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1.
J Nat Prod ; 84(7): 1954-1966, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34170694

RESUMO

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triterpenos Pentacíclicos/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
J Nat Prod ; 83(9): 2578-2586, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32822186

RESUMO

Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a-1t, 2a-2l, and 3a-3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a-2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 µM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.


Assuntos
Imunossupressores/síntese química , Imunossupressores/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína-Tirosina Quinase ZAP-70/efeitos dos fármacos
3.
Org Biomol Chem ; 16(44): 8513-8524, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30357224

RESUMO

Baefrutones A-F (1-6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS2 investigation. Compounds 1-4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, 1H NMR integration) caused by the restricted rotation around the C-6-C-7-C-1' bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2'-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and ß-caryophyllene via a regioselective oxidative hetero-Diels-Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.

4.
J Nat Prod ; 80(8): 2204-2214, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28753309

RESUMO

Frutescones H-R (1-11), new sesqui- or monoterpene-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens. Their structures and absolute configurations were established by means of spectroscopic analyses (HRESIMS, 1D and 2D NMR, and ECD), as well as single-crystal X-ray crystallography of 1, (-)-7, and 9. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages, and the structure-activity relationships of 1-11 are also discussed. Compound 8 exhibited anti-inflammatory activity with an IC50 value of 0.36 µM, which might be related to the regulation of the NF-κB signaling pathway via the suppression of p65 nuclear translocation and the consequent decrease of IL-6 and TNF-α.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Myrtaceae/química , NF-kappa B/antagonistas & inibidores , Componentes Aéreos da Planta/química , Transdução de Sinais/efeitos dos fármacos , Terpenos/isolamento & purificação , Terpenos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anti-Inflamatórios/química , Cristalografia por Raios X , Interleucina-6/química , Lipopolissacarídeos/química , Macrófagos/química , Estrutura Molecular , NF-kappa B/química , Relação Estrutura-Atividade , Terpenos/química , Fator de Necrose Tumoral alfa/química
5.
J Org Chem ; 82(3): 1448-1457, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-28029250

RESUMO

Frutescone A-G [(1-6), (+)-7, (-)-7], a new group of naturally occurring tasmanone-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens L. Compounds 1 and 4 featured a rare carbon skeleton with an unprecedented oxa-spiro[5.8] tetradecadiene ring system, existing as two favored equilibrating conformers in CDCl3 solution, identified by variable-temperature NMR. The regioselective syntheses of 4-7 were achieved in a concise manner by a biomimetically inspired key hetero-Diels-Alder reaction "on water". Compounds 1, 4, and 5 exhibited moderate cytotoxicities in vitro.


Assuntos
Myrtaceae/química , Componentes Aéreos da Planta/química , Terpenos/isolamento & purificação , Estrutura Molecular , Estereoisomerismo , Terpenos/química
6.
J Asian Nat Prod Res ; 13(3): 238-41, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21409685

RESUMO

Two new phenylpropanoids, methyl 3-(2,4-dihydroxy-5-methoxyphenyl)propionate (1) and butyl 3-(2,4-dihydroxy-5-methoxyphenyl)propionate (2), and one unusual propanoate, 5-hydroxyhexyl 2-hydroxypropanoate (3), were isolated from the fruits of Morinda citrifolia. Their structures were established using MS and NMR methods.


Assuntos
Morinda/química , Fenilpropionatos/isolamento & purificação , Propionatos/isolamento & purificação , Frutas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenilpropionatos/química , Gomas Vegetais/química , Gomas Vegetais/isolamento & purificação , Propionatos/química , Vietnã
7.
J Plant Physiol ; 167(7): 534-9, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20022137

RESUMO

A known arabidopsis cDNA clone, the CRT/DRE binding factor 1 (CBF1), was isolated and introduced into tobacco plants. It has been reported that CBF1 is one member of CBF gene family related to low temperature and enhancing low temperature tolerance of plants. In the present work, the transcripts could be detected in the transgenic lines. The photochemical efficiency of PSII (F(v)/F(m)) and the photo-oxidizable P700 in the transgenic lines overexpressing CBF1 were higher than that in the wild type plants during the chilling stress under low irradiance. Similarly, the higher NPQ, higher qf, lower Phi(NF), higher activity of SOD, and lower content of MDA were also detected in the transgenic tobacco lines. Additionally, higher expression levels of Nicotiana tabacum copper/zinc superoxide dismutase (Cu/Zn SOD) were also detected in the transgenic lines. These results suggest that CBF1 protein plays an important role in protection of PSII and PSI during the chilling stress under low irradiance.


Assuntos
Proteínas de Arabidopsis/metabolismo , Temperatura Baixa , Nicotiana/metabolismo , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Transativadores/metabolismo , Antioxidantes/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Membrana Celular/metabolismo , Cloroplastos/metabolismo , Escuridão , Transporte de Elétrons , Fotossíntese , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Nicotiana/genética , Transativadores/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-17960044

RESUMO

LEAFY (LFY) gene plays an important role in determining plant flowering mainly by controlling the timing of phase transition. Constitutive under-expression of LFY in Arabidopsis resulted in the formation of a late-flowering and highly branching phenotype. In this paper, an RNAi approach was used in down-regulated LFY gene expression to delay Chinese cabbage (Brassica rapa L. ssp. pekinensis) bolting and flowering. The results show that transgenic plant has a later transition to the reproductive phase, and the transgenic plants have more branches, more leaves, but a lower height. Results of RQ-RT-PCR analysis show that LFY gene expression was greatly reduced in transgenic plants. These results suggest that inhibiting LFY gene expression by RNA interference can delay bolting in a cold-sensitive long-day (LD) condition. Late flowering of Chinese cabbage can be used as a good genetic resource for the breeding late-bolting Chinese cabbage.


Assuntos
Brassica/crescimento & desenvolvimento , Brassica/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/genética , Interferência de RNA/fisiologia , Southern Blotting , Genes de Plantas/genética , Modelos Genéticos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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