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1.
Org Biomol Chem ; 18(4): 687-693, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903473

RESUMO

The first total synthesis of a marine natural product, exigurin, has been accomplished in 13 steps starting from (+)-menthone. The key intermediate (-)-10-epi-axisonitrile-3 was prepared by stereoselective intramolecular cyclopropanation followed by a cyclopropane ring opening reaction by the azide anion. The bioinspired Ugi reaction of (-)-10-epi-axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and amino acid units were linked through an amide bond.


Assuntos
Produtos Biológicos/síntese química , Iminoácidos/síntese química , Sesquiterpenos/síntese química , Estereoisomerismo
2.
Biosci Biotechnol Biochem ; 84(4): 780-788, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31868104

RESUMO

Sesquiterpenoids are one of the most diverse groups in natural compounds with various chemical structures and bioactivities. In our previous work, we developed the chemoenzymatic oxygenation method based on the combination of Fe(II)-EDTA and ferric-chelate reductase that could synthesize (-)-rotundone, a key aroma sesquiterpenoid of black pepper. Fe(II)-EDTA catalyzed the oxygenation of sesquiterpene to sesquiterpenoid, and ferric-chelate reductase catalyzed the supply and regeneration of Fe(II)-EDTA in this system. We then investigated the effect of various Fe2+-chelates on the catalytic oxygenation of sesquiterpene and applied this system to the synthesis of odor sesquiterpenoids. We determined Fe(II)-NTA to be an efficient oxygenation catalyst by the screening approach focusing on ligand structures and coordination atoms of Fe2+-chelates. Valuable odor sesquiterpenoids such as (+)-nootkatone, (-)-isolongifolenone, and (-)-ß-caryophyllene oxide were oxygenatively synthesized from each precursor sesquiterpene by 66%, 82%, and 67% of the molar conversion rate, respectively.Abbreviations: EDTA: ethylenediaminetetraacetate; NTA: nitrilotriacetate; DTPA: diethylenetriaminepentaacetate; phen: o-phenanthroline; cyclam: 1,4,8,11-tetraazacyclotetradecane; TPA: tris(2-pyridylmethyl)amine; GlcDH: glucose dehydrogenase; HP-ß-CD: hydroxypropyl-ß-cyclodextrin.


Assuntos
FMN Redutase/metabolismo , Quelantes de Ferro/química , Oxigênio/metabolismo , Sesquiterpenos/síntese química , Catálise , Ciclodextrinas/metabolismo , Glucose 1-Desidrogenase/metabolismo , Ligantes
3.
Org Biomol Chem ; 17(45): 9703-9707, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701984

RESUMO

Parthenolide (PTL) strongly inhibits the detyrosination of microtubules and accelerates neuronal growth. In order to access cyclic ether derivatives of PTL, ring-closing metathesis (RCM) was investigated in comparison to intramolecular sulfone alkylation. Incompatibility of RCM with epoxides was found in this setting. Biological evaluation for tubulin carboxypeptidase inhibition indicated that the epoxide is crucial for parthenolide's activity.


Assuntos
Carboxipeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Éter/farmacologia , Microtúbulos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sesquiterpenos/farmacologia , Adulto , Carboxipeptidases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Éter/síntese química , Éter/química , Humanos , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade , Tanacetum parthenium/química
4.
Org Biomol Chem ; 17(30): 7140-7143, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31313801

RESUMO

This report features the first catalytic asymmetric total synthesis of a sesquiterpene, (+)-ar-macrocarpene (1), in 7 steps with 42.1% overall yields from commercially available inexpensive 5,5-dimethylcyclohexane 1,3-dione. This strategy relies on a key [3,3]-sigmatropic rearrangement effecting reductive transposition through allylic diazene rearrangement (ADR) in a single step from intermediate allylic alcohol (+)-12 under the Mitsunobu reaction conditions with o-nitrobenzenesulfonyl hydrazide (o-NBSH). Enantioselective reduction of α-bromo vinylogous ester 16 under the Corey-Bakshi-Shibata reduction conditions forges the required stereocenter in the allylic alcohol (+)-12 in a highly enantioenriched manner (95% ee).


Assuntos
Sesquiterpenos/síntese química , Estrutura Molecular , Sesquiterpenos/química , Estereoisomerismo
5.
Biosci Biotechnol Biochem ; 83(10): 1875-1883, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161886

RESUMO

(-)-Rotundone, a sesquiterpenoid that has a characteristic woody and peppery odor, is a key aroma component of spicy foodstuffs, such as black pepper and Australian Shiraz wine. (-)-Rotundone shows the lowest level of odor threshold in natural compounds and remarkably improves the quality of various fruit flavors. To develop a method for the synthesis of (-)-rotundone, we focused on non-heme Fe2+-chelates, which are biomimetic catalysts of the active center of oxygenases and enzymatic supply and regeneration of those catalysts. That is, we constructed a unique combination system composed of the oxidative synthesis of (-)-rotundone using the non-heme Fe2+-chelate catalyst, Fe(II)-EDTA, and the enzymatic supply and regeneration of Fe2+-chelate by ferric-chelate reductase, YqjH, from Escherichia coli. In addition, we improved the yield of (-)-rotundone by the application of cyclodextrin and glucose dehydrogenase to this system, and thus established a platform for efficient (-)-rotundone production.


Assuntos
FMN Redutase/química , Quelantes de Ferro/química , Odorantes , Sesquiterpenos/síntese química , Catálise , Ciclodextrinas/química , Glucose 1-Desidrogenase/química , Vinho/análise
6.
Org Lett ; 21(9): 3193-3197, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30995050

RESUMO

An asymmetric synthesis of C14-desmethylene corialactone D is described on the basis of strategic application of a metallacycle-mediated annulative cross-coupling reaction, a Still [2,3]-Wittig rearrangement, and Morken's hydroxyl-directed diboration reaction. While representing a convenient approach to access novel compositions of matter inspired by the sesquiterpenoid natural product class (including classic natural product synthesis targets including the picrotaxanes and dendrobine), these studies have led to the discovery of natural product-inspired agents that inhibit nerve growth factor (NGF)-mediated neurite outgrowth in PC-12 cells.


Assuntos
Alcaloides/síntese química , Lactonas/síntese química , Fator de Crescimento Neural/antagonistas & inibidores , Crescimento Neuronal/efeitos dos fármacos , Sesquiterpenos/síntese química , Alcaloides/farmacologia , Animais , Lactonas/farmacologia , Células PC12 , Ratos , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade
7.
Mar Drugs ; 17(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027184

RESUMO

Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1-2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by means of the coupling of the C10 cyclogeranyl moiety with the C5 3-(methylene)furan moiety. The key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers, their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group to afford the whole sesquiterpene framework. The enantioselective synthesis of the α-, 3,4-dehydro-γ- and γ-cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and different regioselective chemical transformations.


Assuntos
Técnicas de Química Sintética/métodos , Furanos/química , Furanos/síntese química , Sesquiterpenos/química , Sesquiterpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Isomerismo , Estereoisomerismo
8.
Nat Commun ; 10(1): 1892, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015442

RESUMO

The dimeric lindenane sesquiterpenoids are mainly isolated from the plants of Chloranthaceae family. Structurally, they have a crowded molecular scaffold decorated with more than 11 stereogenic centers. Here we report divergent syntheses of eight dimeric lindenane sesquiterpenoids, shizukaols A, C, D, I, chlorajaponilide C, multistalide B, sarcandrolide J and sarglabolide I. In particular, we present a unified dimerization strategy utilizing a base-mediated thermal [4 + 2] cycloaddition between a common furyl diene, generated in situ, and various types of dienophiles. Accordingly, all the three types of lindenane [4 + 2] dimers with versatile biological activities are accessible, which would stimulate future probing of their pharmaceutical potential.


Assuntos
Técnicas de Química Sintética , Magnoliopsida/química , Sesquiterpenos/síntese química , China , Reação de Cicloadição , Dimerização , Magnoliopsida/metabolismo , Estrutura Molecular , Extratos Vegetais/química , Sesquiterpenos/isolamento & purificação
9.
Mar Drugs ; 17(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736380

RESUMO

In this study, as part of our continuous search for environmentally-friendly antifoulants from natural resources, subergorgic acid (SA) was identified from the gorgonian coral Subergorgia suberosa, demonstrating non-toxic, significant inhibitory effects (EC50 1.25 µg/mL, LC50 > 25 µg/mL) against the settlement of Balanus amphitrite. To further explore the bioactive functional groups of SA and synthesize more potent antifouling compounds based on the lead SA, the structure-activity relationships of SA were studied, followed by rational design and synthesis of two series of SA derivatives (one being benzyl esters of SA and another being SA derivatives containing methylene chains of various lengths). Our results indicated that (1) both the double bond and ketone carbonyl are essential elements responsible for the antifouling effect of SA, while the acid group is not absolutely necessary for maintaining the antifouling effect; (2) all benzyl esters of SA displayed good antifouling effects (EC50 ranged from 0.30 to 2.50 µg/mL) with the most potent compound being 5 (EC50 0.30 µg/mL, LC50 > 25 µg/mL), which was over four-fold more potent than SA; and (3) the introduction of a methylene chain into SA reduces the antifouling potency while the length of the methylene chain may differently influence the antifouling effect, depending on the functional group at the opposite site of the methylene chain. Not only has this study successfully revealed the bioactive functional groups of SA, contributing to the mechanism of SA against the settlement of B. amphitrite, but it has also resulted in the identification of a more potent compound 5, which might represent a non-toxic, high-efficiency antifoulant.


Assuntos
Antozoários/química , Incrustação Biológica/prevenção & controle , Sesquiterpenos/química , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Thoracica/efeitos dos fármacos
10.
Eur J Med Chem ; 166: 445-469, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30739826

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive cancers with a high recurrence rate and rapidly acquired drug resistance among various breast cancer subtypes. There is no specific drug for treatment of TNBC. Discovery of therapeutic agents with unique modes of actions is urgently needed. In this study, a series of seventy parthenolide derivatives was designed, synthesized, and evaluated for their anti-TNBC activities. Compound 7d exhibited the most potent activity against different breast cancer cells with IC50 values ranging from 0.20 µM to 0.27 µM, which demonstrated 11.6- to 18.6-fold improvement comparing to that of the parent compound parthenolide with IC50 values of 2.68-4.63 µM. It is worth to note that 7d was more active than the positive control drug ADR. Moreover, compound 7d could induce apoptosis of SUM-159 cells through mitochondria pathway and cause G1 phase arrest of SUM-159 cells. These findings indicate that compound 7d deserves further studies as a lead compound for ultimate discovery of effective anti-TNBC drug.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sesquiterpenos/síntese química , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Sesquiterpenos/química , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 29(6): 782-785, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711391

RESUMO

2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células HCT116 , Humanos , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade
12.
Org Lett ; 21(4): 998-1001, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694066

RESUMO

A biomimetic, regio- and stereoselective approach to the 5,6,11-tricyclic core skeleton of xenovulene A, as well as sterhirsutins A and B, is described. The key steps are a biomimetic inverse-electron-demand hetero-Diels-Alder cycloaddition of α-humulene and a ribose-derived vinyl ketone, followed by acid-catalyzed rearrangement of the 1,3-dioxolane that neighbors the resultant cyclic enol ether.


Assuntos
Materiais Biomiméticos/química , Sesquiterpenos/síntese química , Reação de Cicloadição , Modelos Moleculares , Conformação Molecular , Sesquiterpenos/química
13.
Anal Chim Acta ; 1051: 169-178, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30661614

RESUMO

In this study, a novel biocompatible fluorescent probe (DN) capable of detecting ClO- in physiological medium was rationally designed and synthesized from natural and renewable isolongifolanone. This probe underwent a highly specific and sensitive oxidation reaction with ClO- and liberated an isolongifolanone derivative (PA) emitting intensive blue fluorescence. In response to ClO-, the fluorescence emission of DN was obviously enhanced within a short time. The detection limit of DN toward ClO- was found to be as low as 5.86 × 10-9 M. IR, MS and DFT calculation were employed to further confirm the sensing mechanism. Moreover, the test strips coated with DN could easily recognize ClO- from other relevant species through the changes of fluorescence color under 365 nm UV lamp. More importantly, we also successfully demonstrated the potential application of DN for the detection of intracellular hypochloritein living cells.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Ácido Hipocloroso/química , Limite de Detecção , Imagem Óptica/métodos , Sesquiterpenos/química , Animais , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Células RAW 264.7 , Sesquiterpenos/síntese química
14.
Bioorg Chem ; 85: 357-363, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30658235

RESUMO

In this paper, the mechanism of orobanone analogues formation via aromatization rearrangement of curcumol was minutely explored. Aromatization of curcumol with acetone under acidic condition was selected as the model reaction. The formation of a stable aromatic system was the driving force for this reaction. Based on the model reaction, other four new orobanone analogues were prepared through curcumol reacting with different carbonyl compounds. The results showed that the stability of carbocation, which was generated from the carbonyl compounds, and the steric hindrance were main factors affecting the aromatization. We also synthesized the analogue of aromaticane B using compound 2. In vitro anti-proliferative activity of some derivatives were tested by MTT assay. Two derivatives showed weak anti-tumor effect on two cancer cell lines (HepG2 and MCF7) under normoxia. Four orobanone analogue 2, 5, 6 and 9 significantly inhibited hypoxia-induced HIF-1 luciferase reporter activity in HeLa cells with the IC50 values of 13.6, 6.6, 2.4 and 18.2 µM, respectively.


Assuntos
Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fator 1 Induzível por Hipóxia/genética , Sesquiterpenos/síntese química , Transcrição Genética/efeitos dos fármacos
15.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669433

RESUMO

A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, α -epoxyarglabin, cytisinyl epoxyarglabin, 1 ß ,10 α -epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04⁻5.3 Å for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an α -methylene- γ -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.


Assuntos
Glutationa/metabolismo , Lactonas/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Sesquiterpenos/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo , Comunicação Celular , Humanos , Células Jurkat , Lactonas/síntese química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Sesquiterpenos/síntese química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Bioorg Chem ; 83: 348-353, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30399466

RESUMO

Bioactivity-guided fractionation of antileishmanial active CH2Cl2 phase of MeOH extract from leaves of Calea pinnatifida led to isolation of two sesquiterpene lactones calein C (1) and calealactone C (2), which structures were stablished on the basis of spectroscopic analysis. Compounds 1 and 2 displayed potent activity against Leishmania amazonensis promastigotes with EC50 of 1.7 and 4.6 µg mL-1, respectively. Compound 2 presented low cytotoxicity for J774 macrophages and displayed activity against amastigote forms of L. amazonensis similar to miltefosine with CC50 values of 31.73 and 27.18 µg mL-1, respectively. Additionally, compounds 1 and 2 caused ultrastructural changes in promastigotes leading to a loss of their classical structural morphology, as evidenced by electron microscopy. Also compound 2 decreased the mitochondria membrane potential. To the best of our knowledge, this is the first occurrence of 1 and 2 in C. pinnatifida. The results obtained highlighted the importance of studying sesquiterpene lactones isolated from Calea pinnatifida in terms of antileishmanial activity, in order to understand the mechanism of action of the isolated compounds in promastigotes forms of L. amazonensis.


Assuntos
Asteraceae/química , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Tripanossomicidas/farmacologia , Animais , Lactonas/síntese química , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/ultraestrutura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Sesquiterpenos/síntese química , Tripanossomicidas/síntese química
17.
Nat Prod Rep ; 36(2): 354-401, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30090891

RESUMO

Covering: 2006 to 2018 The application of the 6π-azaelectrocyclization of azatrienes as a key strategy for the synthesis of natural products, their analogs and related bioactive or biomedically-relevant compounds (from 2006 to date) is comprehensively reviewed. Details about reaction optimization studies, relevant reaction mechanisms and conditions are also discussed.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Compostos Aza/química , Ciclização , Agonistas dos Receptores Histamínicos/síntese química , Piperidinas/química , Piridinas/química , Pirróis/síntese química , Quinazolinas/síntese química , Quinolizinas/química , Sesquiterpenos/síntese química
18.
Nat Prod Rep ; 36(2): 263-288, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30215657

RESUMO

Covering: January 2012 to January 2018 Sesterterpenoids are a small family of terpenes that often possess intriguing biological profiles and complicated chemical structures. Their total syntheses are usually remarkably challenging, requiring methodological and strategic innovation. In this review, we summarize and discuss the total syntheses of sesterterpenoids published during the coverage period, and the key chemical transformations are highlighted.


Assuntos
Terpenos/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Sesquiterpenos/síntese química , Sesterterpenos/síntese química
19.
J Org Chem ; 83(24): 14843-14852, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30525614

RESUMO

Since the elucidation of the structure of anisatin in the late 1960s, sesquiterpene lactones from various Illicium species of plants have captivated synthetic chemists worldwide, resulting in a large body of synthetic work. In particular, Illicium sesquiterpenes containing the seco-prezizaane carbon framework have seen immense interest in recent years owing to desirable structural and medicinal attributes. This synopsis will focus on recently developed synthetic strategies to access these compact, highly oxidized terpenoids.


Assuntos
Illicium/química , Sesquiterpenos/química , Sesquiterpenos/síntese química , Técnicas de Química Sintética , Lactonas/química , Modelos Moleculares , Conformação Molecular , Compostos de Espiro/química
20.
Org Biomol Chem ; 16(48): 9454-9460, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30516781

RESUMO

Meroterpenoids isolated from guava (Psidium guajava) and Rhodomyrtus tomentosa possess special skeletons which incorporate terpenoids with phloroglucinol derivatives. Most of these meroterpenoids showed high cytotoxicity against cancer cell lines. However, their chemical diversity is very limited. Herein, we employed a biomimetic hetero-cycloaddition starting from ortho-quinone methides and an abundant natural product, ß-caryophyllene, to generate meroterpene-like compounds. Considering that the source plant has hyperglycemic functions, α-glucosidase was selected as a target for bioassay. Nine compounds were screened out for promising activities (IC50 < 15 µM), which were better than the positive controls genistein and acarbose. The best inhibitor 12 (IC50 2.73 µM) possesses two caryophyllene moieties. They represented a new type of skeleton possessing activities against α-glucosidase. The kinetic study exhibited that these inhibitors belong to a non-competitive type. All these inhibitors may provide an opportunity to develop a new class of antidiabetic agents.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Psidium/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , alfa-Glucosidases/metabolismo , Biomimética/métodos , Cristalografia por Raios X , Reação de Cicloadição/métodos , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Cinética , Modelos Moleculares , Sesquiterpenos/síntese química
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