RESUMEN
Eight kaempferol oligosaccharides were isolated and identified from Camellia japonica seed cake. The chemical structures of the isolates were determined by using chromatographic and spectroscopic techniques, such as high-performance liquid chromatography with a photodiode array detector (HPLC-PDA), one-dimensional (1H and 13C), and two-dimensional nuclear magnetic resonance (1H-1H COSY, HSQC and HMBC), ESI-Q-TOF-MS, and optical rotation. To evaluate the anti-aging efficacy of kaempferol oligosaccharides for cosmetic use, the MMP-1 inhibitory effects of the isolates were studied using human dermal fibroblasts which were cultured in HaCaT cell-conditioned media. The MMP-1 inhibitory assay results revealed that kaempferol-3-O-ß-d-xylopyranosyl-(1 â 3)-α-l-rhamnopyranosyl-(1 â 6)-O-ß-d-glucopyranosyl-(1 â 2)-O-ß-d-glucopyranoside showed the most potent MMP-1 inhibitory activity. The basal level inhibition was 50 ppm, which indicated that C. japonica seed cake is a promising material for the development of anti-aging skin cosmetics.
Asunto(s)
Camellia/química , Fibroblastos/efectos de los fármacos , Quempferoles/farmacología , Metaloproteinasa 1 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Oligosacáridos/farmacología , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Quempferoles/síntesis química , Quempferoles/química , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Estructura Molecular , Oligosacáridos/síntesis química , Oligosacáridos/química , Semillas/química , Piel/efectos de los fármacos , Piel/metabolismoRESUMEN
Flavonoids are known for their wide range of bioactive properties including beneficial effect on bone formation. Their intense metal ion chelating capacity endorsed their nomination as a new biomaterial for biomedical applications. The present study examined the functional role of Kaemferal-Zinc(II) (Kaem-Zn) complex in bone formation, in vitro and in vivo. The cyto-compatibility assay confirmed that upto 25 µM of Kaem and Kaem-Zn complex was non-toxic. In fact, it facilitates ALP activity and accumulation of calcium in osteoblast; it was confirmed by Alizarin red and von Kossa staining. In addition to this, osteoblast markers, Runx2, type 1 col., ALP mRNAs expression, and osteocalcin and osteonectin secretory proteins level were also induced by the Kaem-Zn complex. Furthermore, bone forming ability of Kaem and Kaem-Zn was assessed by zebrafish model. The optimal concentration of Kaem and Kaem-Zn was determined by the viability assay of Zebrafish larvae. Osteoblasts distribution in scale, vertebrae and caudal fin ossification was studied by alizarin red staining accompanied by confocal imaging were carried out in adult zebrafish exposed to Kaem and Kaem-Zn complex. To sum up, our findings showed that Kaem promotes bone growth, and Kaem-Zn complex has further strengthened it. Kaem-Zn complex could be an effectively explored and used use in bone tissue engineering.
Asunto(s)
Quempferoles/administración & dosificación , Quempferoles/síntesis química , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Zinc/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Pez Cebra , Zinc/químicaRESUMEN
Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated Kae (Kae-SO3), gallium (Ga) complexes with Kae (Kae-Ga) and Kae-SO3 (Kae-SO3-Ga). The compound structures were characterized by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and thermal methods (TG/DSC). The results showed that a sulfonic group (-SO3) was successfully tethered on the C3' of Kae to form Kae-SO3. And in the metal complexation, 4-CO and 3-OH of the ligand participated in the coordination with Ga(III). The metal-to-ligand ratio 1:2 was suggested for both complexes. Interestingly, Kae-SO3-Ga was obviously superior to other compounds in terms of overcoming the poor water-solubility of free Kae, and the solubility of Kae-SO3-Ga was about 300-fold higher than that of Kae-Ga. Furthermore, the evaluation of antioxidant activities in vitro was carried out for Kae derivatives by using α,α-diphenyl-ß-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging. The results showed that Kae-SO3-Ga was also optimal for scavenging free radicals in a dose-dependent manner. These data demonstrate that sulfonate kaempferol-gallium complex has a promising future as a potential antioxidant and as a potential therapeutic agent for further biomedical studies.
Asunto(s)
Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Quempferoles/síntesis química , Quempferoles/farmacología , Agua/química , Compuestos de Bifenilo/química , Rastreo Diferencial de Calorimetría , Espectroscopía de Resonancia Magnética con Carbono-13 , Espectrometría de Masas , Picratos/química , Espectroscopía de Protones por Resonancia Magnética , Solubilidad , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Ácidos Sulfónicos/química , Temperatura , TermogravimetríaRESUMEN
A series of primary aminomethyl derivatives of kaempferol were synthesized by a combination strategy involving two steps of the Mannich reaction and SN2 nucleophilic substitution. The structures of the products show that the preferential aminomethylations are in the position C-6 or C-8 of the A-ring of kaempferol, especially the latter. Interestingly, the experimental data indicate that the intermolecular hydrogen bonding plays a key role in the formation of primary aminomethyl products of kaempferol. The formation of appropriate hydrogen bonds between strong nucleophilic amino acids and phenol is essential for the smooth reaction of the SN2 nucleophilic substitution. The SN2 mechanism hypothesis involving a hydrogen bond-assisted process was also supported by the density functional theory (DFT) analysis. An antiproliferative test of synthetic compounds shows the moderate to potent cytotoxic activity against three human cancer cell lines (HeLa, HCC1954, and SK-OV-3) by the CCK-8 assay. Compound 4e shows selective antiproliferative activity against HeLa cells with a low IC50 value (4.27 µm) and is worthy of further development. Another interesting result is that the maximum emission bands for most metal complexes are located at about 480 nm, but the ones for Tm and Yb complexes appear at about 533 nm.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Quempferoles/química , Quempferoles/farmacología , Aminación , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética/métodos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Enlace de Hidrógeno , Quempferoles/síntesis química , Metilación , Modelos Moleculares , Neoplasias/tratamiento farmacológicoRESUMEN
A novel water-soluble sulfated derivative, kaempferol-3'-sulfonate acid sodium (KS) with the composition of [C15 H9 O9 SNa]·2.5H2 O, was synthesized and characterized by elemental analysis, IR, (1) H NMR, (13) C NMR, and HRMS. Its protective effects on human vascular smooth muscle cells injured by hydrogen peroxide were evaluated by CCK-8 method, flow cytometry, and Western blotting. The experimental results indicated that the KS can significantly increase cell viability and reduce apoptosis on H2 O2 -injured VSMCs, as well as reverse the effects of H2 O2 on Bcl-2, Bad, and caspase-3 expressions. In addition, LDH leakage, MDA levels, and SOD and GSH activities were also measured with spectrophotometry. The results indicated that the KS acted as antioxidant preventing LDH leakage and MDA production, while increasing intracellular SOD and GSH activities. These findings revealed that KS might potentially serve as an effective antioxidant agent for prevention and treatment of vascular disease caused by H2 O2 -injured VSMCs.
Asunto(s)
Apoptosis/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Quempferoles , Músculo Liso Vascular/lesiones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Quempferoles/síntesis química , Quempferoles/química , Quempferoles/farmacología , L-Lactato Deshidrogenasa/metabolismo , Malondialdehído/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Kaempferide (3,5,7-trihydroxy-4'-methoxyflavone, 1), a naturally occurring flavonoid with potent anticancer activity in a number of human tumour cell lines, was first semisynthesized from naringin. Based on Mannich reaction of kaempferide with various secondary amines and formaldehyde, nine novel kaempferide Mannich base derivatives 2-10 were synthesized. The aminomethylation occurred preferentially in the position at C-6 and C-8 of the A-ring of kaempferide. All the synthetic compounds were tested for antiproliferative activity against three human cancer cell lines (Hela, HCC1954, SK-OV-3) by the standard MTT method. The results showed that compounds 1, 2 and 5-10 were more potent against Hela cells with IC50 values of 12.47-28.24 µM than the positive control cis-platin (IC50 41.25 µM), compounds 5, 6, 8 and 10 were more potent against HCC1954 cells with IC50 values of 8.82-14.97 µM than the positive control cis-platin (IC50 29.68 µM), and compounds 2, 3, 5, 6 and 10 were more potent against SK-OV-3 cells with IC50 values of 7.67-18.50 µM than the positive control cis-platin (IC50 21.27 µM).
Asunto(s)
Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales/métodos , Quempferoles/síntesis química , Bases de Mannich/química , Neoplasias de la Mama/patología , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular , Cisplatino/química , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Humanos , Concentración 50 Inhibidora , Quempferoles/farmacología , Modelos Químicos , Neoplasias Ováricas/patología , Temperatura , Neoplasias del Cuello Uterino/patologíaRESUMEN
Kaempferol-3-O-α-L-rhamanopyranosyl-(1'''-6'')-ß-D-glucopyranoside (1) (Nicotiflorin or kaempferol-3-O-rutinoside), isolated from the aerial parts of Osyris wightiana Wall. ex Wight, exhibited a potent antiglycation activity in vitro. A short and efficient route to kaempferol-3-O-rutinoside (1) is also described in this paper. To study the structure-activity relationship, few other derivatives of kaempferol were also evaluated for their antiglycation activity. Moreover the cytotoxicity analysis was also performed for these compounds. The Structure-Activity Relationship (SAR) studies showed that sugar derivatives of kaempferol possess a promising antiglycation activity.
Asunto(s)
Fibroblastos/efectos de los fármacos , Flavonoides/farmacología , Quempferoles/síntesis química , Quempferoles/farmacología , Fenoles/farmacología , Animales , Bovinos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Flavonoides/síntesis química , Flavonoides/química , Glicosilación/efectos de los fármacos , Quempferoles/química , Ratones , Estructura Molecular , Células 3T3 NIH , Fenoles/síntesis química , Fenoles/química , Albúmina Sérica Bovina/metabolismo , Relación Estructura-ActividadRESUMEN
Kaempferol 3-O-(3'',6''-di-O-E-p-coumaroyl)-ß-D-glucopyranoside (1), an optimal metabolite of Scots pine seedlings for protection of deep-lying tissue against damaging UV-B, represents a typical acylated flavonol 3-O-glycoside. This compound was synthesized for the first time via two approaches. The first approach, starting with kaempferol, featured formation of the flavonol 3-O-glycosidic linkage with a glycosyl bromide under conventional PTC conditions. In the second approach, 5,7,4'-tri-O-benzyl-kaempferol was readily prepared from 2',4',6'-trihydroxyacetophenone and p-hydroxybenzoic acid, which was coupled with a glucopyranosyl o-hexynylbenzoate under the catalysis of a gold(I) complex to provide the desired 3-O-glycoside in excellent yield. A variety of the glycosyl o-hexanylbenzoates equipped with the 2-O-benzoyl group were also proven to be highly efficient donors for construction of the flavonol 3-O-glycosidic linkages.
Asunto(s)
Benzoatos/química , Flavonoles/química , Glucósidos/síntesis química , Glicósidos/química , Quempferoles/síntesis química , Glucósidos/química , Glicosilación , Quempferoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
Phytochemical investigation of the leaves of Astragalus beckari yielded four flavonol aglycones, namely kaempferol, quercetin, 5-deoxy kaempferol and fisitin. These isolated compounds were then synthesised in the laboratory using the Algar-Flyn-Oyamad reaction. Antioxidant activity of both the isolated and synthesised flavonoids was compared using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay method. The isolated flavonoids were found to be more active.
Asunto(s)
Antioxidantes/metabolismo , Planta del Astrágalo/química , Flavonoles/química , Flavonoles/síntesis química , Quempferoles/síntesis química , Quempferoles/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Hojas de la Planta/química , Quercetina/síntesis química , Quercetina/químicaRESUMEN
Inappropriate activity of p90 ribosomal S6 kinase (RSK) has been implicated in various human cancers as well as other pathologies. We previously reported the isolation, characterization, and synthesis of the natural product kaempferol 3-O-(3'',4''-di-O-acetyl-alpha-l-rhamnopyranoside), termed SL0101 [Smith, J. A.; Poteet-Smith, C. E.; Xu, Y.; Errington, T. M.; Hecht, S. M.; Lannigan, D. A. Cancer Res., 2005, 65, 1027-1034: Xu, Y.-M; Smith, J. A.; Lannigan, D. A.; Hecht, S. M. Bioorg. Med. Chem., 2006, 14, 3974-3977: Maloney, D. J.; Hecht, S. M. Org. Lett., 2005, 7, 1097-1099]. SL0101 is a potent and specific inhibitor of RSK; therefore, we performed an analysis of the structural basis for the inhibitory activity of this lead compound. In in vitro kinase assays we found that acylation of the rhamnose moiety and the 4', 5, and 7-hydroxyl groups are responsible for maintaining a high affinity interaction of RSK with SL0101. It is likely that the hydroxyl groups facilitate RSK binding through their ability to form hydrogen bonds. To determine whether the SL0101 derivatives were specific for inhibition of RSK we analyzed their ability to preferentially inhibit the growth of the human breast cancer line, MCF-7, compared to the normal human breast line, MCF-10A. We have previously validated this differential growth assay as a convenient readout for analyzing the specificity of RSK inhibitors [Smith, J. A.; Maloney, D. J.; Clark, D. E.; Xu, Y.-M.; Hecht, S. M.; Lannigan, D. A. Bioorg. Med. Chem., 2006, 14, 6034-6042]. We found that acylation of the rhamnose moiety was essential for maintaining the selectivity for RSK inhibition in intact cells. Further, the efficacy of SL0101 in intact cells is limited by cellular uptake as well as possible hydrolysis of the acetyl groups on the rhamnose moiety by ubiquitous intracellular esterases. These studies should facilitate the development of a RSK inhibitor, based on the SL0101 pharmacophore, as an anti-cancer chemotherapeutic agent.
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Monosacáridos/química , Monosacáridos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas/metabolismo , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Alquilación , Benzopiranos/síntesis química , Línea Celular Tumoral , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hidroxilación , Quempferoles/síntesis química , Quempferoles/química , Quempferoles/farmacología , Modelos Moleculares , Estructura Molecular , Monosacáridos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Ramnosa/síntesis química , Ramnosa/química , Ramnosa/farmacología , Proteínas Quinasas S6 Ribosómicas/química , Relación Estructura-ActividadRESUMEN
A short synthesis of Kaempferitrin (1), a 3,7-diglycosylflavone, is reported. Key features include the synthesis of a protected form of kaempferol in which all four hydroxy groups are differentiated and the first bis-glycosylation of a dihydroxyflavone. This synthesis will allow the preparation of derivatives for further explorations into the origins of this compound's biological activity.
Asunto(s)
Quempferoles/síntesis química , Glicosilación , Quempferoles/química , Floroglucinol/químicaRESUMEN
The glycone part of the flavonoid triglycoside, kaempferol 3-O-beta-D-glucopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-galactopyranoside, has been synthesized in good yield and stereoselectivity using N-iodosuccinimide and HClO4-silica promoted glycosylations of thioglycoside donors.