Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness ...the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC
values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
A method for the enantioselective, intramolecular sulfenoamination of various olefins has been developed using a chiral BINAM-based selenophosphoramide, Lewis base catalyst. Terminal and trans ...disubstituted alkenes afforded pyrrolidines, piperidines, and azepanes in high yields and high enantiomeric ratios via enantioselective formation and subsequent stereospecific capture of the thiiranium intermediate with the pendant tosyl-protected amine.
A method for the catalytic, enantioselective, intramolecular sulfenoamination of alkenes with aniline nucleophiles has been developed. The method employs a chiral, Lewis basic selenophosphoramide ...catalyst and a Brønsted acid co-catalyst to promote stereocontrolled C–N and C–S bond formation by activation of an achiral sulfenylating agent. Benzoannulated nitrogen-containing heterocycles such as indolines, tetrahydroquinolines, and tetrahydrobenzazepines were prepared with high to excellent enantioselectivities. The impact of tether length and electron density of both the nucleophile and olefin on the reactivity, site selectivity, and enantioselectivity were investigated and interpreted in terms of substrate-dependent stereodetermining thiiranium ion formation or capture.
The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise ...challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability
. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability
. When present in chiral ligands
, catalysts
and auxiliaries
, quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations
. For particularly challenging cases-for example, the vicinal all-carbon
, oxa- and aza-quaternary centres
in molecules such as azadirachtin
, scopadulcic acid A
and acutumine
-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.
In the course of developing an enantioselective, Lewis base/Brønsted acid co-catalyzed carbosulfenylation of alkenes, a seemingly impossible conundrum arose: How could a catalyst inhibit a ...stoichiometric reaction? Despite the observation of very good enantioselectivities, the rate of the uncatalyzed reaction (i.e., no Lewis base) was found to be comparable to or slightly faster than that of the catalyzed process. A combination of detailed kinetic and spectroscopic studies revealed that the answer is not the direct involvement of the Lewis base catalyst, but rather the secondary consequences of its conversion to the catalytically active sulfenylating agent. Generation of the chiral sulfenylating species is accompanied by the formation of equimolar amounts of sulfonate ion and phthalimide which serve to buffer the remaining Brønsted acid and thus inhibit the racemic background reaction. Thus, the actual background reaction operative under catalytic conditions is not well mimicked by simply removing the catalyst.
A practical, efficient approach for the synthesis of C4‐arylated 2‐quinolones from propargylic chlorides and anilines has been developed. The synthesis process involves subsequent oxidations of the ...initial products, tetrahydroquinolines and quinolinium ions, eventually leading to desired quinolones. A mechanism for the transformation is proposed based on a meticulous examination of intermediates and comprehensive control experiments. With a thorough understanding of the reaction mechanism, the applicability of the reaction scope is expanded.
Background: Coronary artery calcification (CAC) scores are widely accepted to predict risk of coronary heart diseases and are associated with atherosclerosis in other vasculatures. Cerebral small ...vessel diseases (SVDs), including white matter lesions (WML), silent lacunar infarction (SLI) and cerebral microbleeds (CMB), are considered to develop in conjunction with pro-atherogenic conditions, measured by CAC scores. Methods and Results: Of 672 individuals aged ≥65 years that underwent health screening, 312 subjects with brain magnetic resonance imagings (MRIs) were enrolled in this study. The distribution of baseline characteristics among individuals with or without MRIs was not different. Clinical and laboratory information was collected and CAC scores were measured using multi-detector computed tomography. Cerebral SVD were independently assessed by 2 raters who were unaware of the CAC scores. The prevalence of CAC (CAC>0) was 71.7% in men and 50.0% in women. The associations between moderate-to-extensive CAC (CAC score ≥100) and WML (adjusted odds ratio and 95% confidence interval, 4.99 and 1.33-18.73), SLI (5.04 and 1.86-13.63) and CMB (6.07 and 1.54-23.94) remained significant after adjusting for relevant confounders. Conclusions: This study documents significant associations between CAC and cerebral SVDs. The findings suggest that SVDs in the brain and CAC in the heart may develop under similar systemic pathogenic processes. (Circ J 2011; 75: 451-456)
Self-assemblies between a linear Pt-based donor and ferrocene- chelated metallic acceptors produced novel heterometallic squares 4 and 5, which show fluorescence quenching upon the addition of ...nitro-aromatics.
To evaluate the feasibility of brachial plexus schwannoma enucleation under intraoperative neuromonitoring.
Five patients who were treated for brachial plexus schwannoma under intraoperative ...neuromonitoring from 2008 to 2018 were included in this retrospective review. Neuromonitoring was performed with a 100-μV event threshold of the neuromonitoring system (NIM-2 or 3) at the deltoid, biceps brachii, triceps brachii, and brachioradialis muscles. Patient characteristics, tumor size and location, intraoperative neuromonitoring findings, and postoperative function were evaluated.
The intraoperative neuromonitoring findings were in accordance with the preoperative assessment of the included nerve root. Three patients had no postoperative morbidity, one patient had temporary paresthesia of the forearm for 2 months, and one patient mild loss of grip strength for 1 month.
Intraoperative neuromonitoring of the arm and forearm muscles during enucleation of brachial plexus schwannoma promoted confident and successful surgery with minimal postoperative morbidity.
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