Partial Methyl Ethers Research Articles

Synthesis, Bioactivities and In-silico Docking Studies of Azaleatin-A Quercetin Partial Methyl Ether: SAR Study

Background:During last two decades, good progress has been made for the flavonoids in metabolic and infectious diseases. However, expectations have not been fulfilled when these compounds were extended to the in vivo studies, particularly in humans. This could due to low bioavailability and less absorption of flavonoids in the biological systems. A recent study revealed that methylation of flavonoids can bring about dramatic changes in pharmacokinetic and biochemical properties. Often, the partially methylated flavonoids show better activities by improving their metabolic stability, membrane transport capacity, facilitating absorption and for oral bio-availability. Though, partial methyl ethers occupy a large chemical space, their biological properties has not been well established. Azaleatin (quercetin-5-O-methyl ether) is one of such group of naturally occurring molecules.Methods:In the present study, we have utilized methoxymethyl (MOM) protecting groups for the preparation of azaleatin. Synthesized compounds and their derivatives were subjected for α-Amylase and DPPH activities. α-Amylase activity can be measured in vitro by hydrolysis of starch in presence of α-amylase enzyme. Antioxidant capacity was evaluated by measuring the scavenging activity of azaleatin and related compounds on the 2,2- diphenyl-l-1-picrylhydrazil (DPPH) radical. In order to identify the binding mode of the compound azaleatin, Auto Dock Tools (http://mgltools.scripps.edu) were used.Results:Quercetin, along with their derivatives, monomethyl ethers i.e. azaleatin, isorhamnetin, tamarixetin; dimethyl ether i.e. quercetin-3,7-dimethyl ether; quercetin-3,3',7-trimethyletherpachypodol; quercetin-3,3',4'7-tetramethyl ether and quercetin pentamethyl ether were taken for α- amylase inhibitory activity. The study showed that azaleatin was found to be comparable with the standard for the inhibition of α-amylase amongst the tested compounds. Since, azaleatin is a best for the inhibition of α-amylase, this compound was taken for the in-silico molecular modelling studies. Azaleatin, showed a good docking energy (-8.8 Kcalmol-1) with the α-amylase receptor. Similarly, other closely related derivatives were studied for their antioxidant capacity. It was found that amongst the compound tested quercetin was found to be best (EC50 of 30µg/mL) for their antioxidant capacity and second best compound was azaleatin; which showed EC50 of 36.1µg/mL.Conclusion:An efficient synthesis of azaleatin, a lesser known flavone has been achieved from quercetin. Amongst the compounds tested, azaleatin was found to inhibit α-amylase with the acceptable radical scavenging activity. Further, in-silico modelling studies indicated that azaleatin found to have very good affinity with the key residues i.e. Gln63, Asp197 and Arg195 of α-amylase receptor. Since, azaleatin has other free hydroxyls in their template, it can be effectively utilized for the activity improvement through further structural modifications.

Biflavones of Dacrydium sensu lato

A survey of the biflavonyls in the leaves and branchlets of all three sections of the genus Dacrydium s.l. revealed a complex mixture of amentoflavone and its partial methyl ethers and hinokiflavone in most species. A group of three species in section C, however, were characterised by cupressuflavone derivatives as the major biflavone constituents. The results are used to discuss proposals for revised generic boundaries.

ChemInform Abstract: STUDIES OF TRITYLATED PENTOSES AND METHYL PENTOSES. I. THE O‐TRITYLATION OF METHYL α‐D‐FUCOPYRANOSIDE

Two trityl derivatives of fucose, methyl 2-O- (II) and 3-O-trityl α-D-fucopyranoside (III), were obtained in good yields by the reaction of methyl α-D-fucopyranoside (I) and trityl chloride in pyridine. The ratio of II and III in the reaction mixture was about 3 : 2. The structures were mainly established by NMR with appropriate derivatives. The gas chromatography-mass spectrometry of the partial methyl ethers of I was also discussed.

Studies of Tritylated Pentoses and Methyl Pentoses. I. The O-Tritylation of Methyl α-d-Fucopyranoside

Abstract Two trityl derivatives of fucose, methyl 2-O- (II) and 3-O-trityl α-d-fucopyranoside (III), were obtained in good yields by the reaction of methyl α-d-fucopyranoside (I) and trityl chloride in pyridine. The ratio of II and III in the reaction mixture was about 3 : 2. The structures were mainly established by NMR with appropriate derivatives. The gas chromatography-mass spectrometry of the partial methyl ethers of I was also discussed.

Constitution of the santalin pigments A and B

The heartwood of Pterocarpus santalinus contains two major red pigments, santalin-A and santalin-B which are partial methyl ethers of the same polyphenol (santalin). For locating the position of the methoxyl groups, alkali fission and permanganate oxidation of the mixed ethyl methyl ethers are the most convenient. By this method santalin-A has been shown to be 9,1O,12- tri- O-methylsantalin and santalin-B, 9,10,12,4′-tetra- O-methylsantalin.

Synthesis of naturally occurring partial methyl ethers of myricetin

The synthesis of combretol, annulatin, and europetin—naturally occurring partial methyl ethers of myricetin—is described. Condensation of 2, 4, 6-trihydroxy-ω-methoxyacetophenone with tri-O-methyl galloyl chloride or tri-O-benzyl galloyl chloride furnished the appropriate 3-methoxyflavones, which by a series of reactions furnished the natural myricetin derivatives.

Thin-layer chromatography of biflavonyls on silica gel : Structure—chromatographic behaviour correlations

The chromatographic behaviour of 28 biflavonyls, including partially and fully methylated ethers, has been examined in five solvent systems. Benzene—pyridine—formic acid (36:9:5) has been found to be the most satisfactory developing system both for identification and separation of the biflavonyls and their methyl ethers while benzene—pyridine—ethyl formate—dioxan (5:1:2:2) has been claimed best for fully methylated biflavonyls. Both solvent systems have been used for the first successful separation of biflavonyls and their methyl ethers by preparative thin-layer chromatography. Relative R F values coupled with variations in the shades of the spots developed by spraying with diazotised sulphanilic acid may be used for ascertaining, approximately, the extent of the methylation in partial methyl ethers of the same series. The characteristics shades of fully methylated biflavonyls in UV light have been found to provide a means for their quick and satisfactory identification. An attempt has been made to correlate the structure of biflavonyls and their methyl ethers with their chromatographic behaviour. Isomeric pairs of fully methylated biflavonyls involving different interflavonyl linkages, such as hinokiflavone (C4′OC8″, C4′OC6″), amentoflavone (C3′C8″, C3′C6″), cupressuflavone (C8C8″) and agathisflavone (C6C8″) have easily been distinguished and oriented.

Nuclear reduction in the 5-position of anthoxanthins

Partial methyl ethers of chrysin, apigenin, galangin and quercetin have been subjected to nuclear reduction in the 5-position through their tosyloxy compounds. The products are 7-methoxy flavone, pratol methyl ether, 3:7-dimethoxy flavone and fisetin tetramethyl ether respectively.

Partial methyl ethers of polyhydroxy coumarins

Earlier investigations have shown that partial methylation of the 7-position of 6∶7-dihydroxy coumarin is definitely possible. Claims were made by Schmid that in 5∶7-dihydroxy-4-methyl coumarin also partial methylation takes place in the 7-position. But no proof was provided. This has now been given by the ethylation of the partial methyl ether and subjecting it to nuclear oxidation and final ethylation. The product is found to be 7-methoxy-5∶6-diethoxy-4-methyl coumarin which has also been made by an independent and unambiguous method for purposes of comparison. The constitution of the partial methyl ether is thus established as 7-methoxy-5-hydroxy-4-methyl coumarin.

A new synthesis of asaronic acid and aldehyde and their derivatives

Asaronic acid is conveniently prepared from 4-O-methyl-β-resorcylic acid and isovanillic acid by oxidatron with alkaline persulphate and subsequent methylation. Useful partial methyl ethers and mixed methyl-ethyl ethers are also made by adopting this method. Similarly asarylic aldehyde is obtained from 4-O-methyl-β-resorcylic aldehyde and isovanillin.

Some important ethyl and ethyl-methyl ethers of flavonols

The use of ethylation in the study of naturally occurring glycosides and partial methyl ethers of hydroxy flavones is discussed. This procedure renders the work simpler and more definite. Starting from ω-ethoxy res-and phloracetophenones, the preparation of mixed ethyl methyl ethers of the flavonols, fisetin, kaempferol, and quercetin, with an ethoxyl in the 3-position and methoxyls in the other positions, is described and it is shown that these compounds are useful in the study of the 3-glycosides of these flavonols. The case of rutin has been used as a typical example.

Synthesis of some important partial methyl ethers of flavonols

The following three partial methyl ethers of flavonols which are derivatives of naturally occurring monoglucosides having only one free hydroxyl group have been conveniently synthesised by using the method of partial benzylation: (1) 3 ∶ 5 ∶ 4′-O-trimethyl-kaempferol derived from populnin and related glycosides, (2) 3 ∶ 5 ∶ 3′ ∶ 4′-O-tetramethyl quercetin derived from quercimeritrin and (3) 3 ∶ 5 ∶ 7 ∶ 3′ ∶ 4′-O-pentamethyl gossypetin derived from gossypin.

Formation of quinones by oxidative dealkylation

The observation of Bose and Nath regarding the fission of gardenin with alcoholic potash is confirmed. The formation of ω-methoxy-3∶6-dihydroxy-2∶5-quino-acetophenone (II) in this reaction constitutes an example of oxidative demethylation by means of alcoholic potash. The same compound can be obtained from methyl gardenin through the stages (III) and (IV). Analogous partial methyl ethers of flavones with a free 5-hydroxyl are resistant to this treatment.

Insecticidal properties and chemical constitution

A number of partial methyl ethers of hydroxy flavones and related compounds have been tested for toxicity to fish and the results are discussed with reference to structural characteristics. Calycopterin and its 4′-methyl ether are markedly toxic.