Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer.

Unlabelled: Triple-negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROteolysis TArgeting Chimera (PROTAC) to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment.

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes.

A copper iodide-Pyox complex catalyzes the first conjugate addition of diverse sulfur, nitrogen, and carbon nucleophiles to isocyanoalkenes. The anionic addition generates metalated isocyanoalkanes capable of S displacements, providing a rapid route to a series of functionalized, cyclic isocyanoalkanes. The Cu(I)I-Pyox complex efficiently catalyzes a first-in-class conjugate addition affording a range of complex, functionalized isocyanoalkanes that are otherwise challenging to synthesize while laying a foundation for catalytic reactions that maintain the isocyanide group.

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide).

Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine electrophiles to afford imidazoles. In situ cyclization to the imidazole is promoted by the conjugate acid, hexamethyldisilazane, which facilitates the requisite series of proton transfers.

Oxazole Synthesis by Sequential Asmic-Ester Condensations and Sulfanyl-Lithium Exchange-Trapping.

Oxazoles are rapidly assembled through a sequential deprotonation-condensation of Asmic, anisylsulfanylmethylisocyanide, with esters followed by sulfanyl-lithium exchange-trapping. Deprotonating Asmic affords a metalated isocyanide that efficiently traps esters to afford oxazoles bearing a versatile C-4 anisylsulfanyl substituent. Interchange of the anisylsulfanyl substituent is readily achieved through a first-in-class sulfur-lithium exchange-electrophilic trapping sequence whose versatility is illustrated in the three-step synthesis of the bioactive natural product streptochlorin.

Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs.

Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression.

Asmic: An Exceptional Building Block for Isocyanide Alkylations.

Asmic addresses the long-standing challenge of alkylating isocyanides, providing access to isocyanides with diverse substitution patterns. The o-anisylsulfanyl group serves a critical dual role by facilitating deprotonation-alkylation and providing a latent nucleophilic site through an unusual arylsulfanyl-lithium exchange.

Alkenyl Isocyanide Conjugate Additions: A Rapid Route to γ-Carbolines.

Isocyanides are exceptional building blocks, the wide deployment of which in multicomponent and metal-insertion reactions belies their limited availability. The first conjugate addition/alkylation to alkenyl isocyanides is described, which addresses this deficiency. An array of organolithiums, magnesiates, enolates, and metalated nitriles add conjugately to β- and β,β-disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds.

Isocyano Enones: Addition-Cyclization Cascade to Oxazoles.

Copper iodide catalyzes the conjugate addition of organometallic and heteroatom nucleophiles to isocyano enones to afford oxazoles. A range of enolates, metalated nitriles, amines, and thiols undergo catalyzed conjugate addition to cyclic and acyclic oxoalkene isocyanides. Mechanistic studies suggest that copper complexation facilitates the nucleophilic attack on the isocyano enone to generate an enolate that cyclizes onto the isocyanide leading to a variety of substituted acyclic or ring-fused oxazoles.

Isonitrile alkylations: a rapid route to imidazo[1,5-a]pyridines.

Metalated arylmethylisonitriles readily add to 2-chloropyridines to afford imidazo[1,5-a]pyridines. Analogous additions to imidoyl chlorides and a chloroquinoline provide imidazoles and an imidazo[1,5-a]quinolone which, like imidazo[1,5-a]pyridines, are valuable heterocycles for pharmaceutical synthesis.

Photocatalytic degradation of lignin using Pt/TiO2 as the catalyst.

Photocatalytic degradation of lignin was studied with the use of catalysts TiO(2) and Pt/TiO(2). The influence of several experimental parameters, i.e.

Differentiating ozone direct and indirect reactions on decomposition of humic substances.

The ozonation reaction is accomplished into two pathways: direct ozone oxidation and indirect free hydroxyl radical oxidation. Both reactions are proceeding simultaneously, thus, it is difficult to separate them and study their respective reaction mechanisms. Carbonate and bicarbonate react with free radicals that will effectively inhibit the indirect free radical oxidation without affecting the direct oxidation reaction.

Decolorizing of lignin wastewater using the photochemical UV/TiO2 process.

Studies on applying the photochemical UV/TiO2 oxidation process to treat the lignin-containing wastewater for dissolved organic carbon (DOC), color and reducing A254 (the absorption at the wavelength of 254 nm) have been carried out. The data obtained in this study demonstrate that the UV/TiO2 process is effective in oxidizing the lignin thus reducing the color and DOC of the wastewater treated. The combined UV/TiO2 treatment can achieve better removal of DOC and color than the UV treatment alone.

Applying the Nernst equation to simulate redox potential variations for biological nitrification and denitrification processes.

In this paper, various forms of Nernst equations have been developed based on the real stoichiometric relationship of biological nitrification and denitrification reactions. Instead of using the Nernst equation based on a one-to-one stoichiometric relation for the oxidizing and the reducing species, the basic Nernst equation is modified into slightly different forms. Each is suitable for simulating the redox potential (ORP) variation of a specific biological nitrification or denitrification process.