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"CHEMICAL COMPOUNDS"
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Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings
Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8–11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.
Medium-sized ring systems are common in natural products, however their synthesis is challenging, largely due to entropic factors. Here the authors report a radical-based method for the synthesis of medium to large functionalized, carbon or heterocyclic scaffolds.
Journal Article
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple
in vivo
efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the
Plasmodium
life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.
Bicyclic azetidines, a new type of antimalarial
Antimalarial drugs have thus far been mainly derived from natural products and synthetic 'drug-like' compounds. This study describes the discovery, following screens against libraries of compounds reminiscent of natural products, of promising small molecules that are highly active against the malaria parasite. Of particular interest is a series of bicyclic azetidines that inhibit a novel malaria target, phenylalanine tRNA–ligase. The bicyclic azetidines can cure mice from all life stages of the
Plasmodium
parasite with a single low-dose in different mouse infection assays, including a humanized mouse model of malaria liver-stage disease. These compounds have the potential to cure and prevent transmission of the disease in a single oral exposure.
Journal Article
Isolation of a C5-Deprotonated Imidazolium, a Crystalline \Abnormal\ N-Heterocyclic Carbene
The discovery two decades ago of metal-free stable carbenes, especially imidazol-2-ylidenes [N-heterocyclic carbenes (NHCs)], has led to numerous breakthroughs in organic and organometallic catalysis. More recently, a small range of complexes has been prepared in which alternative NHC isomers, namely imidazol-5-ylidenes (also termed abnormal NHCs or αNHCs, because the carbene center is no longer located between the two nitrogens), coordinate to a transition metal. Here we report the synthesis of a metal-free οNHC that is stable at room temperature, both in the solid state and in solution. Calculations show that the οNHC is more basic than its normal NHC isomer. Because the substituent at the carbon next to the carbene center is a nonbulky phenyl group, a variety of substitution patterns should be tolerated without precluding the isolation of the corresponding αNHC.
Journal Article
Synthesis and Evaluation of Boron-Containing Heterocyclic Compounds with Antimicrobial and Anticancer Activities
Organoboron compounds, especially those containing boronic acid and benzoxaborole in their structure, have been gaining prominence in medicinal chemistry, following the FDA approval of tavaborole for the treatment of onychomycosis and bortezomib for multiple myeloma. The antimicrobial and anticancer effects of organoboron compounds motivate the investigation of the effects of the novel derivatives described here. A total of fourteen new boronic derivatives were synthesized and characterized using analytical methods. The antimicrobial activities were evaluated against M. tuberculosis (Mtb) H37Rv strains and fungal dermatophytes (C. albicans, ATCC 90028; T. rubrum, ATCC 28189; and T. mentagrophytes, ATCC 11481), while the anticancer effect was evaluated against oral squamous cell carcinoma (SCC) cell lines. Several promising boron-containing prototypes were identified, providing a foundation for further molecular optimization in the development of new antimicrobial and anticancer compounds.
Journal Article
A Synthetic Model of the Mn3Ca Subsite of the Oxygen-Evolving Complex in Photosystem II
Within photosynthetic organisms, the oxygen-evolving complex (OEC) of photosystem II generates dioxygen from water using a catalytic Mn 4 CaO n cluster (n varies with the mechanism and nature of the intermediate). We report here the rational synthesis of a [Mn 3 CaO 4 ] 6+ cubane that structurally models the trimanganese-calcium—cubane subsite of the OEC. Structural and electrochemical comparison between Mn 3 CaO 4 and a related Mn 4 O 4 cubane alongside characterization of an intermediate calcium-manganese multinuclear complex reveals potential roles of calcium in facilitating high oxidation states at manganese and in the assembly of the biological cluster.
Journal Article
1,3-Dipolar Cycloaddition of Nitrile Imines and Nitrile Oxides to Exocyclic C=N Bonds—An Approach to Spiro-N-Heterocycles
Nitrile imines and nitrile oxides are capable of undergoing (3+2)-cycloaddition reactions at double and triple carbon–carbon, carbon-heteroatom, or heteroatom–heteroatom bonds of various dipolarophiles, forming five-membered heterocyclic compounds. When cyclic dipolarophiles bearing an exocyclic carbon–nitrogen double bond (exo-C=N) are introduced into the reaction with these dipoles, spiro-fused 1,2,4-triazoline or 1,2,4-oxadiazoline cycles are formed. Such reactions can provide efficient synthetic approaches to spiro-heterocyclic compounds with enhanced biological activity. This review comprehensively summarizes the literature data on the 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides to exo-C=N bonds for spiro compound synthesis. The research area covers reactions of both saturated and unsaturated dipolarophiles, monocyclic and polycyclic molecules, as well as compounds containing one to three heteroatoms, with special emphasis on systems containing biologically significant heterocyclic pharmacophores. Recent advances in reaction techniques, such as microwave and ultrasonic activation, as well as one-pot and diffusion protocols, are also mentioned.
Journal Article
Recent Advances in the Synthesis of Selenophenes and Their Derivatives
The selenophene derivatives are an important class of selenium-based heterocyclics. These compounds play an important role in prospecting new drugs, as well as in the development of new light-emitting materials. During the last years, several methods have been emerging to access the selenophene scaffold, employing a diversity of cyclization-based synthetic strategies, involving specific reaction partners and particularities. This review presents a comprehensive discussion on the recent advances in the synthesis of selenophene-based compounds, starting from different precursors, highlighting the main differences, the advantages, and limitations among them.
Journal Article
Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric Bromination
Despite the widespread use of axially chiral, or atropisomeric, biaryl ligands in modern synthesis and the occurrence of numerous natural products exhibiting axial chirality, few catalytic methods have emerged for the direct asymmetric preparation of this compound class. Here, we present a tripeptide-derived small-molecule catalyst for the dynamic kinetic resolution of racemic biaryl substrates. The reaction proceeds via an atropisomer-selective electrophilic aromatic substitution reaction using simple bromination reagents. The result is an enantioselective synthesis that delivers chiral nonracemic biaryl compounds with excellent optical purity and good isolated chemical yields (in most cases a >95:5 enantiomer ratio and isolated yields of 65 to 87%). A mechanistic model is advanced that accounts for the basis of selectivity observed.
Journal Article
A new method to position and functionalize metal-organic framework crystals
With controlled nanometre-sized pores and surface areas of thousands of square metres per gram, metal-organic frameworks (MOFs) may have an integral role in future catalysis, filtration and sensing applications. In general, for MOF-based device fabrication, well-organized or patterned MOF growth is required, and thus conventional synthetic routes are not suitable. Moreover, to expand their applicability, the introduction of additional functionality into MOFs is desirable. Here, we explore the use of nanostructured poly-hydrate zinc phosphate (α-hopeite) microparticles as nucleation seeds for MOFs that simultaneously address all these issues. Affording spatial control of nucleation and significantly accelerating MOF growth, these α-hopeite microparticles are found to act as nucleation agents both in solution and on solid surfaces. In addition, the introduction of functional nanoparticles (metallic, semiconducting, polymeric) into these nucleating seeds translates directly to the fabrication of functional MOFs suitable for molecular size-selective applications.
Metal-organic frameworks (MOFs) have potential catalysis, filtration and sensing applications, but device fabrication will require controlled MOF growth. Here, α-hopeite microparticles are used to achieve spatial control of MOF nucleation, and accelerate MOF growth.
Journal Article