145916-41-2

Upstream product

• 3973-18-0 2-(prop-2-ynyloxy)ethanol 
• 98-59-9 p-toluenesulfonyl chloride 
• 104-15-4 toluene-4-sulfonic acid 

Downstream Products

• 145916-43-4 1-(3,5-dichlorophenoxy)-2-(2-propynyloxy)ethane 
• 653566-99-5 5,5''-bis-[2,6-dimethyl-4-(2-prop-2-ynyloxy-ethoxy)-phenyl]-[2,2';6',2'']terpyridine 
• 1622092-64-1 dihydrofuran-3(2H)-ylidenemethyl 4-methylbenzenesulfonate 
• 1622092-66-3 dihydrofuran-3(2H)-ylidenemethyl 4-methylbenzenesulfonate 
• 1579957-01-9 3-allyl-8-benzoyl-5,5-dimethyl-2-((2-(prop-2-yn-1-yloxy)ethyl)thio)-5,6-dihydrobenzo[h]quinazolin-4(3H)-one 
• 1579956-86-7 2-((3-(tert-butyldimethylsilyl)prop-2-yn-1-yl)oxy)ethyl 4-methylbenzenesulfonate 
• 18668-74-1 bromo-1 propargyloxy-2 ethane 
• 1287372-68-2 C₃₄H₃₆N₂O₈ 
• 164118-56-3 3-(2-iodoethyloxy)prop-1-yne 
• 89588-92-1 2-(3-iodoprop-2-ynyloxy)ethyl p-toluenesulfonate 
• 136196-50-4 1,6-bis<2-(pentachlorophenoxy)ethoxy>-2,4-hexadiyne 
• 136196-52-6 3,10-dioxa-5,7-dodecadiynylene bis(p-toluenesulfonate) 
• 145916-46-7 1-(pentachlorophenoxy)-2-(2-propynyloxy)ethane 

Relevant academic research and scientific papers

Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs

Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable. RNA is an emerging target for small molecules, but has it been an established one all along? Velagapudi et al. profiled the binding of medicines to thousands of RNA motifs, showing that broad drug classes bind RNA. Indeed, approved anti-cancer drugs target an oncogenic non-coding RNA, affecting its phenotype.

Development of a selective activity-based probe for glycosylated LIPA

Loss of LIPA activity leads to diseases such as Wolman's Disease and Cholesterol Ester Storage Disease. While it is possible to measure defects in LIPA protein levels, it is difficult to directly measure LIPA activity in cells. In order to measure LIPA activity directly we developed a LIPA specific activity based probe. LIPA is heavily glycosylated although it is unclear how glycosylation affects LIPA activity or function. Our probe is specific for a glycosylated form of LIPA in cells, although it labels purified LIPA regardless of glycosylation.

TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE

The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.

HECT E3 LIGASE INHIBITORS AND USES THEREOF

The present invention relates to tricyclic derivatives of formula (I), which are useful as inhibitors of HECT-domain-containing E3 ligases, in particular NEDD4. The present invention also refers to pharmaceutical compositions comprising compounds of formu

A "click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation

Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs.

TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE

The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.

Cyclization of gold acetylides: Synthesis of vinyl sulfonates via gold vinylidene complexes

Differently substituted terminal alkynes that bear sulfonate leaving groups at an appropriate distance were converted in the presence of a propynyl gold(I) precatalyst. After initial formation of a gold acetylide, a cyclization takes place at the β-carbon atom of this species. Mechanistic studies support a mechanism that is related to that of dual gold-catalyzed reactions, but for the new substrates, only one gold atom is needed for substrate activation. After formation of a gold vinylidene complex, which forms a tight contact ion pair with the sulfonate leaving group, recombination of the two parts delivers vinyl sulfonates, which are valuable targets that can serve as precursors for cross-coupling reactions, for example. Gold vinylidene intermediates are generated by the cyclization of gold acetylides that carry a sulfonate leaving group. This result demonstrates for the first time that the formation of these species is not restricted to a dual activation mode. The cyclization products obtained herein contain a vinyl sulfonate moiety, which makes them useful building blocks for cross-coupling reactions.

Development of tag-free photoprobes for studies aimed at identifying the target of novel Group A Streptococcus antivirulence agents

We previously reported the identification and development of novel inhibitors of streptokinase (SK) expression by Group A Streptococcus (GAS), originating from a high throughput cell-based phenotypic screen. Although phenotypic screening is well-suited to

Bimetallic oxidative addition involving radical intermediates in nickel-catalyzed alkyl-alkyl Kumada coupling reactions

Many nickel-based catalysts have been reported for cross-coupling reactions of nonactivated alkyl halides. The mechanistic understanding of these reactions is still primitive. Here we report a mechanistic study of alkyl-alkyl Kumada coupling catalyzed by a preformed nickel(II) pincer complex ([(N 2N)Ni-Cl]). The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is second-order in Grignard reagent, first-order in catalyst, and zero-order in alkyl halide. A transient species, [(N2N)Ni-alkyl 2](alkyl2-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis.

Degradable conjugates from oxanorbornadiene reagents

Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels-Alder fragmentation. A study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at a mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by the reaction with thiol-depleted BSA. The OND-amine adducts were found to be up to 15 times more stable than OND-thiol adducts, and to be sensitive to acid by virtue of a stereochemically dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 min to 7 days at 37 °C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.