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1.
Adv Sci (Weinh) ; : e2403470, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38970207

RESUMO

A Pd-catalyzed enantioselective aminosilylation of alkenes via tandem Aza-Heck/silylation reaction under Pd/Sadphos catalysis is disclosed. A wide array of oxime esters and silicon reagents are tolerated, furnishing the chiral pyrrolines bearing one quaternary or two contiguous stereocenters in good yield with high enantioselectivity. Not only terminal alkenes but also tri-substituented internal alkenes successfully participate in the reaction, delivering vicinal stereocenters in complete diastereoselectivity and high enantioselectivity. DFT study is conducted to probe the reaction pathway and the origin of the enantioselectivity, which revealed that the stereoinduction arises from the weak interaction between the aromatic ring of the substrate fragment and naphthyl group in the ligand.

2.
Angew Chem Int Ed Engl ; : e202407149, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38949229

RESUMO

This paper describes a concise, asymmetric and stereodivergent total synthesis of tacaman alkaloids. A key step in this synthesis is the biocatalytic Baeyer-Villiger oxidation of cyclohexanone, which was developed to produce seven-membered lactones and establish the required stereochemistry at the C14 position (92% yield, 99% ee, 500 mg scale). Cis- and trans-tetracyclic indoloquinolizidine scaffolds were rapidly synthesized through an acid-triggered, tunable acyl-Pictet-Spengler type cyclization cascade, serving as the pivotal reaction for building the alkaloid skeleton. Computational results revealed that hydrogen bonding was crucial in stabilizing intermediates and inducing different addition reactions during the acyl-Pictet-Spengler cyclization cascade. By strategically using these two reactions and the late-stage diversification of the functionalized indoloquinolizidine core, the asymmetric total syntheses of eight tacaman alkaloids were achieved. This study may potentially advance research related to the medicinal chemistry of tacaman alkaloids.

3.
Eur J Med Chem ; 276: 116668, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38996652

RESUMO

Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 µM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 µM, SI > 33144) compared to compound 3 (CC50 = 14.84 µM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.

4.
Org Lett ; 26(27): 5844-5849, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38950387

RESUMO

We have developed a highly regio-, diastereo-, and enantioselective Cu-catalyzed desymmetrization of inert meso-diethers using Grignard reagents. Moreover, previous inaccessible sterically hindered organometallic reagents are realized in the reaction with broad secondary alkyl Grignard reagents. Finally, detailed control experiments and density functional theory calculations revealed the desymmetrization of meso-diethers exploits a direct anti-SN2' pathway, in the absence of an in situ-generated allyl bromine intermediate. The following oxidative addition is the crucial rate-determining and enantioselectivity-determining step.

5.
ChemSusChem ; : e202401214, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39031513

RESUMO

Aftobetin is a non-invasive diagnosis probe of Alzheimer's disease, that can bind with aggregated ß-amyloid peptide in eye's lenses, used for early diagnosis of Alzheimer's disease in a rapid and painless mode. The reported synthesis of this probe fell short in the aspects of greenness and economy due to the involvement of toxic Chromium(IV) oxidant, noble palladium catalyst, elevated reaction temperature, the long reaction time as well as the cumbersome workup. Herein, a holistic optimization of the synthetic process was achieved via the employment of flow technology and heterogenous photocatalysis. Firstly, the integration of heterogenous carbon nitrides photocatalysis and circulation flow technology furnished the air oxidation of alcohol and nickel catalyzed C-N coupling at 20-g scale, thus avoiding the use of toxic Chromium and precious palladium species respectively. Flow-intensified esterification between acyl chloride and alcohol, just taking 30 seconds replaced the Steglich esterification of 6 hours, also avoiding the generation of difficult-to-remove dicyclohexylurea. Finally, C-N coupling, esterification and Knoevenagel condensation were telescoped together, thus simplifying the reaction workup. This fully-flow protocol led to the on-demand synthesis of eight probes.

6.
Chem Sci ; 15(22): 8280-8294, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38846404

RESUMO

The synthesis of enantiomerically pure compounds is a pivotal subject in the field of chemistry, with enantioselective catalysis currently standing as the primary approach for delivering specific enantiomers. Among these strategies, Cu-catalyzed asymmetric allylic substitution (AAS) is significant and irreplaceable, especially when it comes to the use of non-stabilized nucleophiles (pK a > 25). Although Cu-catalyzed AAS of prochiral substrates has also been widely developed, methodologies involving racemic/meso substrates are highly desirable, as the substrates undergo dynamic processes to give single enantiomer products. Inspired by the pioneering work of the Alexakis, Feringa and Gennari groups, Cu-catalyzed AAS has been continuously employed in deracemization and desymmetrization processes for the synthesis of enantiomerically enriched products. In this review, we mainly focus on the developments of Cu-catalyzed AAS with racemic/meso substrates over the past two decades, providing an explicit outline of the ligands employed, the scope of nucleophiles, the underlying dynamic processes and their practical applications.

7.
Angew Chem Int Ed Engl ; : e202409004, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837495

RESUMO

Previous N-glycosylation approaches have predominately involved acidic conditions, facing challenges of low stereoselectivity and limited scope. Herein, we introduce a radical activation strategy that enables versatile and stereoselective N-glycosylation using readily accessible glycosyl sulfinate donors under basic conditions and exhibits exceptional tolerance towards various N-aglycones containing alkyl, aryl, heteroaryl and nucleobase functionalities. Preliminary mechanistic studies indicate a pivotal role of iodide, which orchestrates the formation of a glycosyl radical from the glycosyl sulfinate and subsequent generation of the key intermediate, a configurationally well-defined glycosyl iodide, which is subsequently attacked by an N-aglycone in a stereospecific SN2 manner to give the desired N-glycosides. An alternative route involving the coupling of a glycosyl radical and a nitrogen-centered radical is also proposed, affording the exclusive 1,2-trans product. This novel approach promises to broaden the synthetic landscape of N-glycosides, offering a powerful tool for the construction of complex glycosidic structures under mild conditions.

8.
Org Biomol Chem ; 22(25): 5198-5204, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38864364

RESUMO

Mainly owing to their well-defined pore structures and high surface areas, metal-organic frameworks (MOFs) have recently become a versatile class of materials for enzyme immobilization. Nevertheless, most previous studies were focused on model enzymes such as cytochrome c, catalase, and glucose oxidase, with the application of MOF-derived biocomposites for (asymmetric) organic synthesis being rare. In the present work, the immobilization of the ketoreductase KmCR2 onto the zeolitic imidazolate framework (ZIF), a prominent type of MOF, was pursued using the controlled co-precipitation strategy, with a low 2-methylimidazole (2-mIM)/Zn molar ratio of 8 : 1 being employed. Such fabricated biocomposites denoted as KmCR2@ZIF were found to exist mainly in an amorphous phase, as suggested by the scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) data. Improved thermal and storage stabilities were observed for KmCR2@ZIF compared with the free enzyme. Stereoselective reduction of nine diarylmethanones 1 catalyzed by KmCR2@ZIF was performed, and the corresponding enantioenriched diarylmethanols 2 were afforded in 40-92% conversions with good to excellent optical purities (up to >99% ee). Critically, the current work demonstrated that the unique characteristic of KmCR2, namely the substituent position-controlled stereospecificity (meta versus para or ortho), was not altered upon the enzyme immobilization onto the ZIF.

9.
Int J Biol Macromol ; 274(Pt 2): 133345, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38944066

RESUMO

Engineering biocatalysts with enhanced stereoselectivity is highly desirable, and active-site loop dynamics play an important role in its regulation. However, knowledge of their precise roles in catalysis and evolution is limited. Here, we used the strategy of Rosetta enzyme design combined molecular dynamic simulations (MDs) to reprogram the landscapes of the key active-site loop dynamics of the carbonyl reductase LfSDR1 to improve stereoselectivity. The key flexible loop in the active site showed the potential to regulate the catalytic properties. A library of virtual variants was produced using the Rosetta design and assessed dynamic effect of the loop with the aid of MDs. A potential candidate was obtained with significant stereoselectivity (ee > 99 %) compared to the wild-type (ee = 42 %) without loss of catalytic activity or thermostability. The molecular basis of the catalytic property enhancement was flanked by MDs, which revealed the role of the G92L mutation in regulating loop dynamics to stabilize the environment of the active site. Finally, a series of the challenge bulky substrate derivatives were assessed using the G92L variant, and all showed improved stereoselectivity ee > 99 %. This study provides novel insights for improving stereoselectivity through rational engineering of the loop dynamics of biocatalysts.

10.
Org Lett ; 26(23): 4916-4920, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38821041

RESUMO

The present Letter demonstrates a photoswitched stereodivergent synthesis of allylic sulfones from sodium sulfinates, triphenylvinylphosphonium chloride, and (hetero)aromatic aldehydes in a single step. Mechanistically, cis-allylic sulfones, generated from the unstabilized ylide intermediates and aldehydes in situ, could be finally converted to trans-allylic sulfones via photochemical isomerization in the presence of a catalytic amount of bis(2-thienyl) ketone.

11.
Molecules ; 29(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38731613

RESUMO

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 µM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.


Assuntos
Fármacos Anti-HIV , Simulação de Acoplamento Molecular , Pirimidinas , Relação Quantitativa Estrutura-Atividade , Pirimidinas/química , Pirimidinas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Humanos , Simulação de Dinâmica Molecular , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/metabolismo , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Estrutura Molecular
12.
Org Biomol Chem ; 22(22): 4466-4471, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38771218

RESUMO

A palladium-catalyzed decarboxylative asymmetric [4 + 2] annulation of methyleneindolinones with a zwitterionic oxo-1,4-dipole intermediate was successfully developed to access spirocyclic oxindoles bearing two vicinal stereocenters in good yields with high diastereoselectivities and enantioselectivities. This strategy features a broad substrate scope (28 examples), allowing for efficient scale-up. Further selective transformation of the product and preliminary mechanistic studies were conducted.

13.
Bioorg Chem ; 148: 107495, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38805850

RESUMO

Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC50 value of 4.14 µM, which was about 5-fold increase in potency than the hit compound A1 (IC50 = 21.49 µM). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q2 = 0.658 and R2 = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H.


Assuntos
Desenho de Fármacos , HIV-1 , Simulação de Acoplamento Molecular , Pirimidinas , Relação Estrutura-Atividade , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Estrutura Molecular , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo
14.
Org Lett ; 26(22): 4818-4823, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38809781

RESUMO

We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.


Assuntos
Antivirais , Ciclopentanos , Guanina , Vírus da Hepatite B , Ciclopentanos/química , Ciclopentanos/síntese química , Catálise , Antivirais/química , Antivirais/síntese química , Estereoisomerismo , Estrutura Molecular , Guanina/química , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Ciclização , Paládio/química
15.
Molecules ; 29(9)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38731530

RESUMO

Hydroformylation of olefins is widely used in the chemical industry due to its versatility and the ability to produce valuable aldehydes with 100% atom economy. Herein, a hybrid phosphate promoter was found to efficiently promote rhodium-catalyzed hydroformylation of styrenes under remarkably mild conditions with high regioselectivities. Preliminary mechanistic studies revealed that the weak coordination between the Rhodium and the P=O double bond of this pentavalent phosphate likely induced exceptional reactivity and high ratios of branched aldehydes to linear products.

16.
Bioorg Chem ; 147: 107340, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38593532

RESUMO

In pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound 1. Compound 7ag also demonstrated comparable anti-HIV activity against both WT HIV and K103N, albeit with a marginal reduction in activity against E138K. Of significance, this analog showed augmented selectivity index (SI > 5368) relative to compound 1 (SI > 37764), Nevirapine (SI > 158), Efavirenz (SI > 269), and Etravirine (SI > 1519). Moreover, it displayed a significant enhancement in water solubility, surpassing that of compound 1, Etravirine, and Rilpivirine. To elucidate the underlying molecular mechanisms, molecular docking studies were undertaken to probe the critical interactions between 7ag and both WT and mutant strains of HIV-1 RT. These findings furnish invaluable insights driving further advancements in the development of DAPYs for HIV therapy.


Assuntos
Fármacos Anti-HIV , Compostos de Bifenilo , Desenho de Fármacos , Transcriptase Reversa do HIV , HIV-1 , Quinazolinas , Inibidores da Transcriptase Reversa , Solubilidade , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Farmacorresistência Viral/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade
17.
Nat Rev Chem ; 8(5): 304-318, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38575678

RESUMO

Stapling has emerged as a powerful technique in peptide chemistry. It enables precise control over peptide conformation leading to enhanced properties such as improved stability and enhanced binding affinity. Although symmetric stapling methods have been extensively explored, the field of non-symmetric stapling of native peptides has received less attention, largely as a result of the formidable challenges it poses - in particular the complexities involved in achieving the high chemo-selectivity and site-selectivity required to simultaneously modify distinct proteinogenic residues. Over the past 5 years, there have been significant breakthroughs in addressing these challenges. In this Review, we describe the latest strategies for non-symmetric stapling of native peptides, elucidating the protocols, reaction mechanisms and underlying design principles. We also discuss current challenges and opportunities this field offers for future applications, such as ligand discovery and peptide-based therapeutics.


Assuntos
Peptídeos , Peptídeos/química , Humanos
18.
Nat Prod Rep ; 41(7): 1060-1090, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38450550

RESUMO

Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.


Assuntos
Doença de Alzheimer , Produtos Biológicos , Inibidores da Colinesterase , Galantamina , Galantamina/síntese química , Galantamina/farmacologia , Galantamina/uso terapêutico , Galantamina/química , Doença de Alzheimer/tratamento farmacológico , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Estrutura Molecular , Humanos
19.
J Org Chem ; 89(7): 5038-5048, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38517950

RESUMO

A novel method is described for the synthesis of 2,4-disubstituted oxazole and thiazole derivates via the coupling of α-diazoketones with (thio)amides or thioureas using trifluoromethanesulfonic acid (TfOH) as a catalyst. This protocol is characterized by mild reaction conditions, metal-free, and simplicity and also features good functional group tolerance, good to excellent yields, and a broad substrate scope with more than 40 examples. Experimental studies suggest a mechanism involving 2-oxo-2-phenylethyl trifluoromethanesulfonate as the key intermediate.

20.
Org Lett ; 26(6): 1201-1206, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38308848

RESUMO

We developed an asymmetric decarboxylative allylic alkylation of vinylethylene carbonates with α-fluoro pyridinyl acetates through a synergistic palladium/copper catalysis. This protocol provides chiral allylic alcohol with carbon-fluorine quaternary stereogenic centers in good yield with good enantioselectivities and excellent regioselectivities. The utility of this approach was further demonstrated via a gram-scale experiment and derivatizations of the product.

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