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Unraveling the particular Strategies of Turbulence in the Liquid Smoke.
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).To investigate the importance of the chirality and precise structure at position 3(1') of pyropheophorbide-a for tumor cell specificity and photodynamic therapy (PDT), a series of photosensitizers (PSs) was synthesized (a) with and without chirality at position 3(1'), (b) alkyl ether chain with a variable number of chiral centers, (c) hexyl ether versus thioether side chain, and (d) methyl ester versus carboxylic acid group at position 172. The cellular uptake and specificity were defined in human lung and head/neck cancer cells. PSs without a chiral center and with an alkyl chain or thioether functionalities showed limited uptake and PDT efficacy. Replacing the methyl group at the chiral center with a propyl group or introducing an additional chiral center improved cellular retention and tumor cell specificity. Replacing the carboxylic acid with methyl ester at position 172 lowered cellular uptake and PDT efficacy. A direct correlation between the PS uptake in vitro and in vivo was identified.Aromatically π-extended porphyrins possess exceptionally intense one-photon (1P) and sometimes two-photon (2P) absorption bands, presenting interest for construction of optical imaging probes and photodynamic agents. Here we investigated how breaking the molecular symmetry affects linear and 2PA properties of π-extended porphyrins. First, we developed the synthesis of porphyrins fused with two phthalimide fragments, termed syn-diarylphthalimidoporphyrins (DAPIP). Second, the photophysical properties of H2, Zn, Pd, and Pt DAPIP were measured and compared to those of fully symmetric tetraarylphthalimidoporphyrins (TAPIP). The data were interpreted using DFT/TDDFT calculations and sum-over-states (SOS) formalism. Overall, the picture of 2PA in DAPIP was found to resemble that in centrosymmetric porphyrins, indicating that symmetry breaking, even as significant as by syn-phthalimido-fusion, induces a relatively small perturbation to the porphyrin electronic structure. Collectively, the compact size, versatile synthesis, high 1PA and 2PA cross sections, and bright luminescence make DAPIP valuable chromophores for construction of imaging probes and other bioapplications.Solution self-assembly of coil-crystalline diblock copolypeptoids has attracted increasing attention due to its capability to form hierarchical nanostructures with tailorable morphologies and functionalities. While the N-substituent (or side chain) structures are known to affect the crystallization of polypeptoids, their roles in dictating the hierarchical solution self-assembly of diblock copolypeptoids are not fully understood. Herein, we designed and synthesized two types of diblock copolypeptoids, i.e., poly(N-methylglycine)-b-poly(N-octylglycine) (PNMG-b-PNOG) and poly(N-methylglycine)-b-poly(N-2-ethyl-1-hexylglycine) (PNMG-b-PNEHG), to investigate the influence of N-substituent structure on the crystalline packing and hierarchical self-assembly of diblock copolypeptoids in methanol. With a linear aliphatic N-substituent, the PNOG blocks pack into a highly ordered crystalline structure with a board-like molecular geometry, resulting in the self-assembly of PNMG-b-PNOG molecules into a hierarchical microflower morphology composed of radially arranged nanoribbon subunits. By contrast, the PNEHG blocks bearing bulky branched aliphatic N-substituents are rod-like and prefer to stack into a columnar hexagonal liquid crystalline mesophase, which drives PNMG-b-PNEHG molecules to self-assemble into symmetrical hexagonal nanosheets in solution. A combination of time-dependent small/wide-angle X-ray scattering and microscopic imaging analysis further revealed the self-assembly mechanisms for the formation of these microflowers and hexagonal nanosheets. These results highlight the significant impact of the N-substituent architecture (i.e., linear versus branched) on the supramolecular self-assembly of diblock copolypeptoids in solution, which can serve as an effective strategy to tune the geometry and hierarchical structure of polypeptoid-based nanomaterials.Nitrogen-rich compounds based on heteroaromatic rings with different lengths of nitrogen chains are at the forefront of the energetic materials field. We studied the decomposition processes and reaction kinetics of a series of Nx (x = 4, 8, 10, 11) chain-catenated energetic crystals at various temperatures (2400-3000 K) based on a combinational strategy based on density functional tight binding molecular dynamics (DFTB-MD) simulations and density functional theory (DFT). The results show that the thermal decomposition and reaction kinetics are dependent on both the temperature and nitrogen chain's length. There are two sequential stages in the initial decomposition process for the crystals N8 and N10 (i) competition between cis-trans isomerization and initial unimolecular decomposition and (ii) subsequent complicated global decomposition reactions. Increasing either the temperature or nitrogen chain's length will accelerate the competition and make initial decomposition dominate. However, cis-trans isomerization does not occur in the crystals N4 and N11. The dominant initiation paths for N4, N8, and N10 occur in the heterocycle and in the bond between the heterocycle and azo group, while that for N11 is ring elimination. The decomposition reactions exhibit a clear first-order kinetics character. The energy paths based on DFT calculations are determined as an addition to the DFTB-MD results. learn more Our findings provide insights into the comprehensive understanding of thermal decomposition behaviors of nitrogen chain-catenated and even all-nitrogen energetic materials.
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