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In recent times, diaryliodonium reagents (DAIRs) have witnessed a resurgence as arylating reagents, especially under photoinduced conditions. However, reactions proceeding through electron donor-acceptor (EDA) complex formation with DAIRs are restricted to electron-rich reacting partners serving as donors due to the well-known cage effect. We discovered a practical and high-yielding visible-light-induced EDA platform to generate aryl radicals from the corresponding DAIRs and use them to synthesize key chalcogenides. In this process, an array of DAIRs and dichalcogenides react in the presence of 1,4 diazabicyclo[2.2.2]octane (DABCO) as a cheap and readily available donor, furnishing a variety of di(hetero)aryl and aryl/alkyl chalcogenides in good yields. The method is scalable, features a broad scope with good yields, and operates under open-to-air conditions. The photoinduced chalcogenation technology is suitable for late-stage functionalizations and disulfide bioconjugations and facilitates access to biologically relevant thioesters, dithiocarbamates, sulfoximines, and sulfones. Moreover, the method applies to synthesizing diverse pharmaceuticals, such as vortioxetine, promazine, mequitazine, and dapsone, under amenable conditions.
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Quaternary carbons are embedded in various natural products, pharmaceuticals, and organic materials. However, constructing this valuable motif is far from trivial. Conventional approaches mainly rely on classical polar disconnections and encounter bottlenecks concerning harsh conditions, functional group tolerance, regioselectivity, and step economy. In this context, Kawamata, Baran, Shenvi, and co-workers recently demonstrated that two feedstock chemicals, alkyl carboxylic acids and olefins, could be utilized to construct tetrasubstituted carbons in the presence of an inexpensive iron porphyrin catalyst and a suitable reductant combination through quaternization of the radical intermediates. The method enables access to various sterically encumbered quaternary carbons under mild and robust conditions. Taking a complete detour from conventional approaches, the present heteroselective radical-radical coupling simplifies the synthesis of quaternary carbon-containing molecules through an innovative and distinctive disconnection approach.
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Methods enabling direct C-H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C-H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C-H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals.
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We conceptualized a novel disconnection approach for the synthesis of fused tetrahydroquinolines that exploits a visible light-mediated radical (4 + 2) annulation between alkyl N-(acyloxy)phthalimides and N-substituted maleimides in the presence of DIPEA as an additive. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between alkyl NHPI esters and DIPEA, and the final tetrahydroquinolines were obtained in a complete regioselective fashion. The methodology features a broad scope and good functional group tolerance and operates under metal- and catalyst-free reaction conditions. Detailed mechanistic investigations including density functional theory studies provide insight into the reaction pathway.
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A copper-catalyzed efficient method for the synthesis of a diverse variety of substituted N-aryl pyrazoles from readily available α,ß-alkynic N-tosyl hydrazones and diaryliodonium triflates is realized. This one-pot multi-step methodology features a broad scope with good yields, scalability, and appreciable functional group tolerance. Detailed control experiments reveal that the reaction proceeds through tandem cyclization/deprotection/arylation events where the copper catalyst plays a distinct role.
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A photoredox-catalyzed direct arylation of quinoxalin-2-(1H)-ones using diaryliodonium triflates as the convenient, stable, and cheap aryl source is described. A broad variety of quinoxalin-2-(1H)-ones are shown to react with structurally and electronically diverse diaryliodonium triflates, allowing efficient access to a wide variety of pharmaceutically important 3-arylquinoxalin-2-(1H)-ones. The presented method is attractive with regard to operational simplicity, mild conditions, broad scope, scalability, and high functional group tolerance.
Assuntos
Quinoxalinas , Sais , Catálise , LuzRESUMO
Cancer is a leading cause of human death, and there is a need to identify efficient and novel chemical scaffolds which could provide flexibility to cancer chemotherapeutics. This work introduces S-aryl dithiocarbamates belonging to a versatile group of organo-sulfur containing compounds as a hitherto unexplored class of effective anticancer drugs with promising pharmacophore properties. We synthesized a series of N-Boc piperazine containing S-aryl dithiocarbamates and identified compound 1 as a potent antiproliferative agent in lung, cervical, and breast cancer cell lines. Compound 1 exhibited best inhibitory activity against cervical cancer cells, HeLa with an IC50 of 0.432 ± 0.138 µM for 72 h, and lung cancer cells, A549 with an IC50 of 0.447 ± 0.051 µM for 72 h. We further demonstrate that HeLa cells treated with this compound result in G2/M phase cell cycle arrest, causing cell apoptosis due to the upregulation of the p53-p21 signaling pathway. Importantly, cells treated with compound 1 showed a novel tubulin bundling phenotype in fluorescence microscopy, which is a characteristic of microtubule-stabilizing anticancer drugs like paclitaxel. Interestingly, molecular docking analysis revealed reasonable binding of compound 1 in the taxol-binding pocket of ß-tubulin, making it a promising candidate for microtubule stabilization based anticancer drug discovery.
Assuntos
Antineoplásicos , Tubulina (Proteína) , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
Ras proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl-binding protein PDEδ. Recently, we have reported the specific anti-proliferative effects of PDEδ inhibition in KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC.
Assuntos
Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Interferência de RNARESUMO
Late stage functionalization (LSF) through direct X-H manipulations (X = C, N) enables synthetic chemists to accelerate the diversification of natural products, agrochemicals and pharmaceuticals allowing rapid access to novel bioactive molecules without resorting to arduous de novo synthesis. LSF does not only allow tapping of the hitherto unexplored chemical space but also renders the synthetic sequence more straightforward, atom economical and cost-effective. In this regard, the recent decade has witnessed the emergence of hypervalent iodine(iii) reagents as a powerful synthetic tool owing to their easy availability, mild reaction conditions, remarkable oxidizing properties and high functional group tolerance. Iodine(iii) reagents have tremendous applications in the regio- and chemo-selective late-stage functionalization of a diverse variety of heterocycles through an exciting range of transformations, such as oxidative amination, cross-dehydrogenative coupling (CDC), fluoroalkylation, azidation, halogenation and oxidation. The present review, classified according to the types of synthetic methods involved, encompasses all these recent developments in the field of transition-metal-free iodine(iii)-catalyzed/mediated direct functionalizations of heterocycles with representative examples and insightful mechanistic discussions.
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The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras-PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity. We delineate the structure-property relationship and in vivo pharmacokinetic (PK) and toxicokinetic (Tox) studies for pyrazolopyridazinone-based K-Ras-PDEδ inhibitors. These findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic Ras.
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Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding inâ vitro (KD <10â nm), interference with Ras signaling and growth inhibition require 5-20â µm compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.
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Hypervalent iodine(III) reagents have been widely exploited in a diverse array of synthetic transformations. This chapter focuses on the general application of hypervalent iodine(III) reagents in the de novo synthesis and in the late stage functionalization of heterocyclic compounds.
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The mechanism of the TEMPO mediated oxidative homo-coupling of aryl Grignard reagents is investigated in detail by experimental and computational studies. Experimental data reveal that the nitroxide-mediated homocoupling reaction of aryl Grignard reagents does not occur via free aryl radicals. Evidence for the presence of biaryl radical anions as intermediates in the coupling reaction is provided. It is also shown that PhMgPh under bromide free conditions in the presence of TEMPO does not undergo homocoupling. However, upon addition of MgBr2, C-C bond formation smoothly proceeds documenting the important role of the bromide anions in the oxidative homocoupling. DFT calculations show that an intramolecular electron transfer to a Mg-complexed TEMPO ligand with subsequent biaryl formation in a dimeric complex is viable and in agreement with experimental reaction conditions.
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We report a rhodium(II)-catalyzed highly enantioselective 1,3-dipolar cycloaddition reaction between the carbonyl moiety of tropone and carbonyl ylides to afford troponoids in good to high yields with excellent enantioselectivity. We demonstrate that α-diazoketone-derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity.
Assuntos
Compostos Azo/síntese química , Ródio/química , Tropolona/análogos & derivados , Catálise , Reação de Cicloadição , Estrutura Molecular , Estereoisomerismo , Tropolona/químicaRESUMO
A visible light-induced green and sustainable N-H functionalization of (aza)uracils with α-diazo esters leading to imide alkylation is described. The reaction does not require any catalyst or additive and proceeds under mild conditions. Moreover, an intriguing three component coupling was observed when (aza)uracils were allowed to react with α-diazo esters in cyclic ethers (e. g. 1,4-dioxane, THF) as a solvent. Both the insertion and three-component coupling features broad scope with good to excellent yields and appreciable functional group tolerance. Notably, the divergent method enables modification of natural products and pharmaceuticals, thereby facilitates access to potentially biologically active compounds.
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We present an organophotoredox-catalyzed direct Csp3-H alkylation of 3,4-dihydroquinoxalin-2-ones employing N-(acyloxy)pthalimides to provide corresponding products in good yields. A broad spectrum of NHPI esters (1°, 2°, 3°, and sterically encumbered) participates in the photoinduced alkylation of a variety of 3,4-dihydroquinoxalin-2-ones. In general, mild conditions, broad scope with good functional group tolerance, and scalability are the salient features of this direct alkylation process.
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We present an electrochemical alkylation of azauracils using N-(acyloxy)phthalimides (NHPI esters) as readily available alkyl radical progenitors under metal- and additive-free conditions. Several azauracils are shown to undergo alkylation with an array of NHPI esters (1°, 2°, 3°, and sterically congested), providing the desired products in good to excellent yields. This operationally simple method is robust, scalable, and suitable for both batch and flow setups.
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We disclose N'-arylidene-N-acryloyltosylhydrazides as novel skeletons for the synthesis of biologically relevant alkylated pyrazolones through a photoinduced radical cascade with N-(acyloxy)pthalimides as readily available alkyl surrogates. The reaction proceeds through the formation of a photoactivated electron donor-acceptor (EDA) complex between alkyl N-(acyloxy)phthalimide (NHPI) esters and LiI/PPh3 as a commercially available donor system. The reaction exhibits a broad scope and scalability, thereby enabling synthesis of a broad spectrum of functionally orchestrated alkylated pyrazolones under mild and transition-metal-free conditions.
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We report here a practical and cost-effective method for the synthesis of CHF2-containing benzimidazo- and indolo[2,1,a]-isoquinolin-6(5H)-ones through a visible light-mediated difluoromethylation/cyclization cascade. The method, which affords functionalized multifused N-heterocyclic scaffolds in moderate to high yields under mild reaction conditions, is also easily scalable using low-cost 3D printed photoflow reactors.
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A photoredox-catalyzed arylative radical cascade involving N-acryloyl-2-arylbenzoimidazoles and diaryliodonium triflates leading to the formation of a broad array of pharmaceutically important arylated-benzimidazo[2,1-a]isoquinolin-6(5H)-ones is described. Importantly, the synthesized benzimidazoisoquinolinones are amenable for further synthetic manipulation and allowed efficient access to benzimidazo-fused polycyclic heterocycles.