Overgaardmark0858

The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. GDC-0941 inhibitor This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.Here we report the simultaneous formation of doubly and triply dynamic libraries as a result of exchange reactions between functionalized organic building blocks. A combination of three different reversible covalent linkages involving a boronate ester transesterification along with an imine and disulfide exchange was employed to generate a new type of fully organic triply dynamic molecular assembly.The inherently strained furan-fused cyclobutenes, in situ generated via cycloisomerizations of allenyl ketones bearing cyclopropyl moiety under gold catalysis, have been utilized as reactive building blocks toward cross cycloadditions. The [4 + 2] and [3 + 2] annulations of these species with benzo[c]isoxazoles and N-iminoquinazolinium ylides furnish various three-dimensional cyclobutane-bridged polyheterocycles in good yields. A wide range of typically electron-deficient 1,3-dienes, heterodienes, and 1,3-dipoles can trap furan-fused cyclobutenes to afford several polycyclic architectures.Organocatalytic enantioselective intramolecular oxa-Michael reactions of benzyl alcohol bearing α,β-unsaturated carbonyls as Michael acceptors are presented herein. Using cinchona squaramide-based organocatalyst, enones as well as α,β-unsaturated esters containing benzyl alcohol provided their corresponding 1,3-dihydroisobenzofuranyl-1-methylene ketones and 1,3-dihydroisobenzofuranyl-1-methylene esters in excellent yields with high enantioselectivities. In addition, enantioenriched 1,3-dihydroisobenzofuranyl-1-methylene ketone could be obtained from the Wittig/oxa-Michael reaction cascade of 1,3-dihydro-2-benzofuran-1-ol.Hydrophobic metallic surfaces have attracted much academic and industrial interest due to their promising applications in various fields. Typically, hydrophobicity in metallic materials can be realized by micro/nanostructures and chemical treatment. However, both fragile rough surfaces and low-surface-energy fluorinated silanes are prone to wear and abrasion, leading to the loss of hydrophobicity. In this experiment, we demonstrated a facile and potentially low-cost methodology to fabricate hydrophobic surfaces by integrating a mechanically durable nickel skeleton with an interconnected microwall array filled with hydrophobic poly(tetrafluoroethylene) (PTFE). The interconnected metal frames prevented the removal of the hydrophobic material by abradants, and good hydrophobicity was preserved after more than 1000 cycles of linear abrasion under a local pressure of ∼0.12 MPa. The fabricated surfaces exhibited enhanced anti-icing properties with water droplets compared to unprocessed nickel surfaces. The prepared surfaces also showed superior flexibility. No obvious fracture was observed even after 300 cycles of buckling while the hydrophobic performance was still maintained. The surfaces designed here could provide effective guidance to manufacture large-area surfaces in nickel and other metallic materials that require flexibility, hydrophobic properties, and anti-icing functions for harsh applications.Commercially available [(PPh3)2NiCl2] was found to be an efficient catalyst for the mono-N-alkylation of (hetero)aromatic amines, employing alcohols to deliver diverse secondary amines, including the drug intermediates chloropyramine (5b) and mepyramine (5c), in excellent yields (up to 97%) via the borrowing hydrogen strategy. This method shows a superior activity (TON up to 10000) with a broad substrate scope at a low catalyst loading of 1 mol % and a short reaction time. Further, this strategy is also successful in accessing various quinoline derivatives following the acceptorless dehydrogenation pathway.The alkaline earth metal trimer cluster dianions Be32- and Mg32- lie energetically above their respective monoanions and can therefore decay by electron autodetachment. Consequently, these dianions possess only short-lived resonance states, and here we study these states using regularized analytic continuation as well as complex absorbing potentials combined with a wide a variety of quantum chemistry methods including CCSD(T), SACCI, EOM-CCSD, CASPT2, and NEVPT2. For both Be32- and Mg32-, four low-energy resonance states corresponding to different occupation patterns of the two excess electrons in the two lowest p-σ and p-π orbitals are identified Two states are dominated by doubly occupied configurations and can be characterized as showing σ and π aromatic character. The other two states correspond to the open-shell singlet/triplet pair. All dianion states are found to be highly unstable and to possess short lifetimes They show resonance positions in the energy range 2.3-4.3 eV above the ground states of their respective monoanions and broad widths between 1 and 1.5 eV translating into femtosecond lifetimes. For both Be32- and Mg32-, the differences between the four states are small, but the triplet states tend to be slightly more stable than the three singlet states. Thus, in the case of the multicharged ion aromatic character of the excess electrons takes second stage while Coulomb repulsion takes front and center. In addition to the two isolated cluster dianions, model stabilization by small water clusters is explored. Our results show a dramatic drop in resonance position and width corresponding to a lifetime increase by 2 orders of magnitude. However, the "solvated" clusters are still resonances, and a more pronounced perturbation by, for example, yet larger water clusters or a ligand environment providing larger bond dipoles will be needed to fully stabilize two excess electrons localized on a small system such as an alkaline metal trimer.