Enzymatic inhibition studies of selected flavonoids and chemosystematic significance of polymethoxylated flavonoids and quinoline alkaloids in Neoraputia (Rutaceae)

Abstract

Nosso interesse quimiotaxonômico sobre Neoraputia nos estimulou a examinar N. paraensis, visando a busca de alcalóides. As frações foram monitoradas via RMN 1 H e ESI-EM/EM e foram analisadas somente aquelas cujos espectros apresentavam características de alcalóides do ácido antranílico e flavonóides não isolados anteriormente. Foram isolados do caule os alcalóides flindersina, skimmianina, 8-metoxiflindersina e dictamnina; das folhas os flavonóides 3',4',7,8-tetrametoxi-5,6-(2",2"-dimetilpirano)-flavona, 3',4',5,7,8-pentametoxiflavona, 5-hidroxi-3',4',6,7-tetrametoxiflavona, 3',4'-metilenodioxi-5,6,7-trimetoxiflavona e 5-hidroxi-3',4'-metilenodioxi-6,7-dimetoxiflavona,. Os alcalóides do ácido antranílico não foram encontrados em dez anos.Vários flavonóides isolados de N. paraensis, N. magnifica, Murraya paniculata, enxerto de Citrus sinensis (Rutaceae) e Lonchocarpus montanus (Leguminosae) foram testados frente a gliceraldeído-3-fosfato desidrogenase de Trypanosoma cruzi, visando verificar seus potenciais em inibir a atividade da enzima. Os flavonóides polimetoxilados e um isoflavonóide foram os mais ativos.Our taxonomic interest in the Neoraputia stimulated an investigation of N. paraensis searching for alkaloids. Fractions were monitored by 1 H NMR and ESI-MS/MS and only those which showed features of anthranilate alkaloids and flavonoids absent in the previous investigations were examined. Stems afforded the alkaloids flindersine, skimmianine, 8-methoxyflindersine and dictamnine; leaves yielded 3',4',7,8-tetramethoxy-5,6-(2",2"-dimethylpyrano)-flavone, 3',4',5,7,8-pentamethoxyflavone, 5-hydroxy-3',4',6,7-tetramethoxyflavone, 3',4'-methylenedioxy-5,6,7-trimethoxyflavone and 5-hydroxy-3',4'-methylenedioxy-6,7-dimethoxyflavone. The alkaloids have remained undiscovered for 10 years.A number of flavonoids isolated from N. paraensis, N. magnifica, Murraya paniculata, Citrus sinensis graft (Rutaceae), Lonchocarpus montanus (Leguminosae) were evaluated for their ability to inhibit the enzymatic activity of the protein glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi. Highly oxygenated flavones and isoflavone were the most actives.

Screening of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase enzyme inhibitors

“…Vieira et al (2001) showed the enzymatic activity of several plants of Rutaceae and Meliaceae families and thirteen coumarins isolated from different species, which are considered as one of the most promising class of substances with gGAPDH inhibitory activity. Moreover, the gGAPDH activity of several flavonoids isolated from Meliaceae, Rutaceae and Leguminosae plants, including pyrano chalcones, flavones, flavanones, flavonols and isoflavones, have also been reported (Tomazela et al, 2000;Moraes et al, 2003). Recently, Januário et al (2005) described the activity of 7-hydroxy-4',6-dimethoxyisoflavone on gGAPDH.…”

“…Thus, the activity of the studied extract (CFGH) ( Table 1) is probably related to the presence of the active flavones 2 and 3. However, their enzymatic activity were considered weak, particularly in comparison with chalepin, a coumarin isolated from Pilocarpus spicatus (Rutaceae), which reduced the gGAPDH activity by 75 % at 93 mmol/L (IC 50 = 64 mmol/L) (Vieira et al, 2001;Pavão et al, 2002;Menezes et al, 2003;Moraes et al, 2003;Leitão et al, 2004).…”

“…In this way, we have proposed the utilization of the glycolytic enzyme gGAPDH as a target for the search of new natural trypanocides (Tomazela et al, 2000;Vieira et al, 2001;Pavão et al, 2002;Moraes et al, 2003). In this paper, we report the gGAPDH inhibition activity of 46 crude extracts of Meliaceae and Rutaceae plants, along with three flavones isolated from an active fraction.…”

Chilean Pitavia more closely related to Oceania and Old World Rutaceae than to Neotropical groups: evidence from two cpDNA non-coding regions, with a new subfamilial classification of the family

“…Species of Flindersia , Zanthoxylum , Balfourodendron , and Euxylophora are sources of timbers. More recently, the antimicrobial and antifungal properties of rutaceous compounds are being exploited as natural pesticides (e.g., Oliva et al 2000), herbicides (e.g., Aliotta et al 1996), and antimicrobials (e.g., Mandalari et al 2007), while others are medically useful (e.g., Holmstedt et al 1979; Moraes et al 2003). …”

Planejamento de inibidores baseado em fragmentos moleculares para a enzima gliceraldeído-3-fosfato desidrogenase de Trypanosoma cruzi

“…As classes de produtos naturais que mostraram atividade de inibição da GAPDH são os flavonoides, com IC 50 entre 46 e 86 µM, 44 as coumarinas, com 13 moléculas testadas e IC 50 entre 64 e 617 µM, 45 dentre elas a chalepina, co-cristalizada com a TcGAPDH (estrutura de código PDB 1K3T), além de derivados de ácido anacárdico, com três moléculas ensaiadas e IC 50 entre 38 e 161 µM. 46 e as biantronas, com constante de afinidade, K i, igual a 27,3 µM.…”