1 polarized macrophages. In both types of macrophages HO-1 expression was downregulated by lipopolysaccharide, but only in M2 macrophages HO-1 expression was rescued by LipET-CORM. 15-Lipoxygenase (15-LO) was only expressed in M2 macrophages and was not influenced by LipET-CORM. Collectively our data demonstrate that LipET-CORMs induce HO-1 expression in endothelial cells and M2 polarized macrophages. The role of the intra-cellular released lipoxin A4 in resolution of inflammation, however, remains to be assessed. 相似文献
72.
Dr. Silvia Alonso-de Castro Dr. Alessio Terenzi Juan Gurruchaga-Pereda Prof. Luca Salassa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(27):6651-6660
Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new catalysis strategy in which metal complexes are unconventionally employed as substrates rather than catalysts. 相似文献
73.
Dr. Hana Kostrhunova Dr. Emanuele Petruzzella Prof. Dr. Dan Gibson Prof. Dr. Jana Kasparkova Prof. Dr. Viktor Brabec 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(20):5235-5245
Dual- or multi-action PtIV prodrugs represent a new generation of platinum anticancer drugs. The important property of these PtIV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple-action” prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the PtIV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9 nm (HCT-116) to 74 nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the PtIV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the PtIV prodrug introduced in this study acts as a true “multi-action” prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells. 相似文献
74.
Dr. Alberto Dal Corso Prof. Dr. Luca Pignataro Prof. Dr. Laura Belvisi Prof. Dr. Cesare Gennari 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(65):14740-14757
The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well-known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions). 相似文献
75.
76.
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
77.
Yin Wang Kearsley M. Dillon Zhao Li Ethan W. Winckler John B. Matson 《Angewandte Chemie (International ed. in English)》2020,59(38):16698-16704
Overproduction of superoxide anion (O2.?), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O2.? to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H2S). Termed SOPD‐NAC , this persulfide donor reacts specifically with O2.?, decomposing to generate N‐acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self‐assembling peptide (Bz‐CFFE‐NH2) to make a superoxide‐responsive, persulfide‐donating peptide ( SOPD‐Pep ). Both SOPD‐NAC and SOPD‐Pep delivered persulfides/H2S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD‐Pep mitigated toxicity induced by phorbol 12‐myristate 13‐acetate (PMA) more effectively than SOPD‐NAC and several control compounds, including common H2S donors. 相似文献
78.
Timo Völker Dr. Felix Dempwolff Prof. Dr. Peter L. Graumann Prof. Dr. Eric Meggers 《Angewandte Chemie (International ed. in English)》2014,53(39):10536-10540
The catalysis of bioorthogonal transformations inside living organisms is a formidable challenge—yet bears great potential for future applications in chemical biology and medicinal chemistry. We herein disclose highly active organometallic ruthenium complexes for bioorthogonal catalysis under biologically relevant conditions and inside living cells. The catalysts uncage allyl carbamate protected amines with unprecedented high turnover numbers of up to 270 cycles in the presence of water, air, and millimolar concentrations of thiols. By live‐cell imaging of HeLa cells and with the aid of a caged fluorescent probe we could reveal a rapid development of intense fluorescence within the cellular cytoplasm and therefore support the proposed bioorthogonality of the catalysts. In addition, to illustrate the manifold applications of bioorthogonal catalysis, we developed a method for catalytic in‐cell activation of a caged anticancer drug, which efficiently induced apoptosis in HeLa cells. 相似文献
79.
80.
Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N4 nitrogen atom of diazine-containing sulfonamides. In contrast, only N1 coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported. 相似文献