RESUMEN
Practical synthesis and biological activities of 4-hydroxy-3-methoxy-2-propene derivatives are described. The novel chalcone derivatives were prepared by acid catalysed one-step condensation of 1,3- or 1,4-diacetylbenzene and 1,3,5-triacetylbenzene with 4-hydroxy-3-methoxybenzaldehyde. They were then evaluated for free radical scavenging activity, suppression of lipopolysaccharides (LPS)-induced NO generation, and anti-excitotoxicity in vitro. It was found that all compounds showed good effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, LPS-induced NO generation, and anti-neurotoxicity. Compounds 6 and 7 were potent suppressor of NO generation with the concentration range 10 µM and especially compound 8 showed very potent anti-inflammatory activity with 1 µM. In addition, the di- and tri-acetylbenzyl derivatives 6, 7, and 8 showed enhanced anti-neurotoxicity activity in cultured cortical neurons. Molecular modelling studies to investigate the chemical structural characteristics required for the enhanced biological activities interestingly revealed that compound 8 has the smallest highest occupied molecular orbital-lowest energy unoccupied molecular orbital (HOMO-LUMO) gap, which signifies easy electron and radical transfer between HOMO and LUMO in model studies.
Asunto(s)
Chalconas/síntesis química , Depuradores de Radicales Libres/síntesis química , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Compuestos de Bifenilo/química , Chalconas/química , Chalconas/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Lipopolisacáridos/farmacología , Neuronas/efectos de los fármacos , Óxido Nítrico/metabolismo , Picratos/químicaRESUMEN
The first total synthesis for large-scale production and anticancer activity of novel aminophenylpyridinium-5-(hydroxybenzoyl)hydrazonomethyl-2-oxothiazol-3-ide (PBHT) (1) and its derivatives are reported. The chemical structure of PBHT was unambiguously determined by utilization of the two-dimensional nuclear Overhauser effect (NOE) technique. The anticancer activity against human colon adenocarcinoma (HCT15) cells of all synthesized compounds was approximately four-fold greater than that of 5-fluorouracil, with IC50 values ranging from 10.1 to 14.2 µM. The three structural determinants of hydroxybenzoyl, hydrazinylidene, and pyridinium oxothiazole in the synthesized compounds could be indispensable for exhibiting anticancer activity.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Piridinio/química , Compuestos de Piridinio/farmacología , Tiazoles/química , Tiazoles/farmacología , Adenocarcinoma/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-ActividadRESUMEN
Daumone, a dauer-inducing pheromone and a series of lipid derivatives were synthesized from daumone to investigate structure-activity trends. Lipid derivatives demonstrated potent in vivo antiangiogenic activity on the chorioallantoic membrane, which exceeded that of fumagillin and thalidomide as reference agents. Among the 11 synthetic compounds tested, new derivatives 3, 11 and 13 showed the most potent antiangiogenic activity, which was twice that of fumagillin and thalidomide, replacing these as the most potent known antiangiogenic agents.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Membrana Corioalantoides/efectos de los fármacos , Ácidos Grasos/síntesis química , Ácidos Grasos/farmacología , Feromonas/síntesis química , Feromonas/farmacología , Inhibidores de la Angiogénesis/química , Animales , Embrión de Pollo , Pollos , Relación Dosis-Respuesta a Droga , Ácidos Grasos/química , Estructura Molecular , Feromonas/química , Relación Estructura-ActividadRESUMEN
The practical synthesis and anticancer activity of novel deoxoartemisinin-glycolipid hybrids, which incorporate two drugs into a single molecule and can impact multiple targets simultaneously are presented. These hybrids exhibited potent in vitro anticancer activity against several human cancer cell lines. The deoxoartemisinin-glycolipid hybrids generally demonstrated better anticancer activity than either artemisinin or daumone alone and cisplatin.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Artemisininas/farmacología , Glucolípidos/farmacología , Antineoplásicos/química , Artemisininas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glucolípidos/química , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 3,4,5-trimethoxycinnamic acid derivatives was prepared and evaluated for antinarcotic effects on morphine dependence in mice and binding affinities on serotonergic receptors. The key synthetic strategies involve generation of ketones 6-7, esters 9-12 through condensation reaction, and amides 13-19 via coupling reaction using 1-hydroxybenzotriazole/ethyl(dimethylaminopropryl)carbodiimide system in high yield. We found that the naloxone-induced morphine withdrawal syndrome was significantly suppressed by new synthetic 3,4,5-trimethoxycinnamic acid derivatives (20 mg/kg/day). Most of 3,4,5-trimethoxycinnamic acid derivatives were found to have high affinity to 5-HT(1A) receptor. The naloxone-induced morphine withdrawal syndrome was attenuated by (+)8-OH-DPAT (0.1 mg/kg/day, i.p.), a 5-HT(1A) receptor agonist. In cortical neuronal cells, (+)8-OH-DPAT (1 µM) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5-HT(1A) receptor-specific antagonist. Interestingly, the pERK levels were increased by the 3,4,5-trimethoxycinnamic acid derivatives and the derivatives-mediated changes in pERK levels were blocked by the WAY 100635. These results suggested that new synthetic 3,4,5-trimethoxycinnamic acid derivatives have a potential antinarcotic effect through acting as a 5-HT(1A) receptor agonist in mice.
Asunto(s)
Analgésicos/síntesis química , Cinamatos/química , Analgésicos/química , Analgésicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Células CHO , Células Cultivadas , Cinamatos/síntesis química , Cinamatos/farmacología , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Piridinas/química , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1/química , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
The total synthesis and structure determination of cis- and trans-flocoumafen was described. The key synthetic steps involve Knoevenagel condensation with p-methoxybenzaldehyde, in situ decarboxylation and intramolecular ring cyclization to construct the tetralone skeleton. Stereospecific reduction of the O-alkylated ketone 13 afforded good yield of precusor alcohol 5. Final coupling of alcohol 5 with 4-hydroxy-coumarin yielded flocoumafen (1). Separation and structure determination of cis- and trans-flocoumafen through 2D NMR analyses-assisted computer simulation techniques for the evaluation of anticoagulant activities are reported for the first time. This method is useful for generating the core tetralone skeleton of 4-hydroxycoumarin derivatives and provides a generalized access to various warfarin type anticoagulants.
Asunto(s)
4-Hidroxicumarinas/química , 4-Hidroxicumarinas/síntesis química , Productos Biológicos/química , Productos Biológicos/síntesis química , Alquilación , Anticoagulantes/química , Benzaldehídos/química , Ciclización , DescarboxilaciónRESUMEN
The synthesis and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides 1a-f as novel antinarcotic agents are described. The molecules were prepared by the Wittig reaction, followed by a coupling reaction between 3,4,5-trimethoxycinnamic acid (9) and aliphatic amines, which resulted in good yields. When tested for biological activity, compounds 1d-f exhibited strong inhibitory effects on the morphine withdrawal syndrome in mice due to their high binding affinities with serotonergic 5-HT1A receptors.
Asunto(s)
Acrilamidas/síntesis química , Acrilamidas/farmacología , Antagonistas de Narcóticos/síntesis química , Antagonistas de Narcóticos/farmacología , Acrilamidas/química , Acrilamidas/metabolismo , Animales , Células Cultivadas , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Antagonistas de Narcóticos/química , Antagonistas de Narcóticos/metabolismo , Ensayo de Unión Radioligante , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
An efficient synthesis involving a key aldol reaction and biological properties of 1,3-diphenyl-2-propen-1-ones 8- 20 is described. The in vitro activity for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging of 10 and 11 was 2 times higher than that for resveratrol. Compounds 9 and 11 were the strongest in suppression of in vitro nitric oxide (NO) generation and antiexcitotoxicity. Molecular modeling proposes an electron-donating group at the para position of acetophenones that leads to a dramatic increase in the suppression of NO production.