1517-05-1Relevant articles and documents
Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy
Shin, Weon Sup,Han, Jiyou,Verwilst, Peter,Kumar, Rajesh,Kim, Jong-Hoon,Kim, Jong Seung
, p. 1419 - 1426 (2016)
The development of targeted and effective theranostic (therapeutic and diagnostic) chemotherapeutic agents is highly desirable for precise diagnosis and treatment of cancer. To realize this goal, we developed a cancer-targeting and enzyme-triggered theranostic prodrug 1, containing 7-ethyl-10-hydroxycamptothecin (SN-38), a well-known anticancer drug, which inhibits topoisomerase I in the cell nucleus; hydroquinone as an enzyme-triggered moiety; and biotin as a cancer targeting unit. Enzyme-triggered theranostic prodrug 1 selectively targets cancer cells and is subsequently activated in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), a cytosolic flavoprotein that catalyzes the two-electron reduction of quinone moieties with the concomitant consumption of NADH or NADPH as electron donors. High levels of NQO1 were found in a variety of cancer cell lines compared to healthy cells, and therefore, it is an excellent target for the development of cancer targeted drug delivery systems. Upon preferential cancer cell delivery and uptake, aided by biotin, the enzyme-triggered theranostic prodrug 1 is cleaved by NQO1, with the subsequent release of SN-38, inhibiting topoisomerase I, leading to apoptosis. The drug release and induced apoptosis of cancer cells expressing both biotin receptors and high levels of NQO1 was simultaneously monitored via the innate fluorescence of the released SN-38 by confocal microscopy. In vitro and in vivo studies showed an effective inhibition of cancer growth by the enzyme-triggered theranostic prodrug 1. Thus, this type of enzyme-triggered targeted prodrug therapy is an interesting and promising approach for future cancer treatment.
Safe and efficient membrane permeabilizing polymers based on PLLA for antibacterial applications
Li, Zibiao,Chee, Pei Lin,Owh, Cally,Lakshminarayanan, Rajamani,Loh, Xian Jun
, p. 28947 - 28955 (2016)
Poly(N,N-dimethylaminoethyl methacrylate)-block-poly(l-lactic acid)-block-poly(N,N-dimethylaminoethyl methacrylate) conjugated with poly(ethylene glycol) (D-PLLA-D@PEG) copolymers were synthesized. These non-aggregating polymers showed low MIC values agai
Targeted combinational therapy inducing mitochondrial dysfunction
Shin, Weon Sup,Park, Soon Ki,Verwilst, Peter,Koo, Seyoung,Lee, Joung Hae,Chi, Sung-Gil,Kim, Jong Seung
, p. 1281 - 1284 (2017)
We report on a mitochondria-specific combinational theranostic agent, 1. This system contains a chlorambucil prodrug and an aggregation induced emission dye. In addition, compound 1 bears both an intracellular thiol-triggered moiety and a mitochondria targeting unit (triphenylphosphonium). Glutathione (GSH) is the most abundant thiol and its concentrations are significantly higher in a great number of cancer cell lines, compared to normal cells. The GSH-induced prodrug 1 upon activation releases chlorambucil and exhibits mitochondria targeted aggregation induced emission (AIE) fluorescence, resulting in cell apoptosis via the caspase pathway due to mitochondrial dysfunction.
A study of the thermal decomposition of 2-azidoethanol and 2-azidoethyl acetate by ultraviolet photoelectron spectroscopy and matrix isolation infrared spectroscopy
Dyke,Dias,Barros,Hooper,Costa,Beeching,Barros,Cabral,Morris,Cabral,Moutinho,Ogden,Moutinho
, p. 9968 - 9975 (2002)
The thermal decomposition of 2-azidoethanol and 2-azidoethyl acetate were studied by matrix isolation IR spectroscopy and real-time UV photoelectron spectroscopy. The products detected in a flow system at different temperatures (CH2NH, H2CO, N2, CO, and HCN from N3CH2CH2OH and C2H4, CH2NH, HCN, CO2, and N2 from N3CH2COOCH2CH3) allowed mechanisms for decomposition to be proposed. Ab initio calculations were performed for these azides, and application of Koopmans' theorem to the computed orbital energies yielded vertical ionization energies that agreed with experimental values. Two main mechanisms of decomposition of organic azides of the type considered began to emerge. 2-Azidoacetic acid and 2-azidoehtyl acetate decomposed via a concerted process through a cyclic transition state to give the products, while 2-azidoethanol and azidoacetone decomposed via a stepwise mechanism through imine intermediates, which decomposed to give the products via two possible pathways.
Light-Induced Self-Escape of Spherical Nucleic Acid from Endo/Lysosome for Efficient Non-Cationic Gene Delivery
Duan, Yukun,Hou, Lidan,Liu, Bin,Meng, Xiangjun,Shi, Leilei,Wu, Wenbo,Xu, Li,Xu, Yingying,Zhu, Xinyuan
, (2020)
Developing non-cationic gene carriers and achieving efficient endo/lysosome escape of functional nucleic acids in cytosol are two major challenges faced by the field of gene delivery. Herein, we demonstrate the concept of self-escape spherical nucleic aci
Phenyltriazole-functionalized sulfamate inhibitors targeting tyrosyl- or isoleucyl-tRNA synthetase
De Graef, Steff,De Ruysscher, Dries,Lescrinier, Eveline,Mattelaer, Charles-Alexandre,Nautiyal, Manesh,Pang, Luping,Rozenski, Jef,Strelkov, Sergei V.,Van Aerschot, Arthur,Weeks, Stephen D.
, (2020)
Antimicrobial resistance is considered as one of the major threats for the near future as the lack of effective treatments for various infections would cause more deaths than cancer by 2050. The development of new antibacterial drugs is considered as one of the cornerstones to tackle this problem. Aminoacyl-tRNA synthetases (aaRSs) are regarded as good targets to establish new therapies. Apart from being essential for cell viability, they are clinically validated. Indeed, mupirocin, an isoleucyl-tRNA synthetase (IleRS) inhibitor, is already commercially available as a topical treatment for MRSA infections. Unfortunately, resistance developed soon after its introduction on the market, hampering its clinical use. Therefore, there is an urgent need for new cellular targets or improved therapies. Follow-up research by Cubist Pharmaceuticals led to a series of selective and in vivo active aminoacyl-sulfamoyl aryltetrazole inhibitors targeting IleRS (e.g. CB 168). Here, we describe the synthesis of new IleRS and TyrRS inhibitors based on the Cubist Pharmaceuticals compounds, whereby the central ribose was substituted for a tetrahydropyran ring. Various linkers were evaluated connecting the six-membered ring with the base-mimicking part of the synthesized analogues. Out of eight novel molecules, a three-atom spacer to the phenyltriazole moiety, which was established using azide-alkyne click chemistry, appeared to be the optimized linker to inhibit IleRS. However, 11 (Ki,app = 88 ± 5.3 nM) and 36a (Ki,app = 114 ± 13.5 nM) did not reach the same level of inhibitory activity as for the known high-affinity natural adenylate-intermediate analogue isoleucyl-sulfamoyl adenosine (IleSA, CB 138; Ki,app = 1.9 ± 4.0 nM) and CB 168, which exhibit a comparable inhibitory activity as the native ligand. Therefore, 11 was docked into the active site of IleRS using a known crystal structure of T. thermophilus in complex with mupirocin. Here, we observed the loss of the crucial 3′- and 4′- hydroxyl group interactions with the target enzyme compared to CB 168 and mupirocin, which we suggest to be the reason for the limited decrease in enzyme affinity. Despite the lack of antibacterial activity, we believe that structurally optimizing these novel analogues via a structure-based approach could ultimately result in aaRS inhibitors which would help to tackle the antibiotic resistance problem.
Neoglycopolymers based on 4-vinyl-1,2,3-triazole monomers prepared by click chemistry
Hetzer, Martin,Chen, Gaojian,Barner-Kowollik, Christopher,Stenzel, Martina H.
, p. 119 - 126 (2010)
The synthesis of a new glycomonomer based on mannose, prepared via CuAAC, is reported. The resulting 1,2,3-triazole linkage between mannose and the polymer backbone ensures the formation of highly stable glycopolymers, which will not undergo hydrolysis. The monomer 2′-(4-vinyl-[1,2,3]-triazol-1-yl) ethyl-O-α-D-mannopyranoside was polymerized in the presence of a RAFT agent - 3-benzylsulfanylthiocarbonylsulfanyl propionic acid - to yield well-defined polymers with molecular weights up to 51 500 g mol-1 and a PDI of 1.16. The resulting polymer was employed as a macroRAFT agent in the polymerization of NIPAAm in order to generate thermo-responsive block copolymers, which undergo reversible micelle formation at elevated temperatures. The rapid interaction between the polymers prepared and ConA confirms the high affinity of these structures to proteins. While the linear glycopolymers already undergo a fast complexation with ConA, the reported rates have found to be exceeded by the micellar glycopolymer structure presented in the current contribution.
Reversible lysine modification on proteins by using functionalized boronic acids
Cal, Pedro M. S. D.,Frade, Raquel F. M.,Cordeiro, Carlos,Gois, Pedro M. P.
, p. 8182 - 8187 (2015)
Iminoboronates have been utilized to successfully install azide and alkyne bioorthogonal functions on proteins, which may then be further reacted with their bioorthogonal counterparts. These constructs were also used to add polyethylene glycol (PEG) to insulin, a modification which has been shown to be reversible in the presence of fructose. Finally, iminoboronates were used to assemble a folic acid/paclitaxel small-molecule/drug conjugate in situ with an IC50 value of 20.7 nM against NCI-H460 cancer cells and negligible cytotoxicity against the CRL-1502 noncancer cells. Easy installation: The use of iminoboronates is a successful strategy to install diverse functions on proteins (see picture; GSH=glutathione, PEG=polyethylene glycol) and to assemble a folic acid/paclitaxel small-molecule/drug conjugate in situ.
Autocatalytic Cycles in a Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction
Semenov, Sergey N.,Belding, Lee,Cafferty, Brian J.,Mousavi, Maral P.S.,Finogenova, Anastasiia M.,Cruz, Ricardo S.,Skorb, Ekaterina V.,Whitesides, George M.
, p. 10221 - 10232 (2018)
This work describes the autocatalytic copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between tripropargylamine and 2-azidoethanol in the presence of Cu(II) salts. The product of this reaction, tris-(hydroxyethyltriazolylmethyl)amine (N(Csub
Ultrasound responsive block copolymer micelle of poly(ethylene glycol)-poly(propylene glycol) obtained through click reaction
Li, Fayong,Xie, Chuan,Cheng, Zhengang,Xia, Hesheng
, p. 9 - 17 (2016)
The well-defined amphiphilic poly(ethylene glycol)-block-poly(propylene glycol) copolymer containing 1, 2, 3-triazole moiety and multiple ester bonds (PEG-click-PPG) was prepared by click reaction strategy. The PEG-click-PPG copolymer can self-assemble in
Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis
Fu, Chih-Wei,Tsai, Han-En,Chen, Wei-Sheng,Chang, Tzu-Ting,Chen, Chia-Ling,Hsiao, Pei-Wen,Li, Wen-Shan
supporting information, p. 527 - 542 (2021/01/13)
We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.
A novel18F-labeled clickable substrate for targeted imaging of SNAP-tag expressing cells by PETin vivo
Depke, Dominic Alexej,Hermann, Sven,Konken, Christian Paul,Rentmeister, Andrea,R?sner, Lukas,Sch?fers, Michael
supporting information, p. 9850 - 9853 (2021/10/08)
Bioorthogonal covalent labeling with self-labeling enzymes like SNAP-tag bears a high potential for specific targeting of cells for imagingin vitroand alsoin vivo. To this end, fluorescent SNAP substrates have been established and used in microscopy and fluorescence imaging while radioactive substrates for the highly sensitive and whole-body positron emission tomography (PET) have been lacking. Here, we show for the first time successful and high-contrast PET imaging of subcutaneous SNAP-tag expressing tumor xenografts by bioorthogonal covalent targeting with a novel18F-based radioligandin vivo.
Synthesis, antimicrobial evaluation, and in silico studies of quinoline—1H-1,2,3-triazole molecular hybrids
Awolade, Paul,Cele, Nosipho,Kerru, Nagaraju,Singh, Parvesh
, p. 2201 - 2218 (2020/06/17)
Abstract: Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39?μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36?μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency. Graphic abstract: [Figure not available: see fulltext.].
