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1.
Org Biomol Chem ; 22(2): 348-352, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38086690

RESUMO

Sulfinamides are a versatile class of compounds that find applications in both organic synthesis and pharmaceuticals. Here we developed an efficient photocatalytic approach for the convenient preparation of sulfinamides. Commercially available potassium trifluoro(organo)borates and readily available sulfinyl amines are rationally used and converted to a series of alkyl or aryl sulfinamides in moderate to high yields. The reaction allows for the gram-scale preparation of sulfinamides. Moreover, sulfonimidamides, sulfonimidate esters and sulfonyl amides could be obtained in one pot.

2.
Bioorg Med Chem ; 86: 117299, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37137271

RESUMO

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.


Assuntos
Proteínas , Quimera de Direcionamento de Proteólise , RNA , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas/metabolismo , Proteólise , RNA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Aptâmeros de Nucleotídeos , Quimera de Direcionamento de Proteólise/química
3.
Org Lett ; 25(12): 2134-2138, 2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-36939573

RESUMO

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

4.
J Org Chem ; 88(7): 4581-4591, 2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-36926918

RESUMO

The sulfinamidines as aza analogues of sulfinamides received limited attention from both organic chemists and pharmaceutical chemists. Herein, we present a tandem oxidative/nucleophilic substitution approach for the synthesis of sulfinamidines in high yield (up to 98%). This cascade reaction method is enabled by N-bromosuccinimide (NBS) as an oxidant and diverse readily available amines as nucleophiles without any additives or catalysts. Notably, this method is highly time-economical, safe to operate, and easy to scale up and has excellent functional group compatibility.

5.
J Am Chem Soc ; 145(9): 5439-5446, 2023 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-36811577

RESUMO

Direct construction of chiral S(VI) from prochiral S(II) is a formidable challenge due to the inevitable formation of stable chiral S(IV). Previous synthetic strategies rely on the conversion of chiral S(IV) or enantioselective desymmetrization of preformed symmetrical S(VI) substrates. Here, we report desymmetrizing enantioselective hydrolysis of in situ-generated symmetric aza-dichlorosulfonium from sulfenamides for the preparation of chiral sulfonimidoyl chlorides, which could be used as a general stable synthon for obtaining a series of chiral S(VI) derivatives.

6.
Org Lett ; 24(10): 2069-2074, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35261250

RESUMO

Herein, we disclose a new catalytic asymmetric tandem reaction based on the Heyns rearrangement for the synthesis of chiral α-amino ketones with readily available substrates. The rearrangement is different from the Heyns rearrangement in that the α-amino ketones were obtained without the shift of the carbonyl group. The key to success is using chiral primary amine as a catalyst by mimicking glucosamine-6-phosphate synthase in catalyzing the efficient Heyns rearrangement in organisms.


Assuntos
Aminas , Cetonas , Aminas/química , Catálise , Cetonas/química , Estereoisomerismo
7.
Angew Chem Int Ed Engl ; 61(22): e202201418, 2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35301801

RESUMO

Described herein is the enantioselective synthesis of Hantzsch-type 1,4-dihydropyridines (DHPs), which are frequently contained in pharmaceuticals. Readily available symmetrical 1,4-DHPs were used as substrates, and the methyl group at the 2- or 6-position of the 1,4-DHP was selectively monobrominated by desymmetrizing enantioselective bromination. The inert C-H bond was converted into a versatile C-Br bond, which guaranteed the modification of the chiral 1,4-DHP derivatives with high efficiency. Furthermore, axially chiral 4-aryl pyridines were accessible by central-to-axial chirality conversion.


Assuntos
Di-Hidropiridinas , Catálise , Di-Hidropiridinas/química , Halogenação , Ácidos Fosfóricos , Estereoisomerismo
8.
J Org Chem ; 87(5): 3311-3318, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35166530

RESUMO

Polysubstituted 1,2-dihydronaphthofurans were efficiently obtained in high yields and good diastereoselectivities with readily available substrates. The reaction proceeds smoothly via a series of tandem reactions, including Heyns rearrangement, oxidation, Friedel-Crafts reaction, and cyclization. The high stereoselectivity of the reaction is ascribed to the activation of the imine via an intramolecular hydrogen bond. Air is directly used as the oxidation medium, which makes the reaction safe and easy to perform. Moreover, the reaction features multiple components, which ensures the diversity of products.


Assuntos
Radical Hidroxila , Cetonas , Ciclização , Cetonas/química , Estrutura Molecular
9.
Eur J Med Chem ; 226: 113850, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34628235

RESUMO

The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pironas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Proteólise/efeitos dos fármacos , Pironas/síntese química , Pironas/química , Relação Estrutura-Atividade
10.
ACS Omega ; 6(39): 25412-25420, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34632199

RESUMO

The phase transition law between ordered and disordered phases, second phase reinforcement, microstructure, and mechanical properties were systematically studied in the rapid cooling coupling deep supercooled solidification process through an arc melting furnace, electromagnetic induction heating, and high-speed cooling single-roll technology. The results show that uniform nucleation and grain refinement are promoted under rapid cooling coupling deep supercooled solidification, and the phase transition from the disordered phase (A2) to the ordered phase (B2 and DO3) is also effectively suppressed. The decreased crystalline grain size and optimized microstructure morphology improved the plasticity and magnetic property. The Fe-6.5wt%Si steel strip at 42 m/s has a good phase composition of Fe (predominant), Fe2Si, and SiC. The sample showed an equiaxed ferrite crystal structure, and the saturation magnetizations were 302.5 and 356.6 emu/g in the parallel magnetic direction and the vertical magnetic direction, respectively. This phase transition behavior contributed to the exceptional magnetic property of the Fe-6.5wt%Si steel.

11.
Org Lett ; 23(17): 6819-6824, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34406013

RESUMO

α-Imino ketone is a useful building block for the preparation of α-amino ketones and α-amino alcohols. However, its preparation has been seldomly seen. Herein, a metal-free and operationally simple strategy has been developed to generate α-imino ketones with high regioselectivity. Meanwhile, the method allowed for the preparation of various N,O-ketals with high regioselectivities and diastereoselectivities through cascade reactions in one pot.

12.
Chem Sci ; 12(13): 4789-4793, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-34168757

RESUMO

N-Substituted tetrahydroquinoxalines (37 examples) were step-economically obtained in good yield (<97%) and ee (<99%) with readily available substrates. The reaction proceeds through an interesting regioselective Heyns rearrangement/enantioselective transfer hydrogenation in one pot. The substrate scope and the reaction mechanism were systematically investigated.

13.
J Org Chem ; 86(7): 5110-5119, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33724032

RESUMO

The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).


Assuntos
Benzodiazepinas , Substâncias Redutoras , Catálise , Ciclização , Estereoisomerismo
14.
Chem Commun (Camb) ; 56(16): 2499-2502, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32003369

RESUMO

Hydroxyl alkylation of indoles by Friedel-Crafts reaction with a carbonyl compound is a useful strategy. However, the reaction was restricted to ketones due to the easy formation of a bisindole byproduct. Therefore, hydroxyl alkylation of an aldehyde with indole is confronted with great challenges. Here, we report an efficient strategy for asymmetric hydroxyl alkylation of 2-substituted indoles with aldehydes under 0.1 mol% chiral phosphoric acid. A series of α-hydroxyl ketones were obtained in high yields (up to 99%) and good enantioselectivities (up to 97%).

15.
Org Biomol Chem ; 15(48): 10167-10171, 2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29184953

RESUMO

A three component reaction with two different ketones and aromatic amines was firstly investigated. The difference in reactivity between ordinary ketones and ketone esters allowed for the production of 1,2-DHQs efficiently. The possible Skraup reaction with 2 equiv. of the same ketones was prohibited due to the fast formation of imines.

16.
Chem Commun (Camb) ; 53(77): 10652-10655, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28905049

RESUMO

An unprecedented method that enables the direct coupling of an α-C-H bond in alcohols with 2-arylacetaldehydes through a [1,3]-hydride transfer ([1,3]-HT) of oxocarbenium ions catalyzed by a Lewis acid has been developed. The redox neutral preparation of the isochroman derivatives proceeds via a tandem condensation/[1,3]-HT/Friedel-Crafts sequence with moderate to good yields. Deuterium-labeling studies provide mechanistic insights and reveal that the redox functionalization proceeds via a [1,3]-HT.

17.
Org Lett ; 19(1): 58-61, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27934062

RESUMO

A novel Povarov-type reaction for straightforward synthesis of novel spiro bi-tetrahydroquinolines with readily available 1,2-DHQs (1,2-dihydroquinolines) and aromatic imines was developed. The reaction could be selectively stopped at the first stage under a Brønsted acid catalyst to afford the corresponding functionalized 1,2-DHQs conveniently.

18.
Org Lett ; 18(18): 4526-9, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27574098

RESUMO

In situ generation of the reactive amphoteric α-amino aldehyde with simple α-hydroxy ketones and phenylamine via Heyns rearrangement was proven to be feasible. Metal-free domino reactions based on this reactive intermediate were effectively used to afford important N-heterocycles including polysubstituted pyrroles, indoles, and quinoxalines conveniently. A simple starting material, water as the only byproduct, and diversity of the useful products will make this method greatly attractive for pharmaceutics.

19.
Chem Commun (Camb) ; 52(11): 2304-6, 2016 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-26727999

RESUMO

Tetrahydroquinolines () with an all-carbon quaternary stereocenter were effectively obtained via the in situ formation of aza-ortho-xylylene () with easily accessible 1,2-dihydroquinolines as precursors. The reaction was rationalized with chiral phosporic acid to afford chiral with high yield and excellent enantioselectivity.


Assuntos
Carbono/química , Quinolonas/síntese química , Catálise , Quinolonas/química , Estereoisomerismo
20.
Cancer Lett ; 371(1): 71-8, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26582657

RESUMO

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), ß-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.


Assuntos
Anticarcinógenos/farmacologia , Citocromo P-450 CYP1A2/metabolismo , Dieta , Imidazóis , Neoplasia Prostática Intraepitelial/prevenção & controle , Neoplasias da Próstata/prevenção & controle , Tocoferóis/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Anticarcinógenos/administração & dosagem , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP1A2/genética , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animais de Doenças , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Neoplasia Prostática Intraepitelial/induzido quimicamente , Neoplasia Prostática Intraepitelial/enzimologia , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tocoferóis/administração & dosagem , Tirosina/análogos & derivados , Tirosina/metabolismo
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