RESUMO
INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µ
Assuntos
Degranulação Celular , Mastócitos , Receptores de IgE , Transdução de Sinais , Quinase Syk , Animais , Mastócitos/imunologia , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Receptores de IgE/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Quinase Syk/metabolismo , Quinase Syk/antagonistas & inibidores , Interleucina-4/metabolismo , Liberação de Histamina/efeitos dos fármacos , Antígenos/imunologia , Antialérgicos/farmacologia , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Hipersensibilidade/tratamento farmacológicoRESUMO
A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.
Assuntos
Antineoplásicos , Isodon , Humanos , Antineoplásicos/farmacologia , Relação Estrutura-Atividade , Células HL-60 , Células HCT116RESUMO
A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.
Assuntos
Diterpenos , Quinonas , Extratos Vegetais , Quinonas/farmacologiaRESUMO
Retusone A (1), a new sesquiterpene dimer consisting of two guaiane-type sesquiterpenoids, and oleodaphnal (2) were isolated from heartwood of Wikstroemia retusa (Thymelaeaceae). The planar structure of 1 was elucidated on the basis of HRESIMS and NMR spectroscopic data, and the relative stereochemistry was established by X-ray diffraction analysis. The absolute configuration of 1 was determined by electronic circular dichroism. Compound 1 suppressed luciferase reporter gene expression driven by the HBO1 (histone acetyltransferase binding to ORC1) gene promoter in human breast cancer MCF7 cells. Compound 1 also decreased the expression of endogenous HBO1 mRNA and protein, and inhibited proliferation of the cells. These results suggest that retusone A (1), which has a unique dimeric sesquiterpenoid structure with inhibitory activity against HBO1 expression, may contribute to the development of a novel therapeutic candidate for the treatment of breast cancer.
Assuntos
Neoplasias da Mama , Sesquiterpenos , Wikstroemia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Histona Acetiltransferases/genética , Humanos , Estrutura Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos de Guaiano , Wikstroemia/químicaRESUMO
Cytotoxicity and apoptosis-inducing properties of compounds isolated from Garcinia subelliptica leaves were investigated. The hexane-soluble portion of MeOH extracts of G. subelliptica leaves that showed cytotoxic activity was separated to yield seven compounds 1-7. Chemical structure analysis using NMR spectroscopy and mass spectrometry confirmed that compound 1 was canophyllol, and compounds 2-7 were garcinielliptones N, O, J, G, F, and garcinielliptin oxide, respectively. Among them, garcinielliptone G (5) showed growth inhibition by causing apoptosis in THP-1 and Jurkat cells derived from human acute monocytic leukemia and T lymphocyte cells, respectively. Apoptosis induced by garcinielliptone G (5) was demonstrated by the detection of early apoptotic cells with fluorescein-labeled Annexin V and increases in cleaved caspase-3 and cleaved PARP protein levels. However, the addition of caspase inhibitor Z-VAD-FMK did not affect growth arrest or apoptosis induction. These results suggest that garcinielliptone G (5) can induce both caspase-3 activation and caspase-independent apoptosis. Therefore, garcinielliptone G (5) may be a potential candidate for acute leukemia treatment.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Garcinia/química , Triterpenos/química , Triterpenos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Leucemia , Células THP-1RESUMO
A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.
Assuntos
Extratos Vegetais/síntese química , Extratos Vegetais/farmacologia , Salvia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Trypanosoma brucei brucei/fisiologiaRESUMO
A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan-Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.
Assuntos
Peptídeos Cíclicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Oligopeptídeos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Raízes de Plantas/química , Conformação Proteica , Rubia/química , Relação Estrutura-AtividadeRESUMO
The oxygenated long-chain mycolic acids from many mycobacteria are characterized by the presence of mid-chain cyclopropane groups, which can have either cis-configuration or trans-configuration with an adjacent methyl branch. To determine the effect of these functional groups on mycolic acid conformation, surface pressure (π) versus mean molecular area isotherms of methoxy- (MeO-) mycolic acids (MAs) from Mycobacterium kansasii, Mycobacterium tuberculosis (Mtb) Canetti and Mtb H37Ra, and of keto-MAs from Mycobacterium avium-intracellulare complex (MAC) and Mtb H37Ra were recorded and analysed. The MeO- and keto-MAs from Mtb H37Ra, containing scarcely any trans-cyclopropyl groups, apparently took no fully folded 'W-form' conformations. Keto-MA from MAC, whose trans-cyclopropyl group content is nearly 90â%, showed a very solid W-form conformation. MeO-MAs from M. kansasii and Mtb Canetti gave stable W-form conformations at lower temperatures and surface pressures and extended conformations at higher temperatures and surface pressures; their W-form conformation was not as stable as expected from their cis-cyclopropyl group content, probably because they had a wide range of constituent homologues. Energy level calculations of cis- or α-methyl trans-cyclopropane-containing model molecules and computer simulation studies confirmed the superior folding properties of the latter functional unit. The present results were compared with those of MeO- and keto-MAs from Mtb and from M. bovis Bacillus Calmette-Guérin (BCG) reported previously. Among the oxygenated MAs, those having higher trans-cyclopropane content tended to take W-form conformations more firmly, implying that the meromycolate proximal intra-chain α-methyl trans-cyclopropane groups facilitated MA folding more than cis-cyclopropane groups.
Assuntos
Complexo Mycobacterium avium/química , Mycobacterium kansasii/química , Mycobacterium tuberculosis/química , Ácidos Micólicos/química , Simulação por Computador , Conformação Molecular , Ácidos Micólicos/isolamento & purificaçãoRESUMO
An aza-cycloisodityrosine analogue of RA-VII, 3, was designed and synthesized. The key aza-cycloisodityrosine unit was prepared by copper(II)-acetate-mediated intramolecular phenylamine/arylboronic acid coupling of dipeptide followed by connection with the tetrapeptide segment to afford a hexapeptide. Subsequent macrocyclization of the hexapeptide with EDC · HCl and HOOBt under dilute conditions gave 3. Analogue 3 showed significant cytotoxic activity against human promyelocytic leukemia HL-60 cells and human colon carcinoma HCT-116 cells, but its activity was weaker than that of parent peptide RA-VII (1).
Assuntos
Antineoplásicos Fitogênicos/química , Peptídeos Cíclicos/química , Peptídeos/química , Tirosina/análogos & derivados , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/toxicidade , Compostos Aza/química , Cristalografia por Raios X , Células HCT116 , Células HL-60 , Humanos , Conformação Molecular , Peptídeos/síntese química , Peptídeos/toxicidade , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/toxicidade , Rubia/química , Rubia/metabolismo , Tirosina/síntese química , Tirosina/química , Tirosina/toxicidadeRESUMO
Four new abietane diterpenoids (1-4), a new 9(10â20)-abeo-abietane diterpenoid (5), and a new sesquiterpene pyridine alkaloid (6) were isolated from the roots of Euonymus lutchuensis along with 19 known compounds. The structures of the new compounds were elucidated by interpretation of the spectroscopic data.
Assuntos
Abietanos/isolamento & purificação , Alcaloides/isolamento & purificação , Euonymus/química , Piridinas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Abietanos/química , Alcaloides/química , Japão , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Raízes de Plantas/química , Piridinas/química , Sesquiterpenos/químicaRESUMO
A new alkaloid, stemona-lactam S, and a known alkaloid, tuberostemospiroline, were isolated from the roots of Stemona tuberosa LOUR. (Stemonaceae). Their structures and absolute stereochemistry were established by X-ray crystallography and vibrational circular dichroism.
Assuntos
Alcaloides/química , Lactamas/química , Compostos de Espiro/química , Stemonaceae/química , Alcaloides/isolamento & purificação , Dicroísmo Circular , Cristalografia por Raios X , Lactamas/isolamento & purificação , Conformação Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Compostos de Espiro/isolamento & purificação , Stemonaceae/metabolismoRESUMO
Two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), were isolated from the roots of Rubia cordifoliaâ L. Their gross structures were elucidated on the basis of spectroscopic analysis and X-ray crystallography of compound 5. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the absolute stereochemistry of compound 6 by chemical correlation with deoxybouvardin (3). Comparison of the 3D structures of highly active RA-VII (1) with less-active compounds 4 and 5 suggests that the orientation of the Tyr-5 and/or Tyr-6 phenyl rings plays a significant role in their biological activity. The isolation of peptides 4-6, along with compound 3, and the comparison of their structures seem to indicate that peptide 6 may be the common precursor to bicyclic peptides 3-5 in the plant.
Assuntos
Peptídeos Cíclicos/síntese química , Rubia/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HL-60 , Humanos , Conformação Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Raízes de Plantas/química , Relação Estrutura-Atividade , Tirosina/químicaRESUMO
A reduced peptide bond analogue of RA-VII, [Tyr-5-Ψ(CH(2)NMe)-Tyr-6]RA-VII (3), was designed and synthesized. The key reduced cycloisodityrosine unit was prepared by reduction of the cycloisodityrosine derived from natural RA-VII, followed by connection with the tetrapeptide segment to afford a hexapeptide. Subsequent macrocyclization of the hexapeptide with FDPP under dilute conditions gave 3. Analogue 3 showed cytotoxic activity against P-388 cells, but its activity was much weaker than that of parent peptide RA-VII.
Assuntos
Antineoplásicos/síntese química , Descoberta de Drogas , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Peptídeos Cíclicos/farmacologiaRESUMO
Triptolide γ-lactone and C-14 analogues were prepared and evaluated cytotoxity against human lung adenocarcinoma epithelial A549 cells and human colon adenocarcinoma HT-29 cells. γ-Lactone substructure and C-14 substituents affected the biological activities significantly.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Diterpenos/síntese química , Diterpenos/farmacologia , Lactonas/síntese química , Fenantrenos/síntese química , Fenantrenos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/química , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Lactonas/química , Lactonas/farmacologia , Estrutura Molecular , Fenantrenos/químicaRESUMO
Penta-N-methyl and hexa-N-methyl analogues of RA-VII, an antitumor bicyclic hexapeptide of plant origin, were prepared. In the former, the nitrogens of d-Ala-1 and Ala-4 and in the latter, those of d-Ala-1, Ala-2, and Ala-4 were methylated under the phase-transfer catalysis conditions. Their solution structures were established by NOESY experiments and the crystal structures by X-ray crystallography. Those two methylated analogues showed much weaker cytotoxicity against P-388 leukemia cells than the parent RA-VII.
Assuntos
Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Humanos , Leucemia P388/tratamento farmacológico , Camundongos , Conformação Molecular , Rubia/químicaRESUMO
The 14-membered cycloisodityrosine is the core structure of RA-series antitumor bicyclic peptides obtained from Rubia plants (Rubiaceae). In this study, an efficient method for the synthesis of cycloisodityrosines from commercially available L-tyrosine derivatives was developed. Using synthetic cycloisodityrosines and cycloisodityrosines with modified structures, several RA-VII analogues were designed and synthesized to explore structure-activity relationships of the cycloisodityrosine moiety of the RA-series peptides, and newly isolated natural peptides were synthesized to establish their structures.
Assuntos
Rubia , Rubiaceae , Peptídeos Cíclicos , Relação Estrutura-AtividadeRESUMO
Labisia pumila var. alata (Myrsinaceae) or "Kacip fatimah" is a famous Malay traditional herb used for the maintenance of women's health. The extracts of L.pumila displayed estrogenic activity in rats. Nonetheless, the estrogenic bioactives were not identified. The aim of the study is to identify estrogenic compounds contributing to the established estrogenic activity. Bioactivity-guided-isolation method guided the isolation of pure bioactives. The hexane extract was subjected to a series of silica gel flash and open column chromatography with increasing amount of ethyl acetate in hexane or methanol in chloroform. Each fraction or pure compounds were evaluated on it's estrogen receptor (ER) binding activity with the fluorescence polarization competitive ERα and ERß binding assay kit. Cytotoxic assay using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method was used to establish the cytotoxic activity of the compounds. Four alkyl resorcinols and a dimeric 1,4-benzoquinone, namely belamcandol B (1), 5-pentadec-10'-(Z)-enyl resorcinol (2), 1,3-dihydroxy-5-pentadecylbenzene (3), 5-(heptadec-12'-(Z)-enyl) resorcinol (4) and demethylbelamcandaquinone B (5) were identified with selective binding affinities towards either ERα or ERß exhibiting selectivity ratio from 0.15-11.9. Alkyl resorcinols (2)-(4) exhibited cytotoxic activity towards HL60 cells with IC50 values from 19.5-22.0⯵M. Structural differences between compounds influence the binding affinities to ER subtypes. Further study is needed to establish the agonist or antagonist effect of these compounds on various tissues and to identify if these compounds exert cytotoxic activity through the ERs. When consuming L.pumila as a complementary medicine, careful consideration regarding it's estrogenic compound content should be given due consideration.
Assuntos
Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/efeitos dos fármacos , Estrogênios/farmacologia , Primulaceae/química , Benzoquinonas/isolamento & purificação , Benzoquinonas/farmacologia , Estrogênios/isolamento & purificação , Células HL-60 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Resorcinóis/isolamento & purificação , Resorcinóis/farmacologiaRESUMO
Two RA-series bicyclic hexapeptides, RA-XXV (4) and RA-XXVI (5), which have no N-methyl group at Tyr-5, were isolated from the roots of Rubia cordifolia L. Their amino acid compositions and sequences were determined by interpretation of MS, and 1D and 2D NMR data and their relative structures were elucidated by XRD analysis of 4 and RA-XXVI acetate (6). The absolute stereochemistry of 4 was established by the total synthesis of 4, and that of 5, by the chemical correlation with 4. Peptidesâ 4 and 5 exhibited cytotoxicity toward human promyelocytic leukemia HL-60 (IC50 =0.062 and 0.066â µm, respectively) and human colonic carcinoma HCT-116 (IC50 =0.028 and 0.051â µm, respectively) cell lines. Analysis of the conformational structures of 4 and 6 in the crystalline state and those of 4 and 5 in solution revealed that the N-methyl group at Tyr-5 functions to make this series of peptides preferentially adopt the active conformation.
Assuntos
Antineoplásicos Fitogênicos/química , Peptídeos Cíclicos/química , Rubia/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HL-60 , Humanos , Modelos Moleculares , Método de Monte Carlo , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Conformação ProteicaRESUMO
Phase diagrams of Langmuir monolayers of oxygenated mycolic acids, i.e. methoxy mycolic acid (MeO-MA), ketomycolic acid (Keto-MA), and artificially obtained deoxo-mycolic acid (deoxo-MA) from Mycobacterium bovis BCG were obtained by thermodynamic analysis of the surface pressure (pi) vs. average molecular area (A) isotherms. At lower temperatures and lower surface pressures, both Keto- and MeO-MAs formed rigid condensed monolayers where each MA molecule was considered to be in a 4-chain form, in which the three carbon chain segments due to bending of the 3-hydroxy aliphatic carboxylate chain and the 2-side chain were in compact parallel arrangement. At higher temperatures and surface pressures, MeO-MA and deoxo-MA tended to take stretched-out conformations in which the 3-hydroxy aliphatic carboxylate chain was more or less in an extended form, but Keto-MA retained the original 4-chain structure. The thickness measurement of the monolayers in situ by ellipsometry at different pi values and temperatures supported the above conclusions derived from the phase diagrams. The enthalpy changes associated with the phase transitions of MeO-MA and deoxo-MA implied that the MeO-MA needed larger energy to change from a compact conformation to an extended one, possibly and partly due to the dehydration of the methoxy group from water surface involved. Molecular dynamics studies of MA models derived from Monte Carlo calculations were also performed, which confirmed the conformational behavior of MAs suggested by the thermodynamic studies on the Langmuir monolayers.
Assuntos
Conformação Molecular , Mycobacterium bovis/química , Ácidos Micólicos/química , Oxigênio/farmacologia , Simulação por Computador , Propriedades de Superfície , Termodinâmica , Lipossomas Unilamelares/químicaRESUMO
A new bicyclic peptide of RA-series, RA-XVIII (3), was isolated from the roots of Rubia cordifolia L. Its structure was established to be a hydroxylated derivative of RA-VII by the semi-synthesis of 3 from deoxybouvardin, and its cytotoxicity against P-388 cells was 0.012 microg/mL.