RESUMO
Aervalanata possesses various useful medicinal and pharmaceutical activities. Phytochemical investigation of the plant has now led to the isolation of a new 2α,3α,15,16,19-pentahydroxy pimar-8(14)-ene diterpenoid (1) together with 12 other known compounds identified as ß-sitosterol (2), ß-sitosterol-3-O-ß-D-glucoside (3), canthin-6-one (4), 10-hydroxycanthin-6-one (aervine, 5), 10-methoxycanthin-6-one (methylaervine, 6), ß-carboline-1-propionic acid (7), 1-O-ß-D-glucopyranosyl-(2S,3R,8E)-2-[(2'R)-2-hydroxylpalmitoylamino]-8-octadecene-1,3-diol (8), 1-O-(ß-D-glucopyranosyl)-(2S,3S,4R,8Z)-2-[(2'R)-2'-hydroxytetracosanoylamino]-8(Z)-octadene-1,3,4-triol (9), (2S,3S,4R,10E)-2-[(2'R)-2'-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (10), 6'-O-(4â³-hydroxy-trans-cinnamoyl)-kaempferol-3-O-ß-D-glucopyranoside (tribuloside, 11), 3-cinnamoyltribuloside (12) and sulfonoquinovosyldiacylglyceride (13). Among these, six compounds (8-13) are reported for the first time from this plant. Cytotoxicity evaluation of the compounds against five cancer cell lines (CHO, HepG2, HeLa, A-431 and MCF-7) shows promising IC50 values for compounds 4, 6 and 12.
Assuntos
Abietanos/química , Amaranthaceae/química , Abietanos/isolamento & purificação , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
A new family of andrographolide analogues were synthesized and screened in vitro against kidney (HEK-293) and breast (MCF-7) cancer cells. The anti-cancer effects of the active analogues (2b, 2c and 4c) were determined by multiple cell based assays such as MTT, immunostaining, FACS, western blotting and transcriptional inhibition of NF-κB activity. Importantly, these compounds were found to possess higher anti-cancer potency than andrographolide and low toxicity to normal (VERO and MCF-10A) cells. Increased level of Bax/Bcl-xL ratio, caspase 3, and sub G1 population, higher expression level of tumor suppressor protein p53 and lower expression level of NF-κB suggested potent apoptotic property of the active analogues. Data revealed that the andrographolide derivative-mediated cell death in cancer cells was p53 dependent.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Diterpenos/síntese química , Diterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Diterpenos/química , Diterpenos/metabolismo , Glutationa/metabolismo , Meia-Vida , Humanos , Hidrólise , NF-kappa B/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
A 24-methylenecycloartane-3 ß, 16 ß, 23 ß-triol, Longitriol (1), rare bisclerodane imides, Longimide A (2) and previously known Longimide B (3) were isolated from ethanolic extract of the leaves of Polyalthia longifolia var. pendula. This is the first example of isolation of any cycloartane triterpene from this plant source. Structures were determined by extensive (1D and 2D NMR) spectroscopic data analysis combined with ESI MS/MS fragmentation and X-ray analysis. Furthermore, Compounds 1 and 2 were evaluated for their cytotoxic effects against four human cancer cell lines and found to be most active against cervical carcinoma cell lines with IC(50) value of 10.03 and 4.12 µg/mL, respectively.
Assuntos
Diterpenos/química , Polyalthia/química , Triterpenos/química , Linhagem Celular Tumoral , Diterpenos/isolamento & purificação , Diterpenos/toxicidade , Humanos , Isomerismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Folhas de Planta/química , Triterpenos/isolamento & purificação , Triterpenos/toxicidadeRESUMO
Generation of phosphocholine by choline kinase is important for phosphatidylcholine biosynthesis via Kennedy pathway and phosphatidylcholine biosynthesis is essential for intraerythrocytic growth of malaria parasite. A putative gene (Gene ID PF14_0020) in chromosome 14, having highest sequence homology with choline kinase, has been identified by BLAST searches from P. falciparum genome sequence database. This gene has been PCR amplified, cloned, over-expressed and characterized. Choline kinase activity of the recombinant protein (PfCK) was validated as it catalyzed the formation of phosphocholine from choline in presence of ATP. The K(m) values for choline and ATP are found to be 145+/-20 microM and 2.5+/-0.3 mM, respectively. PfCK can phosphorylate choline efficiently but not ethanolamine. Southern blotting indicates that PfCK is a single copy gene and it is a cytosolic protein as evidenced by Western immunoblotting and confocal microscopy. A model structure of PfCK was constructed based on the crystal structure of choline kinase of C. elegans to search the structural homology. Consistent with the homology modeling predictions, CD analysis indicates that the alpha and beta content of PfCK are 33% and 14%, respectively. Since choline kinase plays a vital role for growth and multiplication of P. falciparum during intraerythrocytic stages, we can suggest that this well characterized PfCK may be exploited in the screening of new choline kinase inhibitors to evaluate their antimalarial activity.
Assuntos
Colina Quinase/química , Plasmodium falciparum/enzimologia , Trifosfato de Adenosina/química , Sequência de Aminoácidos , Animais , Caenorhabditis elegans , Eritrócitos/metabolismo , Humanos , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Fosforilcolina/química , Conformação Proteica , Homologia de Sequência de AminoácidosRESUMO
The needles of Taxus wallichiana gave a taxoid 1-hydroxy- 2-deacetoxy-5-decinnamoyl-taxinine j, whose structure has been established by spectroscopic data and confirmed by X-ray crystallography. The taxoid possesses significant cytotoxic and immunomodulatory activity.
Assuntos
Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Taxoides/farmacologia , Taxus/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Concanavalina A/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Linfócitos/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Taxoides/química , Taxoides/isolamento & purificação , Vimblastina/farmacologia , Vincristina/farmacologiaRESUMO
The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.
Assuntos
Antimaláricos/farmacologia , Clotrimazol/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores do Crescimento/farmacologia , Heme/metabolismo , Hemeproteínas/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Peroxidases/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Animais , Antígenos de Protozoários/química , Catálise , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres , Glutationa/química , Heme/química , Hemeproteínas/química , Cinética , Peroxidação de Lipídeos , Espectrometria de Massas , Modelos Químicos , Nitrogênio/química , Estresse Oxidativo , Oxigênio/química , Peroxidases/química , Ligação Proteica , Espécies Reativas de Oxigênio , Espectrometria de Fluorescência , Espectrofotometria , Fatores de TempoRESUMO
Absolute configuration of taxiresinol 1, a lignan from the heartwood of Taxus wallichiana has been determined as 8R, 8'R, and 7'R with the help of chemical correlation method and X-ray crystallography. The anticancer activity of taxiresinol 1 and other two lignans 2, 3 were also studied. Taxiresinol 1 showed notable anticancer activity in the in vitro bioassays against colon, liver, ovarian and breast cancer cell lines.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Furanos/química , Furanos/farmacologia , Lignanas/química , Lignanas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Taxus/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Mono- and bis-benzo[b]oxepine derivatives have been rationally synthesized to meet the molecular requirement for interaction with estrogen receptor. Bis-benzo[b]oxepines (7 and 9) and mono-benzo[b]oxepine (10) acquire geometry with phenolic groups disposed in a fashion to stimulate estrogen receptor. Structure-based investigation, in vivo activity and docking studies have been described and correlated to demonstrate a practical approach for suitable ligand design.