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1.
Comput Struct Biotechnol J ; 23: 1408-1417, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38616962

ABSTRACT

Utilizing α,ß-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated kinact/ki for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRASG12C and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRASG12C and other similar targets.

2.
Chemistry ; 28(30): e202200264, 2022 May 25.
Article in English | MEDLINE | ID: mdl-35301762

ABSTRACT

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B2 pin2 ) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.


Subject(s)
Indolequinones , Indolequinones/chemistry , Metals , Nitriles , Pyridines
3.
Beilstein J Org Chem ; 17: 2822-2831, 2021.
Article in English | MEDLINE | ID: mdl-34925621

ABSTRACT

Chemoselective sulfonylation and isonitrilation reactions for the divergent synthesis of valuable diarylmethyl sulfones and isonitrile diarylmethanes starting from easy-to-synthesize para-quinone methides (p-QMs) and commercially abundant p-toluenesulfonylmethyl isocyanide (TosMIC) by using respectively zinc iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalysts were developed. The distinguishing feature of this method is that TosMIC plays a dual role from the same substrates in the reaction: as a sulfonyl source or as an isonitrile source. The synthetic utility of this protocol was also demonstrated in the synthesis of difluoroalkylated diarylmethane 5 and diarylmethane ketone derivatives 6 and 7, which are important core structures in natural products and medicines.

4.
Anal Bioanal Chem ; 412(28): 7685-7699, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32870351

ABSTRACT

Pathogen-host cell interactions play an important role in many human infectious and inflammatory diseases. Several pathogens, including Escherichia coli (E. coli), Mycobacterium tuberculosis (M. tb), and even the recent 2019 novel coronavirus (2019-nCoV), can cause serious breathing and brain disorders, tissue injury and inflammation, leading to high rates of mortality and resulting in great loss to human physical and mental health as well as the global economy. These infectious diseases exploit the microbial and host factors to induce serious inflammatory and immunological symptoms. Thus the development of anti-inflammatory drugs targeting bacterial/viral infection is an urgent need. In previous studies, YojI-IFNAR2, YojI-IL10RA, YojI-NRP1,YojI-SIGLEC7, and YojI-MC4R membrane-protein interactions were found to mediate E. coli invasion of the blood-brain barrier (BBB), which activated the downstream anti-inflammatory proteins NACHT, LRR and PYD domains-containing protein 2(NLRP2), using a proteomic chip conjugated with cell immunofluorescence labeling. However, the studies of pathogen (bacteria/virus)-host cell interactions mediated by membrane protein interactions did not extend their principles to broad biomedical applications such as 2019-nCoV infectious disease therapy. The first part of this feature article presents in-depth analysis of the cross-talk of cellular anti-inflammatory transduction signaling among interferon membrane protein receptor II (IFNAR2), interleukin-10 receptor subunit alpha (IL-10RA), NLRP2 and [Ca2+]-dependent phospholipase A2 (PLA2G5), based on experimental results and important published studies, which lays a theoretical foundation for the high-throughput construction of the cytokine and virion solution chip. The paper then moves on to the construction of the novel GPCR recombinant herpes virion chip and virion nano-oscillators for profiling membrane protein functions, which drove the idea of constructing the new recombinant virion and cytokine liquid chips for HTS of leading drugs. Due to the different structural properties of GPCR, IFNAR2, ACE2 and Spike of 2019-nCoV, their ligands will either bind the extracellular domain of IFNAR2/ACE2/Spike or the specific loops of the GPCR on the envelope of the recombinant herpes virions to induce dynamic charge distribution changes that lead to the variable electron transition for detection. Taken together, the combined overview of two of the most innovative and exciting developments in the immunoinflammatory field provides new insight into high-throughput construction of ultrasensitive cytokine and virion liquid chips for HTS of anti-inflammatory drugs or clinical diagnosis and treatment of inflammatory diseases including infectious diseases, acute or chronic inflammation (acute gouty arthritis or rheumatoid arthritis), cardiovascular disease, atheromatosis, diabetes, obesity, tissue injury and tumors. It has significant value in the prevention and treatment of these serious and painful diseases. Graphical abstract.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , High-Throughput Screening Assays/instrumentation , Lab-On-A-Chip Devices , Microbial Sensitivity Tests/instrumentation , Animals , Bacterial Infections/drug therapy , Bacterial Infections/immunology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokines/immunology , Drug Discovery/instrumentation , Drug Discovery/methods , Equipment Design , High-Throughput Screening Assays/methods , Humans , Microbial Sensitivity Tests/methods , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Small Molecule Libraries/pharmacology , Virion/drug effects , Virion/immunology , Virus Diseases/drug therapy , Virus Diseases/immunology
5.
J Org Chem ; 85(19): 12785-12796, 2020 10 02.
Article in English | MEDLINE | ID: mdl-32847359

ABSTRACT

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

6.
Org Biomol Chem ; 18(12): 2223-2226, 2020 03 25.
Article in English | MEDLINE | ID: mdl-32162639

ABSTRACT

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.

7.
Org Lett ; 21(20): 8169-8173, 2019 Oct 18.
Article in English | MEDLINE | ID: mdl-31430159

ABSTRACT

A transition-metal-free protocol for the difluoroalkylation of imidazopyridines with bromodifluoroaryl ketones promoted by visible light irradiation is presented. This protocol is distinguished by simple, mild, and catalyst-free reaction conditions with a wide reaction scope, which is complementary to existing difluoroalkylation strategies by photoredox scenarios. Additionally, this protocol potentially offers a new way for streamlining the synthesis of compounds containing the difluoro moiety.

8.
Chem Commun (Camb) ; 52(100): 14400-14403, 2016 Dec 13.
Article in English | MEDLINE | ID: mdl-27892551

ABSTRACT

A new method for the synthesis of 3-arylindoles has been developed by visible light mediated dual gold/photoredox catalysis. This transformation has many features such as cascade catalysis, high efficiency, redox-neutral reaction conditions and good functional group tolerance. The reaction proceeds through the photoredox-promoted formation of an electrophilic arylgold(iii) intermediate that undergoes coupling with the arylamine nucleophile.

9.
Chem Commun (Camb) ; 51(70): 13508-10, 2015 Sep 11.
Article in English | MEDLINE | ID: mdl-26215213

ABSTRACT

A novel visible light mediated radical cyclization of enol lactones with difluoroacyl arenes is presented. The reaction experienced a tandem radical cyclization and tolerated a wide range of substrates, resulting in fluorinated γ-butyrolactones in good chemical yield and with excellent diastereoselectivity.

11.
Org Biomol Chem ; 11(36): 6142-9, 2013 Sep 28.
Article in English | MEDLINE | ID: mdl-23925493

ABSTRACT

A simple approach for synthesis of novel aza-fused scaffolds such as pyrido[1,2-α]benzimidazoles and imidazo[1,2-α]pyridines was developed by Rh(III)-catalyzed direct oxidative coupling between alkenes and unactivated alkynes without an extra directing group. The method would allow a broad substrate scope, providing fused heterocycles with potential biological properties.


Subject(s)
Benzimidazoles/chemical synthesis , Organometallic Compounds/chemistry , Pyridines/chemical synthesis , Rhodium/chemistry , Benzimidazoles/chemistry , Catalysis , Molecular Structure , Pyridines/chemistry
12.
Org Lett ; 15(8): 1878-81, 2013 Apr 19.
Article in English | MEDLINE | ID: mdl-23537406

ABSTRACT

Double C-H activations of C(5)-H and Csp(2)-H of 2-substituted N-vinyl- or arylimidazoles were realized without heteroatom-directing assistance by rhodium(III) catalyst. A subsequent oxidative annulation reaction with alkynes efficiently produced aza-fused heterocycles with high molecular complexity in low to excellent yields.


Subject(s)
Alkynes/chemistry , Heterocyclic Compounds/chemical synthesis , Imidazoles/chemistry , Rhodium/chemistry , Catalysis , Cyclization , Heterocyclic Compounds/chemistry , Molecular Structure , Oxidation-Reduction , Stereoisomerism
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