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1.
Org Lett ; 25(19): 3456-3460, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37154475

RESUMO

Clavicipitic acid, a communesin alkaloid precursor, has attracted significant attention due to its unique azepino[5,4,3-cd]indole framework. Herein, we report a novel biomimetic synthesis of clavicipitic acid diastereomers by utilizing a DDQ-mediated cross-dehydrogenative coupling (CDC) reaction. The synthesis involves Suzuki coupling for the prenylation of a 4-bromotryptophan derivative, followed by an intramolecular CDC reaction to construct the azepinoindole core. The trans isomer was obtained as the major product, and the two diastereomers were separable. The CDC reaction conditions, including temperature, solvent, and protecting groups, were investigated, and a plausible mechanism for the observed diastereoselectivity was proposed.

2.
Sci Adv ; 9(14): eade9944, 2023 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-37027467

RESUMO

Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1-Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti-PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line-derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti-PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral , Linfócitos do Interstício Tumoral
3.
Angew Chem Int Ed Engl ; 62(9): e202215566, 2023 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-36583947

RESUMO

(-)-Antrocin (1), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol (2) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2. Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2. Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold.


Assuntos
Agaricales , Sesquiterpenos , Terpenos/metabolismo , Difosfatos , Agaricales/metabolismo , Anticorpos Anticitoplasma de Neutrófilos , Cinética , Sesquiterpenos/química , Pirofosfatases/metabolismo , Família Multigênica
4.
J Org Chem ; 88(1): 559-572, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36541794

RESUMO

We devised a new method for asymmetric cyclopropanation by employing (S)-(thiolan-2-yl)diphenylmethanol benzyl ether as an organocatalyst. Under optimal conditions, an in situ generated sulfur ylide reacts with (E)-chalcones via a Johnson-Corey-Chaykovsky reaction to afford a variety of cyclopropanes in excellent yields and stereoselectivities. This strategy employs low-environmental-risk reaction conditions and reusable catalysts. Hence, it is a green and efficient method for constructing cyclopropane scaffolds.


Assuntos
Chalconas , Éter , Estereoisomerismo , Etil-Éteres , Éteres , Ciclopropanos , Catálise
5.
Org Biomol Chem ; 20(43): 8405-8409, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36255332

RESUMO

The generation of sulfur-stabilized borenium cations by SnCl4, a halophilic Lewis acid, leads to the formation of oxathiaborolium pentachlorostannate, which is an excellent Lewis acid and is successfully used to catalyze the [2 + 2] cycloadditions of N-substituted maleimides and silyl enol ethers to afford cycloadducts with excellent enantioselectivities (17 examples, up to 96% ee). This efficient synthetic methodology provides a new viable and significantly efficient route to ring-fused cyclobutanes bearing quaternary stereogenic centers by combining pot, atom, and step economy to synthesize complex organic molecules.


Assuntos
Éteres , Ácidos de Lewis , Reação de Cicloadição , Estereoisomerismo , Catálise
6.
Chem Commun (Camb) ; 58(61): 8564-8567, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35815846

RESUMO

Herein, an enantioselective total synthesis of (-)-panduratin D, a novel secondary metabolite against human pancreatic PANC-1 cancer cell, from commercially available 3-methoxyphenol is reported. The synthesis was completed in nine steps and the key features include Sonogashira coupling, anionic Snieckus-Fries rearrangement, directed ortho metalation, tandem Si → C Alkyl rearrangement/Claisen-Schmidt condensation, and chiral boron complex-promoted asymmetric Diels-Alder cycloaddition. These endeavors could facilitate the biological studies of (-)-panduratin D and its analogs.


Assuntos
Estereoisomerismo , Reação de Cicloadição , Humanos
7.
Inorg Chem ; 60(21): 16266-16272, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34672549

RESUMO

A tricoordinate borenium ion has received considerable attention in recent years for its applications in Lewis acid catalysis. Over the years, asymmetric catalysis mediated by a chiral borenium ion has also been developed. To stabilize the electron-deficient boron atom, a series of chloroborane masked borenium ions featuring the symmetrical [B-Cl-B]+ linkage are prepared and utilized as the catalyst for the enantioselective Diels-Alder cycloaddition of cyclopentadiene and 2,2,2-trifluoroethyl acrylate. The presence of a Cp* ligand is critical in realizing the cyclic diboron compounds, and the stability of the resulting [B-Cl-B]+ cation is dependent on the steric bulkiness of the oxazolidinone moiety. The stereoselectivity of the Diels-Alder cycloaddition is controlled by the substituents of the chiral oxazolidinone ligand and could be further improved via the coordination of SnCl4 at the bridging chloride of the [B-Cl-B]+ cation.

8.
Org Lett ; 23(20): 8104-8108, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34612649

RESUMO

We report a new class of chiral tetrahydroselenophene based on (S)-diphenyl(tetrahydroselenophen-2-yl)methanol, which was prepared from (R)-3-(3-bromopropyl)-2,2-diphenyloxirane and sodium selenide. These chiral tetrahydroselenophene-based compounds were used to catalyze asymmetric cyclopropanation reactions; the selenonium ylide intermediates formed from these selenium-containing catalysts and benzyl bromide efficiently react with (E)-chalcones to give various cyclopropanes (27 examples) with excellent enantioselectivities of ≤99% ee and are the first examples of organoselenium-catalyzed asymmetric cyclopropanations.


Assuntos
Chalconas/síntese química , Ciclopropanos/química , Compostos Organosselênicos/química , Catálise , Chalconas/química , Estrutura Molecular
9.
Org Lett ; 23(17): 6760-6764, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34410733

RESUMO

The nascency of second-generation sulfur-stabilized borenium cations by halophilic Lewis acid SnCl4 leads to highly active chiral Lewis acids that are very effective catalysts for [4 + 2] cycloaddition. Oxathiaborolium pentachlorostannate (5-10 mol %) successfully catalyzed cycloaddition of various dienes and dienophiles to afford cycloadducts with excellent enantioselectivity (20 examples, up to 99% ee). This super Lewis acid also exhibited good enantioselectivity for the first Lewis acid coordinated and chiral Lewis acid catalyzed [4 + 2] cycloaddition to α,ß-unsaturated mixed ester amide.

10.
Org Lett ; 23(5): 1904-1909, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33570417

RESUMO

Meleagrin B is a terpene-alkaloid hybrid natural product that contains both the conidiogenone and meleagrin scaffold. Their derivatives show diverse biological activities. We characterized the biosynthesis of (-)-conidiogenone B (1), which involves a diterpene synthase and a P450 monooxygenase. In addition, an α,ß-hydrolase (Con-ABH) was shown to catalyze an aza-Michael addition between 1 and imidazole to give 3S-imidazolyl conidiogenone B (6). Compound 6 was more potent than 1 against Staphylococcus aureus strains.


Assuntos
Diterpenos/química , Imidazóis/química , Ovomucina/biossíntese , Estrutura Molecular , Ovomucina/química
11.
Proc Natl Acad Sci U S A ; 118(5)2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33452205

RESUMO

The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 µM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.


Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , SARS-CoV-2/efeitos dos fármacos , Adulto , Animais , Antivirais/química , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Reposicionamento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pandemias , Extratos Vegetais/farmacologia , SARS-CoV-2/genética , Células Vero
12.
Org Biomol Chem ; 18(43): 8899-8907, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33112336

RESUMO

Glucagon-like peptide-1 (GLP-1) signaling is an established therapeutic target for type 2 diabetes mellitus (T2DM). We developed a 7-step synthesis of N55, a positive modulator of GLP-1 signaling isolated from fenugreek (Trigonella foenum-graecum) seeds, with 29% overall yield, and we determined the absolute structure of N55 to be N-((3R,4R,5S)-4,5-dimethyl-2-oxotetrahydrofur-3-yl)linoleic amide.


Assuntos
Peptídeo 1 Semelhante ao Glucagon
13.
Angew Chem Int Ed Engl ; 59(32): 13537-13541, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32343875

RESUMO

The 1,3-enyne moiety is commonly found in cyclohexanoid natural products produced by endophytic and plant pathogenic fungi. Asperpentyn (1) is a 1,3-enyne-containing cyclohexanoid terpenoid isolated from Aspergillus and Pestalotiopsis. The genetic basis and biochemical mechanism of 1,3-enyne biosynthesis in 1, and other natural products containing this motif, has remained enigmatic despite their potential ecological roles. Identified here is the biosynthetic gene cluster and characterization of two crucial enzymes in the biosynthesis of 1. A P450 monooxygenase that has a dual function, to first catalyze dehydrogenation of the prenyl chain to generate a cis-diene intermediate and then serve as an acetylenase to yield an alkyne moiety, and thus the 1,3-enyne, was discovered. A UbiA prenyltransferase was also characterized and it is unusual in that it favors transferring a five-carbon prenyl chain, rather than a polyprenyl chain, to a p-hydroxybenzoic acid acceptor.


Assuntos
Alcinos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dimetilaliltranstransferase/metabolismo , Proteínas Fúngicas/metabolismo , Terpenos/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Dimetilaliltranstransferase/genética , Proteínas Fúngicas/genética , Fungos/enzimologia , Fungos/genética , Fungos/metabolismo , Estrutura Molecular , Família Multigênica
14.
Org Lett ; 22(8): 3302-3306, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32243182

RESUMO

(-)-Aurantioclavine (1), which contains a characteristic seven-membered ring fused to an indole ring, belongs to the azepinoindole class of fungal clavine alkaloids. Here we show that starting from a 4-dimethylallyl-l-tryptophan precursor, a flavin adenine dinucleotide (FAD)-binding oxidase and a catalase-like heme-containing protein are involved in the biosynthesis of 1. The function of these two enzymes was characterized by heterologous expression, in vitro characterization, and deuterium labeling experiments.


Assuntos
Azepinas/metabolismo , Alcaloides de Claviceps/biossíntese , Indóis/metabolismo , Oxirredutases/metabolismo , Azepinas/química , Biocatálise , Alcaloides de Claviceps/química , Indóis/química , Conformação Molecular , Oxirredutases/química , Penicillium/enzimologia , Triptofano/química , Triptofano/metabolismo
15.
J Med Chem ; 63(6): 3172-3187, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32125853

RESUMO

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Manutenção de Minicromossomo/metabolismo , Naftoquinonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Furanos/síntese química , Furanos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Chem Commun (Camb) ; 55(90): 13522-13525, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31650990

RESUMO

A mild and efficient combined-acid system using a zinc(ii) salt [ZnI2 or Zn(OTf)2] and p-toluene sulfonic acid (TsOH) was investigated for catalytic cationic cyclizations, including intramolecular hydrocarboxylation, hydroalkoxylation, hydroamination, hydroamidation, hydroarylation and polyene cyclizations. This reaction provides easy access to five- and six-membered O- and N-containing saturated heterocyclic compounds, tetrahydronaphthalene derivatives and polycyclic skeletons in excellent yield with perfect Markovnikov selectivity and under mild conditions. The operational simplicity, broad applicability, and use of inexpensive commercially available catalysts make this protocol superior to existing methodologies.

17.
Eur J Med Chem ; 181: 111584, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419740

RESUMO

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of ß-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and ß-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.


Assuntos
Quinolonas/química , Quinolonas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/química
18.
Org Lett ; 20(17): 5362-5366, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30148638

RESUMO

A highly efficient one-pot procedure was developed for the synthesis of various 2'-hydroxychalcones from phenyl diethylcarbamate, featuring consecutive Snieckus-Fries rearrangement, anionic Si → C alkyl rearrangement, and Claisen-Schmidt condensation in a single operation. The applicability of this protocol was demonstrated by the highly efficient synthesis of the anti-inflammatory natural product lonchocarpin. The mechanism insight is also provided.

19.
Cancer Sci ; 109(3): 832-842, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29285847

RESUMO

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents has become critical for lung cancer treatment. In this study, compound AS7128 was selected from a 2-million entry chemical library screening and identified as a candidate drug against non-small cell lung cancer in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and, thus, increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs through disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insight for using iASPP as a therapeutic target for non-small cell lung cancer treatment.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Repressoras/metabolismo , Tiazóis/administração & dosagem , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Ligação Proteica/efeitos dos fármacos , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Org Lett ; 19(1): 22-25, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27981849

RESUMO

The first reported sulfur-stabilized borenium cations were synthesized through halide abstraction of a haloborane intermediate by halophilic reagents. Different from the well-known cationic oxazaborolidines, a sulfide instead of an amine was used to not only simplify the preparation of the catalysts but also increase Lewis acidity of the boron atom. The in situ generated borenium salts showed exceptional Lewis acidity and successfully catalyzed asymmetric Diels-Alder reactions of cyclopentadiene and dienophiles in excellent yields and enantioselectivities. The NMR studies of these oxathiaborolium structures were reported as well.

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