Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties
Graphical abstract
Introduction
In recent years, many herbs and natural compounds have increasingly been receiving public interest as complementary and alternative medicines.1 World Health Organization (WHO) has urged the evaluation on the effectiveness of plant-based drugs due to the lack of scientific information.2
The natural Rutin (3′,4′,5,7-tetrahydroxyflavone-3-rutinoside) is one of the most attractive phytochemicals because of its pharmacological activities. Therefore, it is considered as an important flavonoid in pharmaceutical industry.3
Flavonoids are polyphenolic compounds that are found ubiquitously in plants. The flavonoids have aroused considerable interest because of their potential beneficial effects on human health; they have been reported to have antiviral, antiallergic, antiplatelet, anti-inflammatory, antitumor, prebiotic, antimicrobial and antioxidant activities.4, 5, 6, 7The flavonoids consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet.
Among them, Rutin (2-(3,4-dihydroxyphenyl)-4,5-dihydroxy-3-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxy-6 methyl-oxan-2-yl)oxy-methyl]oxan-2-yl]oxy-chromen-7-one) also known as quercitin-3-rutinoside or sophorin, is a flavonol glycoside containing the flavonol quercitin and the disaccharide rutinose. It is consumed in fruits, vegetables and plant-derived beverages such as tea and wine. It is abundantly found and distributed in plants such as in buckwheat seed, fruits, and fruits rinds, especially citrus fruits (orange, grape-fruit, lemon). Rutin displays cardiac protective, cholesterol- and blood pressure-lowering effects,8 also helps inflammation recovery,9 arthritis,10 and cancers.11
Natural products are frequently used for the development of novel actives to treat various bacterial infections. Different secondary metabolites such as flavonoids have shown significant antimicrobial properties.12 Rutin has shown potent antimicrobial activity against a wide range of pathogens, that is, bacteria, fungi, and viruses.13
Rutin has significant range scavenging properties on oxidizing species such as OH radical, superoxide radical, and peroxyl radical.14 Rutin has been reported to have clinical relevant functions, including antihypertensive, antihemorrhagic activity, the strengthening of the capillaries of blood vessels, the regulation of the capillary permeability, and the stabilization of platelets.6, 15 The inflammatory response is also an important component in the pathogenesis of vascular injury and endothelial dysfunction is related especially to leukocyte recruitment during formation of the vascular inflammatory lesion.16, 17 Two important mediators are involved in vascular inflammatory processes: tumor necrosis factor-α (TNF-α) and NF-kB which are factors belonging to same strictly regulate pathways. For instance, NF-kB is a well known proinflammatory transcriptional factor that is activated in response to proinflammatory cytokines such as TNF-α and interleukin 1β (IL-1β).18, 19 There is considerable evidence suggesting that suppression of NF-kB signaling pathway confers significant vascular protective effects which delays or prevents vascular diseases in animal models of disease.19, 20 Therefore, preventing the production of TNF-α and/or inhibiting TNF-α mediated NF-kB activation in vascular endothelial cells are considered to be promising therapeutic targets for vascular inflammatory diseases. Taken together, these properties are potentially beneficial in preventing and reducing peripheral capillary problems, mainly involved in water retention and capillary fragility thus encouraging topical applications.
Beside these properties, the major disadvantage associated with this molecule is the limited bioavailability, connected with its low liposolubility, that limits its practical applications21 in topical field.
Continuing our studies on phytochemicals bearing phenylpropanoids structure,22, 23 we modified Rutin in order to devise a semi-synthetic derivative liable to improve lipid solubility, while maintaining the characteristic polyphenol free hydroxyl moieties to express activity characteristic of the aglicone moiety. This properties are particularly interesting to the dermatology field, were biological properties of biophenols are often impaired by the poor lipophilicity, thus with difficulties in the distribution in topical formulation. For these reasons, Rutin and R2 were investigated for their stability in finished topical formulations. The biological activity was evaluated by preliminary model assays suitable to give indications on interesting polyphenols activities, namely antioxidant, anti-inflammatory, anti-proliferation, apoptosis induction and lastly antimicrobial infections that are particularly sensitive to permeability of the cell walls to antimicrobial agents.24, 25
Section snippets
Chemistry
Rutin was esterified at all hydroxyl moieties using propionyl chloride in presence of 4-dimethylaminopyridine (4-DMAP) and then selectively deacylated at the phenolic hydroxyl groups, using N,N,N-triethylamine (TEA) in methanol (Scheme 1). The selective removal of acyl groups from phenol moieties represented a difficult task because of the competition with the sugar one. After several trials satisfactory yields were obtained by the use of methanol in presence of TEA at room temperature. The
Conclusions
Rutin and its derivative R2 were investigated to explore the effect on activity profile and possible topical applications of lipidization by a propionyl side chain. Very interestingly, R2 maintained similar antioxidant capacity to the parent Rutin in PCL analysis (lipophilic environment) and ORAC test (hydrophilic environment). This demonstrates that the structural modification does not decrease efficacy toward oxidative species. By the formulation study, we have demonstrated that the
General
All reactives were from Sigma–Aldrich srl (Milan, Italy). Reaction course was routinely monitored by thin-layer chromatography on silica gel using precoated Macherey-Nagel Durasil-25 plates with detection under a 254-nm UV lamp and/or by spraying the plates with FeCl3 solution or potassium permanganate diluted solution. Column chromatography was performed with Macherey-Nagel 0.063–0.2 mm/70–230 mesh silica gel. The molecular weights of the compounds were determined by ESI (Micromass ZMD 2000),
Acknowledgements
S.M. thanks the Ministry of Education and Research of Italy (PRIN, Grant 20105YY2HL_006) and Ambrosialab srl, Italy for financial support and Elisa Durini and Alberto Casolari for NMR analysis. R.G. is supported by AIRC, Italy (contract IG 13575).
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