103-40-2Relevant articles and documents
Self-assembly of a 5-fluorouracil-dipeptide hydrogel
Sun, Yuan,Kaplan, Jonah A.,Shieh, Aileen,Sun, Hui-Lung,Croce, Carlo M.,Grinstaff, Mark W.,Parquette, Jon R.
, p. 5254 - 5257 (2016)
The self-assembly of 5-fluorouracil dilysine conjugates into self-supporting hydrogels, comprised of entangled nanofibers or rigid nanotubes with diameters of 10 and 16 nm, respectively, is reported. The rate of release of 5-Fu from the conjugates was highly dependent on concentration in solution, whereas, release from the fully formed hydrogels was significantly slower. The 5-Fu conjugate also exhibited promising in vitro cytotoxicity against human tumor cell lines A549, H460 and H23.
Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics
Krishnan, K. Syam,Bengtsson, Christoffer,Good, James A. D.,Mirkhanov, Shamil,Chorell, Erik,Johansson, Lennart B.-A.,Almqvist, Fredrik
, p. 12207 - 12213 (2013)
Thiazolino fused 2-pyridone peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibers. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.
Preferential binding of E. coli with type 1 fimbria to D-mannobiose with the Manα1→2Man structure
Ajisaka, Katsumi,Yuki, Kaoru,Sato, Kaori,Ishii, Nozomi,Matsuo, Ichiro,Kuji, Ryo,Miyazaki, Tatsuo,Furukawa, Kiyoshi
, p. 128 - 134 (2016)
Manα1→2Man, Manα1→3Man, Manα1→4Man, and Manα1→6Man were converted to the glycosylamine derivatives. Then, they were mixed with monobenzyl succinic acid to obtain their amide derivatives. After removing the benzyl group by hydrogenation, the succinylamide derivatives were coupled with the hydrazino groups on BlotGlyco beads in the presence of water-soluble carbodiimide. D-Mannobiose-linked beads were incubated with fluorescence-labeled Escherichia coli with type 1 fimbria, and the number of the fluorescent dots associated with the beads was counted in order to determine the binding preference among D-mannobiose isomers. The results showed that the bacteria bind strongly to Manα1→2Man1→beads, Man- α1→3Man1→beads, Manα1→4Man1→beads, and Manα1→6Man1→beads, in order. In the presence of 0.1 M methyl α-D-mannopyranoside, most of the bacteria failed to bind to these beads. These results indicate that E. coli with type 1 fimbria binds to all types of D-mannobiose isomers but preferentially to Manα1→2Man disaccharide.
Strain-Promoted Reaction of 1,2,4-Triazines with Bicyclononynes
Horner, Katherine A.,Valette, Nathalie M.,Webb, Michael E.
, p. 14376 - 14381 (2015)
Strain-promoted inverse electron-demand Diels-Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5-tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5-tetrazines is complex and can involve volatile reagents. 1,2,4-Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4-triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4-triazin-3-ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37°C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late-stage functionalization of other probe molecules, and the 1,2,4-triazine-SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.
A General Strategy for the Preparation of Thalidomide-Conjugate Linkers
Papatzimas, James W.,Gorobets, Evgueni,Brownsey, Duncan K.,Maity, Ranjan,Bahlis, Nizar J.,Derksen, Darren J.
, p. 2881 - 2885 (2017)
The synthesis of small-molecule linkers for installation of thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These small-molecule tethers act as linkages between molecules, can also aid in cell permeability, and act as solubilizing agents. This work shows our progress in synthesizing conjugates with a variety of linker characteristics. The adaptability and manipulation of these and other linkers holds potential in improving synthetic control of chemical connectivities toward therapeutic development.
Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties
Bellany, Fiona,Tsuchiya, Yugo,Tran, Trang M.,Chan, A.W. Edith,Allan, Helen,Gout, Ivan,Tabor, Alethea B.
, (2020)
Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.
From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
Papatzimas, James W.,Gorobets, Evgueni,Maity, Ranjan,Muniyat, Mir Ishruna,Maccallum, Justin L.,Neri, Paola,Bahlis, Nizar J.,Derksen, Darren J.
, p. 5522 - 5540 (2019)
Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
Peptide conjugates of 4-aminocyclophosphamide as prodrugs of phosphoramide mustard for selective activation by prostate-specific antigen (PSA)
Jiang, Yongying,Hu, Longqin
, p. 7507 - 7514 (2013)
In our continued effort to develop prodrugs of phosphoramide mustard, conjugates of 4-aminocyclophosphamide (4-NH2-CPA) with three PSA-specific peptides were synthesized and evaluated as substrates of PSA. These include conjugates of cis-(2R,4R)-4-NH2-CPA with a tetrapeptide Succinyl-Ser-Lys-Leu-Gln-OH, a hexapeptide Succinyl-His-Ser-Ser-Lys-Leu-Gln-OH, and a pentapeptide Glutaryl-Hyp-Ala-Ser-Chg-Gln-OH. These conjugates were cleaved by PSA efficiently and exclusively after the expected glutamine residue to release 4-NH2-CPA, the activated prodrug form of phosphoramide mustard. The cleavage was most efficient for the pentapeptide conjugate 3 (Glutaryl-Hyp-Ala-Ser-Chg-Gln-NH-CPA), which showed a half-life of 55 min with PSA, followed by the hexapeptide conjugate 2 (Succinyl-His-Ser-Ser-Lys-Leu-Gln- NH-CPA) and the tertrapeptide conjugate 1 (Succinyl-Ser-Lys-Leu-Gln-NH-CPA) with half-lives of 6.5 and 12 h, respectively. These results indicate a potential of the conjugate 3 as an anticancer prodrug of phosphoramide mustard for selective PSA activation.
Esterification of dicarboxylic acids with benzyl alcohol under the action of the microwave radiation
Aver'yanov,Batrakova,Samuilov,Spiridonova,Kochnev,Galibeev,Gnezdilov
, p. 1920 - 1923 (2008)
Reaction of dicarboxylic acid with benzyl alcohol under the microwave irradiation proceeds faster as compared to the thermal conditions. The main reaction products are alkyl dicarboxylates, and the monoester and dibenzyl ether are formed as the side products. A proposal about the nature of the nonthermal effect in the reactions stimulated by the microwave irradiation is considered.
Biotin and glucose dual-targeting, ligand-modified liposomes promote breast tumor-specific drug delivery
Fu, Qiuyi,Guo, Li,Huang, Mengyi,Peng, Yao,Pu, Yanchi,Wu, Yong,Zheng, Yongxiang
, (2020)
Breast cancer is the second leading cause of cancer-related deaths in women. Ligand-modified liposomes are used for breast tumor-specific drug delivery to improve the efficacy and reduce the side effects of chemotherapy; however, only a few liposomes with high targeting efficiency have been developed because the mono-targeting, ligand-modified liposomes are generally unable to deliver an adequate therapeutic dose. In this study, we designed biotin-glucose branched ligand-modified, dual-targeting liposomes (Bio-Glu-Lip) and evaluated their potential as a targeted chemotherapy delivery system in vitro and in vivo. When compared with the non-targeting liposome (Lip), Bio-Lip, and Glu-Lip, Bio-Glu-Lip had the highest cell uptake in 4T1 cells (3.00-fold, 1.60-fold, and 1.95-fold higher, respectively) and in MCF-7 cells (2.63-fold, 1.63-fold, and 1.85-fold higher, respectively). The subsequent cytotoxicity and in vivo assays further supported the dual-targeting liposome is a promising drug delivery carrier for the treatment of breast cancer.
