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A copper-catalyzed selectivity-reversed borocarbonylation of terminal alkenes has been described. A variety of β -boryl ketones were achieved in moderate yields. [Display omitted] • A copper-catalyzed selectivity-reversed borocarbonylation of terminal alkenes is described. • Sterically hindered alkyl bromides have been activated as the electrophiles. • A variety of β -boryl ketones were achieved in moderate yields. Copper-catalyzed borocarbonylation of terminal alkenes usually gives terminal boron substituted β -boryl carbonyl compounds. In this communication, a copper-catalyzed selectivity-reversed borocarbonylation has been described. In the presence of CuOAc/BuPAd 2 catalytic system, a series of unactivated terminal alkenes were transformed into β -boryl ketones in moderate yields, with sterically hindered alkyl bromides as the electrophiles. [ABSTRACT FROM AUTHOR]

A mesoporous ionic MOF-based catalyst (Br−)C 3 H 7 -Imidazolium-MOF-1 for the cycloaddition of CO 2 to epoxides (CCE) was synthesized by template-assisted method, and its composite and structure were determined by FT-IR, PXRD, NMR, SEM, TEM, XPS and N 2 adsorption. (Br−)C 3 H 7 -Imidazolium-MOF-1, is constructed by Zr 6 O 4 (OH) 4 clusters and linear dicarboxylic acid ligands covalently modified by flexible alkyl imidazolium groups (1-methylene-3-propyl-imidazolium bromide). By the synergistic effect of Zr4+ Lewis acid sites and Br− nucleophiles, (Br−)C 3 H 7 -Imidazolium-MOF-1 shown superior catalytic performance for the cycloaddition of CO 2 to epichlorohydrin in the absence of any co-catalyst under mild conditions. Small steric hindrance from the flexible imidazolium groups and rapid mass transport of reactants and products in the mesoporous catalyst acted synergistically to promote this process. A firm bond between the imidazolium bromide and the framework of (Br−)C 3 H 7 -Imidazolium-MOF-1 made it a recyclable heterogeneous catalyst. Furthermore, several additional coupling reactions were investigated with other epoxides as substrates. (Br−)C 3 H 7 -Imidazolium-MOF-1 integrated Lewis acid metal sites and Br− nucleophiles and exhibited efficient catalytic activity for cycloaddition of CO 2 to epoxides. [Display omitted] • A mesoporous ionic MOF-based catalyst (Br−)C 3 H 7 -Imidazolium-MOF-1 for the cycloaddition of CO 2 to epoxides (CCE) was built by template-assisted method. • (Br−)C 3 H 7 -Imidazolium-MOF-1 shown superior catalytic performance for the cycloaddition of CO 2 to epichlorohydrin in the absence of any co-catalyst under mild conditions. [ABSTRACT FROM AUTHOR]

A photocatalytic borylation of alkyl bromides and chlorides in air under visible-light irradiation by graphene-supported Cu-Pd alloy nanoparticles is reported. [Display omitted] • An efficient photocatalytic protocol for borylation of alkyl halides is reported. • A graphene supported Cu/Pd alloy nanoparticles was employed as photocatalyst. • The borylations were conducted at 30 °C in air under visible light. • Primary and secondary alkyl bromides and chlorides were borylated in good yields. • The high activity results from LSPR of Cu and alloy surface charge heterogeneity. A highly efficient photocatalytic protocol for borylation of alkyl bromides and chlorides with graphene supported Cu/Pd alloy nanoparticles as a heterogeneous catalyst is reported. This photocatalytic system operates with visible light in air, providing a wide range of primary and secondary alkyl halides with B 2 pin 2 or B 2 neop 2 in high yields at low temperatures, thereby demonstrating its broad utility and functional group tolerance. The high performance is attributed to a synergistic effect of localized surface plasmon resonance (LSPR) of Cu and charge transfer from Cu to Pd due to the alloy surface charge heterogeneity. Transfer of energetic electrons from Pd to electrophilic alkyl halides lead to the formation of the alkyl radicals, which quickly react with a nucleophilic adduct of a diboron compound with base adsorbed on the positively charged Cu sites to form the corresponding borylation product. [ABSTRACT FROM AUTHOR]

A catalytic manifold that enables photoredox cross-electrophile coupling of alkyl bromides with DNA-tagged aryl iodides in aqueous solution is presented. This metallaphotoredox transformation was aided by the identification of a new pyridyl bis(carboxamidine) ligand, which proved critical to the nickel catalytic cycle. The described C(sp2)-C(sp3) coupling tolerates a wide range of both DNA-tagged aryl iodides as well as alkyl bromides. Importantly, this reaction was optimized for parallel synthesis, which is a paramount prerequisite for the preparation of combinatorial libraries, by using a 96-well plate-compatible blue LED array as the light source. Therefore, this mild and DNA-compatible transformation is well positioned for the construction of DNA-encoded libraries. Image 1 • Cross-electrophile coupling of alkyl bromides with DNA-tagged aryl iodides. • DNA-compatible C(sp2)-C(sp3) coupling. • Water-compatible nickel-metallaphotoredox catalysis manifold. • 96-well plate-compatible blue LED array as light source. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New 2,4,6-trisubstituted pyrimidines and their N -alkyl derivatives were synthesized. • Most compounds showed significant anti-proliferative potency (IC 50 ~2–10 µg/mL). • All new compounds bound DNA more strongly than cisplatin and 5FU anticancer drugs. • New compounds showed remarkable antibacterial activity (MIC values 7.81–125 µg/mL). • Alkyl chain of varying length showed significant effect on biological activities. Abstract A series of new 2,4,6-trisubstituted pyrimidines and their N- alkyl bromide derivatives were prepared based upon methoxy substituted azachalcones as the starting materials. All newly synthesized compounds were screened for their anti-proliferative, cytotoxic, antibacterial activities and DNA/protein binding affinity. In vitro cell proliferation inhibitory and cell cytotoxic effects of 2,4,6-trisubstituted pyrimidines (1 – 9) and their N -alkyl bromide derivatives (2a-c, 3a-c, 5a-c, 6a-c, 8a-c , 9a-c) were obtained with the help of the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell proliferation, LDH cytotoxicity detection, and microdilution assays. The antimicrobial activity for these compounds was also evaluated following the European Pharmacopoeia 8.0 protocol. The interactions of these compounds with DNA or bovine serum albumin were investigated by the spectrophotometric titration method. When the cytotoxic analysis and anticancer properties of the compounds were examined, most of the compounds significantly exhibited an anti-proliferative potency on cancer cells (IC 50 ∼ 2–10 µg/mL) and caused a cytotoxic effect as low as control drugs, 5-fluorouracil, and cisplatin (∼7–15%). Because the compound-DNA adducts are hyperchromic or hypochromic, they caused variations in their spectra. This situation shows they can be linked to DNA by the groove binding mode at a binding constant range of 2.0 × 104 and 2.4 × 105 M−1. The antimicrobial screening results revealed that our new compounds for some human Gram(+) and Gram(−) pathogen bacteria showed remarkable activity with MIC values between <7.81 and 125 µg/mL. Overall, incorporation of alkyl chain to pyrimidines in the generation of N -alkyl bromides has resulted in showing differences in DNA/protein binding affinity, along with anti-proliferative and cytotoxic activity in favor of new compounds. [ABSTRACT FROM AUTHOR]

Abstract The mutagenic-impurity control strategy for a second generation manufacturing route to the non-mutagenic antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required. Following a thorough review of process purging detail, spiking and purging experimentation, and an understanding of the process parameters to which they were exposed an ICH M7 Option 4 approach could be justified for their control. The development of two 1H NMR spectroscopy methods for measurement of these impurities is also described as well as a proposed summary table for describing the underlying rationale for ICH M7 control rationales to regulators. This manuscript demonstrates that process purging of potential mutagenic impurities can be realised even when they are introduced in the later stages of a process and highlights the importance of scientific understanding rather than relying on a stage-counting approach. Graphical abstract Image 1 Highlights • Retrospective ICH M7 assessment applied to second generation atovaquone process. • Predicted versus measured impurity purge confirms conservatism of Teasdale approach. • Robust science justifies ICH M7 Option 4 control for late introduced impurities. [ABSTRACT FROM AUTHOR]

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. [ABSTRACT FROM AUTHOR]

• Novel 2-amino-4-aryl-6-pyridopyrimidines and N -alkyl derivatives were synthesized. • Anticancer, antibacterial properties and DNA/protein binding affinities were investigated. • Compounds significantly exhibited anti-proliferative and cytotoxic effects as low as control drugs. • N -alkyl bromide derivatives demonstrated stronger pharmacological activities than their ancestor compounds 'pyrimidines'. • Alkyl chain elongation showed significant effect on biological activities. A series of new 2-amino-4-aryl-6-pyridopyrimidines, and their N- alkyl bromide derivatives were designed and synthesized by employing methyl substituted azachalcones. These novel compounds were evaluated and compared to the well-known chemotherapeutics in terms of their anti-cancer and anti-microbial functions, and their DNA/protein binding affinities. In order for the cell proliferation, cytotoxicity and microdilution features to be observed, various cancer cell lines (Hep3B, A549, HeLa, C6, HT29, MCF7) were treated with 2-amino-4-aryl-6-pyridopyrimidines (1 - 9) and their N -alkyl bromide derivatives (2a-c, 3a-c, 5a-c, 6a-c, 8a-c , 9a-c). Studies on the cells revealed that both pyrimidines and their alkyl derivatives (i) have a high anti-proliferative and anti-microbial activities, (ii) cause cell rounding, cytoplasmic blebs, and anomalous globular structure, and (iii) strongly bound to DNA/BSA macromolecules. Especially the length of the alkyl chain of the N -alkyl bromides has an increasing effect on the antiproliferative, antibacterial and cytotoxic functions, also DNA/protein binding affinity. Those results indicate the novel compounds to be promising antiproliferative agents, and their anti-cancer potential makes them candidates to be used for cancer therapy. [ABSTRACT FROM AUTHOR]