18523-47-2Relevant articles and documents
Synthesis of the 5,6-dihydroxymorpholin-3-one fragment of monanchocidin a
Shi, Yunlong,Pierce, Joshua G.
, p. 968 - 971 (2015)
Monanchocidin A is a recently isolated pentacyclic guanidinium alkaloid that contains an unusual highly oxidized morpholinone fragment. Herein we report a rapid synthesis of this heterocyclic scaffold and confirm its structure. The key reaction involves an acid promoted hemiketalization/hemiaminalization of an α-hydroxyamide and α-ketoaldehyde that proceeds with exclusive regioselectivity and high diastereoselectivity to form the natural scaffold in moderate to high yield.
Azide-alkyne cycloaddition for universal post-synthetic modifications of nucleic acids and effective synthesis of bioactive nucleic acid conjugates
Su, Yu-Chih,Lo, Yu-Lun,Hwang, Chi-Ching,Wang, Li-Fang,Wu, Min Hui,Wang, Eng-Chi,Wang, Yun-Ming,Wang, Tzu-Pin
, p. 6624 - 6633 (2014)
The regioselective post-synthetic modifications of nucleic acids are essential to studies of these molecules for science and applications. Here we report a facile universal approach by harnessing versatile phosphoramidation reactions to regioselectively incorporate alkynyl/azido groups into post-synthetic nucleic acids primed with phosphate at the 5′ termini. With and without the presence of copper, the modified nucleic acids were subjected to azide-alkyne cycloaddition to afford various nucleic acid conjugates including a peptide-oligonucleotide conjugate (POC) with high yield. The POC was inoculated with human A549 cells and demonstrated excellent cell-penetrating ability despite cell deformation caused by a small amount of residual copper chelated to the POC. The combination of phosphoramidation and azide-alkyne cycloaddition reactions thus provides a universal regioselective strategy to post-synthetically modify nucleic acids. This study also explicated the toxicity of residual copper in synthesized bioconjugates destined for biological systems. This journal is the Partner Organisations 2014.
Alendronate-Modified Polymeric Micelles for the Treatment of Breast Cancer Bone Metastasis
Liu, Tong,Romanova, Svetlana,Wang, Shuo,Hyun, Megan A.,Zhang, Chi,Cohen, Samuel M.,Singh, Rakesh K.,Bronich, Tatiana K.
, (2019)
Although the prognosis of patients with breast cancer continues to improve, breast cancer metastasis to bones remains high in incidence and challenging to manage. Here, we report the development of bone-homing alendronate (ALN)-anchored biodegradable polymeric micelles for the targeted treatment of metastatic cancer to bone. These micelles exhibited bone protective capacity including the recruitment, differentiation, and resorption activity of the osteoclasts. Encapsulation of docetaxel (DTX), the first-line chemotherapeutic for treatment of metastatic breast cancer, in ALN-modified micelles results in a sustained release, enhanced cytotoxicity, and improved pharmacokinetics. In the syngeneic animal model of late-stage disseminated breast cancer bone metastasis, the treatment with targeted DTX-loaded micelles attenuated the tumorigenesis and significantly improved animal lifespan compared to the conventional surfactant-based formulation (free DTX). These findings indicate potential applications of the osteotropic nanomedicines for bone metastasis treatment.
Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells
Chen, Deng,Cool, Robbert H.,Dekker, Frank J.,Melgert, Barbro N.,Poelarends, Gerrit J.,Quax, Wim J.,Song, Shanshan,Xiao, Zhangping,van Merkerk, Ronald,van der Wouden, Petra E.
, p. 17514 - 17521 (2021)
Macrophage migration inhibitory factor (MIF) is involved in protein-protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein-protein interaction network. We report the first potent MIF-directed PROTAC, denoted MD13, which induced almost complete MIF degradation at low micromolar concentrations with a DC50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF-directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.
Design and synthesis of novel dual-target agents for HDAC1 and CK2 inhibition
Purwin,Hernández-Toribio,Coderch,Panchuk,Skorokhyd,Filipiak,De Pascual-Teresa,Ramos
, p. 66595 - 66608 (2016)
Drug entities able to address multiple targets can be more effective than those directed to just one biological target. We disclose herein a series of novel dual inhibitors to target histone deacetylase 1 (HDAC 1) and protein kinase CK2. Our bifunctional compounds combine two complementary chemo-active prototypical scaffolds: a hydroxamate essential for the chelation of the zinc ion present in the active site of HDAC (Zinc Binding Group), and a 4,5,6,7-tetrabromobenzotriazole (TBB) moiety introduced to interact with the ATP binding site in CK2 and to act simultaneously as the cap group in the interaction with HDAC1. The synthesized dual-acting agents exhibited promising inhibitory activities towards HDAC1 and CK2. The best result was obtained for 5c with an IC50 of 5 μM for both enzymes. However, its N-2 substituted isomer 5e presented the best profile in cell-based assays, with cytotoxic activity in the low micromolar LC50 in two mammalian cancer cell lines and 4-fold less activity towards a pseudonormal mammalian cell line. Furthermore, this hybrid molecule induced apoptosis in leukemia cells in a concentration-dependent manner. All together this makes 5e a promising lead compound for future in vivo assays in animal tumor models.
Salivary hydrogen sulfide measured with a new highly sensitive self-immolative coumarin-based fluorescent probe
Zaorska, Ewelina,Konop, Marek,Ostaszewski, Ryszard,Koszelewski, Dominik,Ufnal, Marcin
, (2018)
Ample evidence suggests that H2S is an important biological mediator, produced by endogenous enzymes and microbiota. So far, several techniques including colorimetric methods, electrochemical analysis and sulfide precipitation have been developed for H2S detection. These methods provide sensitive detection, however, they are destructive for tissues and require tedious sequences of preparation steps for the analyzed samples. Here, we report synthesis of a new fluorescent probe for H2S detection, 4-methyl-2-oxo-2H-chromen-7-yl 5-azidopentanoate (1). The design of 1 is based on combination of two strategies for H2S detection, i.e., reduction of an azido group to an amine in the presence of H2S and intramolecular lactamization. Finally, we measured salivary H2S concentration in healthy, 18–40-year-old volunteers immediately after obtaining specimens. The newly developed self-immolative coumarin-based fluorescence probe (C15H15N3O4) showed high sensitivity to H2S detection in both sodium phosphate buffer at physiological pH and in saliva. Salivary H2S concentration in healthy volunteers was within a range of 1.641–7.124 μM.
A comparative approach to the most sustainable protocol for the β-azidation of α,β-unsaturated ketones and acids
Andraos, John,Ballerini, Eleonora,Vaccaro, Luigi
, p. 913 - 925 (2015)
In this contribution we have used green metrics analysis to compare the material efficiency, environmental impact, and safety-hazard impact in order to compare flow and batch procedures for azidation of α,β-unsaturated carbonyls. It has been proved that flow protocols possess a greener profile over the corresponding batch procedures based on identical chemistries. In this work the new flow procedure described is very efficient; however, the significant uncertainties in the environmental and safety-hazard impact scores are due to the lack of toxicity, hazard, and occupational exposure data available on trimethylsilyl azide and the resin catalysts used here. The results for the new flow procedure show significant and definite improvements over previously published work with respect to waste minimization/material efficiency and are consistent with satisfying green chemistry principles. The results obtained in this work prove the usefulness of our flow-approach for realizing highly efficient processes featuring minimal waste production.
Efficient Synthesis of Pyrrolo [2,3-d] Pyrimidines Containing 1,4-Disubstituted-1,2,3-Triazole Derivatives
Ruddarraju, Radhakrishnamraju,Murugulla, Adharvana Chari,Donthabakthuni, Shobha,Kotla, Ravindar,Deshmukh, Sandeep,Maroju, Ravichandar,Palle, Sadhanandam
, p. 495 - 502 (2017)
Here, we demonstrate a simple but highly efficient method for the synthesis of multifunctionalized pyrrolo[2,3-d]pyrimidines containing 1,4-disubstituted 1,2,3-triazole derivative coupled with various amines (10a, 10b, 10c, 10d, 10e, 10f, 10g) and alcohol (10h) to obtain final compounds (11a, 11b, 11c, 11d, 11e, 11f, 11g, 11h) with reasonable to excellent yields (25% to 94%). The newly synthesized compounds were characterized by IR,1HNMR,13CNMR, and mass spectroscopy analysis.
Labeling lysine acetyltransferase substrates with engineered enzymes and functionalized cofactor surrogates
Yang, Chao,Mi, Jiaqi,Feng, You,Ngo, Liza,Gao, Tielong,Yan, Leilei,Zheng, Yujun George
, p. 7791 - 7794 (2013)
Elucidating biological and pathological functions of protein lysine acetyltransferases (KATs) greatly depends on the knowledge of the dynamic and spatial localization of their enzymatic targets in the cellular proteome. We report the design and application of chemical probes for facile labeling and detection of substrates of the three major human KAT enzymes. In this approach, we create engineered KATs in junction with synthetic Ac-CoA surrogates to effectively label KAT substrates even in the presence of competitive nascent cofactor acetyl-CoA. The functionalized and transferable acyl moiety of the Ac-CoA analogs further allowed the labeled substrates to be probed with alkynyl or azido-tagged fluorescent reporters by the copper-catalyzed azide-alkyne cycloaddition. The synthetic cofactors, in combination with either native or rationally engineered KAT enzymes, provide a versatile chemical biology strategy to label and profile cellular targets of KATs at the proteomic level.
A cryptophane-based "turn-on" 129Xe NMR biosensor for monitoring calmodulin
Riggle, Brittany A.,Greenberg, Mara L.,Wang, Yanfei,Wissner, Rebecca F.,Zemerov, Serge D.,Petersson, E. James,Dmochowski, Ivan J.
, p. 8883 - 8887 (2017)
We present the first cryptophane-based "turn-on" 129Xe NMR biosensor, employing a peptide-functionalized cryptophane to monitor the activation of calmodulin (CaM) protein in solution. In the absence of CaM binding, interaction between the peptide and cryptophane completely suppresses the hyperpolarized 129Xe-cryptophane NMR signal. Biosensor binding to Ca2+-activated CaM produces the expected 129Xe-cryptophane NMR signal.
