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1.
Org Lett ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874571

RESUMO

Here, we explore a dehydrogenative 6π photocyclization method for N-substituted naphthalene carboxamides, which can be conducted in air. This method employs DMSO as both the reaction solvent and oxidant while also stabilizing the excited state of the substrate. Furthermore, the addition of photosensitizer enables the reaction to proceed under a 440-445 nm LED source via energy transfer. The proposed mechanism is initially validated through DFT calculations.

2.
J Med Chem ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847373

RESUMO

Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel anticancer agent.

3.
Brief Bioinform ; 25(3)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38670158

RESUMO

Despite the widespread use of ionizable lipid nanoparticles (LNPs) in clinical applications for messenger RNA (mRNA) delivery, the mRNA drug delivery system faces an efficient challenge in the screening of LNPs. Traditional screening methods often require a substantial amount of experimental time and incur high research and development costs. To accelerate the early development stage of LNPs, we propose TransLNP, a transformer-based transfection prediction model designed to aid in the selection of LNPs for mRNA drug delivery systems. TransLNP uses two types of molecular information to perceive the relationship between structure and transfection efficiency: coarse-grained atomic sequence information and fine-grained atomic spatial relationship information. Due to the scarcity of existing LNPs experimental data, we find that pretraining the molecular model is crucial for better understanding the task of predicting LNPs properties, which is achieved through reconstructing atomic 3D coordinates and masking atom predictions. In addition, the issue of data imbalance is particularly prominent in the real-world exploration of LNPs. We introduce the BalMol block to solve this problem by smoothing the distribution of labels and molecular features. Our approach outperforms state-of-the-art works in transfection property prediction under both random and scaffold data splitting. Additionally, we establish a relationship between molecular structural similarity and transfection differences, selecting 4267 pairs of molecular transfection cliffs, which are pairs of molecules that exhibit high structural similarity but significant differences in transfection efficiency, thereby revealing the primary source of prediction errors. The code, model and data are made publicly available at https://github.com/wklix/TransLNP.


Assuntos
Lipídeos , Lipossomos , Nanopartículas , RNA Mensageiro , Nanopartículas/química , RNA Mensageiro/genética , RNA Mensageiro/química , Lipídeos/química , Transfecção , Humanos , Modelos Moleculares , Sistemas de Liberação de Medicamentos
4.
J Org Chem ; 89(1): 44-56, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38088910

RESUMO

In this paper, we present an example of a photoinduced catalyst, halogen-, and base-free TEMPO-mediated interrupted 6π-photocyclization/dehydrogenative aromatization of ortho-biaryl-appended 1,3-dicarbonyl compounds for the preparation of 10-phenanthrenols. The reaction involves rapid photocycloaddition via a 1,2-biradical of 1,3-dicarbonyl compounds, followed by subsequent dehydrogenative aromatization of 1,4-biradical intermediates using TEMPO as the commercially available oxidant rather than trapped by TEMPO to form an alkoxyamine product.

5.
Angew Chem Int Ed Engl ; 63(5): e202313030, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38072915

RESUMO

Carboxylation with carbon dioxide (CO2 ) represents one notable methodology to produce carboxylic acids. In contrast to carbon-heteroatom bonds, carbon-carbon bond cleavage for carboxylation with CO2 is far more challenging due to their inherent and less favorable orbital directionality for interacting with transition metals. Here we report a photocatalytic protocol for the deconstructive carboxylation of alkenes with CO2 to generate carboxylic acids in the absence of transition metals. It is emphasized that our protocol provides carboxylic acids with obviously unchanged carbon numbers when terminal alkenes were used. To show the power of this strategy, a variety of pharmaceutically relevant applications including the modular synthesis of propionate nonsteroidal anti-inflammatory drugs and the late-stage carboxylation of bioactive molecule derivatives are demonstrated.

6.
J Org Chem ; 88(21): 14874-14886, 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37862710

RESUMO

An efficient oxidant-free, photoredox-mediated cascade cyclization strategy for the synthesis of 1,3,4-oxadiazoles by using an organo acridinium photocatalyst and a cobaloxime catalyst has been developed. Various acylhydrazones have been transformed into the corresponding 1,3,4-oxadiazole products in up to 96% yield, and H2 is the only byproduct. Mechanistic experiments and density functional theory (DFT) calculation studies indicate carbon-centered radicals rather than oxygen-centered radicals as π-radicals produced by the oxidation of photoexcited Mes-Acr+* along with deprotonation, which is responsible for this transformation. The practical utility of this method is highlighted by the one-pot gram-scale synthesis starting directly from commercially available aldehydes and acylhydrazides.

7.
J Org Chem ; 88(13): 9094-9104, 2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37314129

RESUMO

A photocatalyst- and additive-free visible-light-induced 6π-photocyclization of ortho-biaryl-appended ß-ketoesters has been developed. Upon irradiation with visible light, substrates undergo 6-endo-trig cyclization/1,5-H shift to 9,10-dihydrophenanthren-9-ols with high efficiency and selectivity. The reaction proceeds via conrotatory ring closure followed by a suprafacial 1,5-hydrogen shift leading to the observed single trans-fused products. Preliminary mechanistic studies reveal the feasibility of both 1,5-H shift and intersystem crossing of the diradical intermediate.


Assuntos
Hidrogênio , Luz , Ciclização
8.
Angew Chem Int Ed Engl ; 62(7): e202214944, 2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36510781

RESUMO

A new way to form fluorenones via the direct excitation of substrates instead of photocatalyst to activate the C(sp2 )-H bond under redox-neutral condition is reported. Our design relies on the photoexcited aromatic aldehyde intermediates that can be intercepted by cobaloxime catalyst through single electron transfer for following ß-H elimination. The generation of acyl radical and successful interception by a metal catalyst cobaloxime avoid the use of a photocatalyst and stoichiometric external oxidants, affording a series of highly substituted fluorenones, including six-membered ketones, such as xanthone and thioxanthone derivatives in good to excellent yields, and with hydrogen as the only byproduct. This catalytic system features a readily available metal catalyst, mild reaction conditions and broad substrate scope, in which sunlight reaction and scale-up experiments by continuous-flow approach make the new methodology sustainable and amenable for potentially operational procedures.

9.
J Org Chem ; 87(24): 16458-16472, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36441578

RESUMO

Due to the inert redox activity and high triplet energy, radical chemistry of 1,3-dicarbonyl compounds usually requires prefunctionalization substrates, external oxidant, and high-energy UV light. Here, we report a visible-light-driven photocatalyst/cobaloxime system composed of a photosensitized energy transfer reaction (PEnT) and photoinduced electron transfer reaction (PET) and with an interrupted 6π-photocyclization/dehydrogenative aromatization in one pot to synthesize 10-phenanthrenols. Preliminary mechanistic studies revealed that fac-Ir(ppy)3 plays the dual roles of energy transfer catalysis for photocycloaddition via 1,2-biradical intermediates of 1,3-dicarbonyl compounds and photoredox/cobaloxime catalysis dehydrogenative aromatization of 1,4-biradical rather than the intermediates via 6π photocyclization in the tandem reaction. In contrast to previous well-established radical chemistry of 1,3-dicarbonyl compounds, we provide a new strategy for the activation of 1,3-dicarbonyl compounds under visible light catalysis, affording a novel cyclization strategy with extremely high atom economy for the synthesis of 10-phenanthrenols.


Assuntos
Cobalto , Elétrons , Oxirredução , Catálise , Transferência de Energia
10.
Org Lett ; 22(24): 9627-9632, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33289571

RESUMO

The first example of photoredox strategy for synthesis of phenanthrene skeletons through C(sp3)-H functionalization under external oxidant-free conditions is achieved. This transformation relies on the keto-enol tautomerism of 1,3 dicarbonyl moiety, i.e., the enol form of 1,3-dicarbonyl derivatives with relatively lower oxidation potential can be activated by the excited acridinium photocatalyst. The electron and proton eliminated from the substrate are immediately captured by a cobaloxime catalyst to exclusively afford a-carbonyl radical for highly substituted 10-phenanthrenols in good to excellent yields.

11.
J Org Chem ; 85(14): 9080-9087, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32434320

RESUMO

By combining "N-chlorosuccinimide (NCS)" as the safe chlorine source with "Acr+-Mes" as the photocatalyst, we successfully achieved benzylic C-H bond chlorination under visible light irradiation. Furthermore, benzylic chlorides could be converted to benzylic ethers smoothly in a one-pot manner by adding sodium methoxide. This mild and scalable chlorination method worked effectively for diverse toluene derivatives, especially for electron-deficient substrates. Careful mechanistic studies supported that NCS provided a hydrogen abstractor "N-centered succinimidyl radical," which was responsible for the cleavage of the benzylic C-H bond, relying on the reducing ability of Acr•-Mes.

12.
Angew Chem Int Ed Engl ; 59(13): 5365-5370, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-31957949

RESUMO

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic ß-ketoesters by using a photocatalyst. Under visible-light irradiation, a small amount of photocatalyst fac-Ir(ppy)3 generates a transient α-carbonyl radical and persistent ketyl radical in situ. In contrast to the well-established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α-carbonyl radicals with alkynes to give a series of highly substituted 1-naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional-group tolerance make this reaction a useful synthetic tool.

13.
J Am Chem Soc ; 141(35): 13941-13947, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31401832

RESUMO

Direct activation of H-phosphine oxide to react with an unsaturated carbon-carbon bond is a straightforward approach for accessing alkenylphosphine oxides, which shows significant applications in both synthetic and material fields. However, expensive metals and strong oxidants are typically required to realize the transformation. Here, we demonstrate the utility of earth-abundant cobaloxime to convert H-phosphine oxide into its reactive radical species under visible light irradiation. The radical species thus generated can be utilized to functionalize alkenes and alkynes without any external photosensitizer and oxidant. The coupling with terminal alkene generates E-alkenylphosphine oxide with excellent chemo- and stereoselectivity. The reaction with terminal alkyne yields linear E-alkenylphosphine oxide via neutral radical addition, while addition with internal ones generates cyclic benzophosphine oxides and hydrogen. Mechanistic studies on radical trapping experiments, electron spin resonance studies, and spectroscopic measurements confirm the formation of phosphinoyl radical and cobalt intermediates that are from capturing the electron and proton eliminated from H-phosphine oxide. The highlight of our mechanistic investigation is the dual role played by cobaloxime, viz., both as the visible light absorber to activate the P(O)-H bond as well as a hydrogen transfer agent to influence the reaction pathway. This synergetic feature of the cobaloxime catalyst preforming multiple functions under ambient condition provides a convergent synthetic approach to vinylphosphine oxides directly from H-phosphine oxides and alkenes (or alkynes).

14.
Org Lett ; 20(10): 2916-2920, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29737179

RESUMO

A redox-neutral reaction without using any external oxidant and reductant in one pot is described. By combining a Ru(bpy)32+ photocatalyst and cobaloxime catalyst, a number of tertiary anilines can be oxidized by Ru(bpy)32+ to realize oxidative cyclization of tetrahydroquinolines, and the electron and proton eliminated from the substrate anilines are captured by a cobaloxime catalyst to achieve hydrogen transfer in situ to maleimides, in good to excellent yields, under redox-neutral conditions.

15.
Chem Commun (Camb) ; 53(59): 8320-8323, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28686240

RESUMO

With visible light irradiation of a catalytic amount of Ir(ppy)3 at room temperature, a number of N-aryl enamines were transformed into their corresponding indoline products in good to excellent yields without requiring any extra additives. This is the first example of the synthesis of indolines via the intramolecular cyclization of enamines under visible light irradiation.

16.
Org Lett ; 19(12): 3251-3254, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28548863

RESUMO

The construction of substituted indole skeletons is always an important concern of synthetic chemists because of its prevalent structure found in natural products and biological molecules. Here, we succeeded in preparing indoles and their derivatives from a wide variety of simple enamines via radical cyclization only with catalytic amounts of an iridium(III) photosensitizer (PS) in DMSO solution under air atmosphere. The mechanistic investigation suggests that the reaction involves a radical course to accomplish the conversion of enamines to indoles under visible light irradiation.

17.
Org Lett ; 18(9): 2070-3, 2016 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-27120574

RESUMO

A novel, facile, and efficient method for the synthesis of tetrahydropyridazines by a one-pot tandem reaction of easily accessible ketohydrazones and olefins in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) has been successfully developed. The reaction involves the initial generation of azoalkenes from direct oxidative dehydrogenation of ketohydrazones using TEMPO as the commercially available oxidant, followed by a subsequent aza-Diels-Alder reaction with olefins.

18.
J Org Chem ; 81(7): 3042-50, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26954339

RESUMO

A novel, metal-free, and regioselective approach for the synthesis of isoxazoline/cyclic nitrone-featured methylenes has been developed by the reaction of readily accessible ß,γ- and γ,δ-unsaturated ketoximes with TEMPO via tandem iminoxyl radical-promoted cyclization/TEMPO-mediated Cope-like elimination, respectively. This protocol utilizes commercially available TEMPO as the iminoxyl radical initiator as well as the ß-hydrogen acceptor in the Cope-like elimination.

19.
Org Lett ; 17(24): 6022-5, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26641278

RESUMO

An efficient and practical tandem cyclization/addition/cyclization strategy is developed for the initial generated hydrazonyl radicals derived from the oxidation of ß,γ-unsaturated hydrazones. By using this protocol, structurally novel pyrazoline-functionalized oxindoles are prepared by the reaction of easily accessible ß,γ-unsaturated hydrazones with N-aryl acrylamides under the metal- and solvent-free conditions of DTBP (di-tert-butyl peroxide) via a tandem intra/intermolecular C-N/C-C/C-C bond formation.

20.
Inorg Chem ; 54(16): 7670-2, 2015 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-26222271

RESUMO

A mononuclear compound, [Co(II)(pyterpy)2](PF6)2·2CH3OH [2; pyterpy = 4'-(4‴-pyridyl)-2,2':6',2″-terpyridine], shows a phase-transition-coupled, abrupt spin transition with a 9 K wide hysteresis that can transform to a spin-crossover compound, [Co(II)(pyterpy)2](PF6)2·2CH2Cl2·CH3OH (3).

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