Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2 preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.
A direct synthesis of new donor materials for organic photovoltaic cells is reported. Diaryindenotetracenes were synthesized utilizing a Kumada-Tamao-Corriu cross-coupling of peri-substituted tetrachlorotetracene with spontaneous indene annulation via C-H activation. Vacuum deposited planar heterojunction organic photovoltaic cells incorporating these molecules as electron donors exhibit power conversion efficiencies exceeding 1.5% with open-circuit voltages ranging from 0.7 to 1.1 V when coupled with C(60) as an electron acceptor.
Electron-deficient asymmetrically substituted diarylindenotetracenes were prepared via a series of Friedel-Crafts acylations, aryl-aryl cross-couplings, and an intramolecular oxidative cyclization to form the indene ring. Single-crystal X-ray experiments showed good π-π overlap with π-π distances ranging from 3.26 to 3.76 Å. Both thermogravimetric analysis and differential scanning calorimetry indicated that asymmetrically substituted indenotetracenes (ASIs) are stable at elevated temperatures. From cyclic voltammetry experiments, HOMO/LUMO energy levels of ASI derivatives were determined to be near -5.4/-4.0 eV. UV/visible absorption spectra showed strong absorption of light between 400 and 650 nm with molar attenuation coefficients from 10 to 10 M cm. ASIs were also found to have very low fluorescence quantum yields, less than 4%. Using the solid-state packing determined from the single-crystal X-ray experiments, computational modeling indicated that ASI molecules should favor electron transport.
A process using an engineered phenylalanine ammonia lyase (PAL) enzyme was developed as part of an alternative route to a key intermediate of olodanrigan (EMA401). In the first part of this report, the detailed results from a screening for the optimal reaction conditions are presented, followed by a discussion of several workup strategies investigated. In the PAL-catalyzed reaction, 70−80% conversion of a cinnamic acid derivative to the corresponding phenylalanine derivative could be achieved. The phenylalanine derivative was subsequently telescoped to a Pictet−Spengler reaction with formaldehyde, and the corresponding tetrahydroisoquinoline derivative was isolated in 60−70% yield with >99.9:0.1 er. On the basis of our screenings, carbonate/ carbamate-buffered ammonia at an NH 3 concentration of 9−10 M and pH 9.5−10.5 was found to be optimal. Enzyme loadings down to 2.5 wt % (E:S = 1:40 w/w) could be achieved, and substrate concentrations between 3−9 v/w (1.17−0.39 M) were found to be compatible with the reaction conditions. A temperature gradient was applied in the final process: a pre-equilibrium was established at 45 °C, before making use of the temperature dependence of the entropy term with subsequent cooling to 20 °C to achieve maximum conversion. This temperature gradient also allowed balancing of the enzyme stability (low at 45 °C, high at 20 °C) with the activity (high at 45 °C, low at 20 °C) in order to achieve optimal conversion (low at 45 °C, high at 20 °C). From the various workup operations investigated, a sequence consisting of denaturation of the enzyme, NH 3 /CO 2 removal by distillation, acidification, and telescoping to the subsequent Pictet−Spengler cyclization was our preferred approach. The process presented in this study is a more sustainable, shorter, and more cost-effective alternative to the previous process.
LCZ696 is a novel treatment for patients
suffering from heart failure
that combines the two active pharmaceutical ingredients sacubitril
and valsartan in a single chemical compound. While valsartan is an
established drug substance, a new manufacturing process suitable for
large-scale commercial production had to be developed for sacubitril.
The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art
technologies allowed to efficiently build up the structure of sacubitril
and achieve the defined performance targets.
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