58113-36-3Relevant academic research and scientific papers
Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes
Huang, Tao,Hosseinibarkooie, Seyyedmohsen,Borne, Adam L.,Granade, Mitchell E.,Brulet, Jeffrey W.,Harris, Thurl E.,Ferris, Heather A.,Hsu, Ku-Lung
, p. 3295 - 3307 (2021)
Sulfonyl-triazoles are a new class of electrophiles that mediate covalent reaction with tyrosine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. Recent studies demonstrate the broad utility and tunability of SuTEx chemistry for chemical proteomics and protein ligand discovery. Here, we present a strategy for mapping protein interaction networks of structurally complex binding elements using functionalized SuTEx probes. We show that the triazole leaving group (LG) can serve as a releasable linker for embedding hydrophobic fragments to direct molecular recognition while permitting efficient proteome-wide identification of binding sites in live cells. We synthesized a series of SuTEx probes functionalized with a lipid kinase fragment binder for discovery of ligandable tyrosines residing in catalytic and regulatory domains of protein and metabolic kinases in live cells. We performed competition studies with kinase inhibitors and substrates to demonstrate that probe binding is occurring in an activity-dependent manner. Our functional studies led to discovery of probe-modified sites within the C2 domain that were important for downregulation of protein kinase C-alpha in response to phorbol ester activation. Our proof of concept studies highlight the triazole LG of SuTEx probes as a traceless linker for locating protein binding sites targeted by complex recognition elements in live cells.
Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer
Akwii, Racheal,Alvina, Karina,Ashraf-Uz-Zaman, Md,Farshbaf, Mohammad Jodeiri,German, Nadezhda A.,Kallem, Raja Reddy,Mikelis, Constantinos M.,Putnam, William,Sajib, Md Sanaullah,Shahi, Sadisna,Trippier, Paul C.,Wang, Wei,Zhang, Ruiwen
, (2020/10/12)
Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.
COMPOSITIONS AND USES THEREOF
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Page/Page column 89; 92, (2019/01/17)
The disclosure is directed to compounds of the formula (IA), (I)-(V) and others disclosed herein and uses of such compounds.
Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer
Suzuki, Tsuneji,Fukazawa, Nobuyuki,San-nohe, Kunio,Sato, Wakao,Yano, Osamu,Tsuruo, Takashi
, p. 2047 - 2052 (2007/10/03)
The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentrations, these compounds enhanced the accumulation of [3H]vincristine in K562/ADM cells and reversed tumor cell MDR. The results of the structure-activity relationship analysis indicate that in highly active compounds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors of P-170 glycoprotein (P- gp) via π-hydrogen-π interactions. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. Furthermore, in highly active compounds, the distance between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 A?. Several compounds were found to reverse vincristine resistance in K562/ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.
[[Bis(aryl)methylene]-1-piperidinyl]alkyl-pyrimidinones
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, (2008/06/13)
Novel [[bis(aryl)methylene]-1-piperidinyl]alkyl-pyrimidinones, wherein the pyrimidinone-ring is embraced within a bicyclic system, being useful compounds in the treatment of psychosomatic disorders.
