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.
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Boyer
, p. 5248,5249 (1951)
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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.
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.
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.
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.
Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
, (2021/01/25)
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
Amino-Acid-Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G-Quadruplexes
Auricchio, Davide,Desiderati, Giovanni,Gianoncelli, Alessandra,Memo, Maurizio,Ongaro, Alberto,Oselladore, Erika,Ribaudo, Giovanni,Sissi, Claudia
, (2021/12/30)
Guanine-rich sequences are known to fold into G-quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H-bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.
