Methoxy Ether Research Articles

Enantioselective Total Synthesis of (+)-Alterbrassicicene C.

Herein, the first total synthesis of (+)-alterbrassicicene C (2) is described. Key features of the synthesis include an oxiranium mediated ether ring expansion, an oxa-Michael/retro-oxa-Michael cascade, and installation of a vinyl methoxy ether moiety via Stille coupling.

Hyperbranched Polyesters Based on Indole- and Lignin-Derived Monomeric Aromatic Aldehydes as Effective Nonionic Antimicrobial Coatings with Excellent Biocompatibility.

This research aims to investigate nonionic hyperbranched polyesters (HBPs) derived from indole and lignin resources as new nontoxic antimicrobial coatings. Three nonionic HBPs with zero to two methoxy ether substituents on each benzene ring in the polymer backbones were synthesized by melt-polycondensation of three corresponding AB2 monomers. The molecular structures and thermal properties of the obtained HBPs were characterized by gel permeation chromatography, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry analyses. These HBPs were conveniently spin-coated on a silicon substrate, which exhibited significant antibacterial effect against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). The presence of methoxy substituents enhanced the antimicrobial effect, and the resulting polymers showed negligible leakage in water. Finally, the polymers with the methoxy functionality exhibited excellent biocompatibility according to the results of hemolysis and MTT assay, which may facilitate their biomedical applications.

Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone.

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4-dimethoxy-5,8-bis[2-(2-methoxyethylamino)ethylamino]anthracene-9,10-dione) with methoxy ether containing side chains. Treatment of melanoma-bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.

ChemInform Abstract: Selective Methoxy Ether Cleavage of 2,6‐Dimethoxyphenol Followed by a Selective Acylation.

AbstractTreatment of (I) with AlCl3 and acyl chlorides at elevated temperature results in selective cleavage of one methoxy group followed by a regioselective acylation.

Selective methoxy ether cleavage of 2,6-dimethoxyphenol followed by a selective acylation

A Friedel–Crafts reaction of 2,6-dimethoxyphenol in the presence of aluminum chloride and propanoyl or butanoyl chloride, respectively, lead, at elevated temperatures, to a selective cleavage of one of the methoxy groups followed by a selective acylation of the meta position with respect to the phenolic hydroxyl group. Under the same reaction conditions 2-methoxyphenol does not get demethylated; a mechanism to account for these findings is proposed. This reaction gives access to a variety of ortho-acylated catechols. Substituted catechols are widely used in supramolecular chemistry and are precursors of pesticides, flavors, and fragrances. Additionally, catechol moieties are found in various natural products.

A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells

A 17β-estradiol (E 2) is hydrolyzed to 2-hydroxy-E 2 (2-OHE 2) and 4-hydroxy-E 2 (4-OHE 2) via cytochrome P450 (CYP) 1A1 and 1B1, respectively. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE 2 is predominantly formed in cancerous tissues. In this study, we investigated the inhibitory effects of chrysoeriol (luteorin-3′-methoxy ether), which is a natural methoxyflavonoid, against activity of CYP1A1 and 1B1 using in vitro and cultured cell techniques. Chrysoeriol selectively inhibited human recombinant CYP1B1-mediated 7-ethoxyresorufin- O-deethylation (EROD) activity 5-fold more than that of CYP1A1-mediated activity in a competitive manner. Additionally, chrysoeriol inhibited E 2 hydroxylation was catalyzed by CYP1B1, but not by CYP1A1. Methylation of 4-OHE 2, which is thought to be a detoxification process, was not affected by the presence of chrysoeriol. In human breast cancer MCF-7 cells, chrysoeriol did not affect the gene expression of CYP1A1 and 1B1, but significantly inhibited the formation of 4-methoxy E 2 without any effects on the formation of 2-methoxy E 2. In conclusion, we present the first report to show that chrysoeriol is a chemopreventive natural ingredient that can selectively inhibit CYP1B1 activity and prevent the formation of carcinogenic 4-OHE 2 from E 2.

Rhenium Calix[4]arenes: Precursors to Novel Imaging and Cancer Therapy Agents

AbstractInteraction of [ReOCl3(PPh3)2] with tert‐butylcalix[4]areneH4, Cax(OH)4, in the presence of MOtBu (M = Na, K), or MH, under anaerobic conditions affords the isostructural rhenium(V) oxo complexes [Re(O)(PPh3)Cax(O)4M(NCMe)2] · 4MeCN [M = Na, (1); K, (2)] containing an alkali‐metal cation within an elliptical ligand conformation. In the presence of air, the same reaction affords dioxo rhenium(VII) complexes of the form [Re(O)2Cax(O)4M(NCMe)2] [M = Na, · ca. 2.8MeCN (3); K, · 3MeCN (4)]. Prolonged heating also led to the isolation of the first examples of rhenium–rhenium bonding supported by calixarene ligands, viz. [ReCax(O)4M(NCMe)2(μ‐O)]2 · 4MeCN [M = Na, (5); K, (6)], and in one case to {ReCax(O)4K(NCMe)2[μ‐OK(NCMe)2]}2Cax(O)2(OH)2 · 7MeCN (7). The use of 2 as starting material led to the isolation of the complex {[Re(O)Cax(O)4K(NCMe)2]2(μ‐O)} · 2MeCN (8). Given the diversity and complexity of the products arising from these “oxo” reactions, attention was switched to the isoelectronic organoimido [NR] group, and given its synthetic utility, the tert‐butylimido group [NtBu] was chosen as our entry point. Reaction of [Re(NtBu)2Cl3] with Cax(OH)4 in a 1:1 ratio afforded the orange [Re(NtBu)2ClCax(O)2(OH)2]· MeCN (9), containing both a linear and a bent imido group. Increasing the amount of Cax(OH)4 (2:3 ratio) afforded both 9 together with the dark red complex [Re(NtBu)Cax(O)4Cax(O)(OH)3]· 6MeCN (10), which contains both mono‐ and tetra‐dentate calixarene ligands. In the presence of adventitious oxygen, the complex {[Re(NtBu)Cax(O)4]2(μ‐O)} · 3MeCN (11) was formed. To favour monomeric complex formation, the lithium salt of the monomethoxycalix[4]arene, namely Cax(OLi)3(OMe), was treated with [Re(NtBu)2Cl3] affording the mono‐ and bisacetonitrile‐ligated species [Re(NtBu)2Cax(O)4Li(NCMe)2][Re(NtBu)2Cax(O)4Li(NCMe)] · MeCN (12). To avoid the lithium incorporation of 12, Cax(OH)3(OMe) was treated with [Re(NtBu)3(OSiMe3)] affording [Re(NtBu)2Cax(O)3(OMe)] (13), for which the methoxy ether group protudes into the calixarene cavity. The compounds 1–13 have been structurally characterised by single‐crystal X‐ray diffraction (synchrotron radiation was used for 4, 6, 7, 9, 11–13).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

In vitro reactivation of sarin inhibited electric eel acetylcholinesterase by bis-pyridinium oximes bearing methoxy ether linkages

Bis-pyridinium oximes connected by methoxy alkane ether linker were synthesized and their in vitro reactivation efficacy was evaluated for sarin inhibited AChE. Reactivation efficacy of synthesized compounds was compared with 2-PAM and obidoxime. Among the synthesized compounds, 1,2-dimethoxy ethylene bis-[3,3'-(hydroxyiminomethyl) pyridinium] dichloride (3P-2) and 1,3-dimethoxy propylene bis-[3,3'-(hydroxyiminomethyl) pyridinium] dichloride (3P-3) were found to be most potent reactivators for AChE inhibited by nerve agent sarin. 3P-2 and 3P-3, respectively exhibited 80% and 69% regeneration of inhibited AChE, whereas 2-PAM (well known antidote for nerve agent poisoning) showed 42% regeneration.

Synthesis and characterisation of peripherally functionalised dendritic molecules

A number of peripherally functionalised dendritic molecules were synthesised in almost quantitative yield by a synthetic method involving the reaction between amines and isocyanates. The peripheral functional groups were incorporated by preparing a number of branched subunits, based on tris(hydroxymethyl)aminomethane (TRIS), 1, possessing three nitro, methoxy, methyl or maleimide terminal functionalities. Attachment of these branched units to the core molecules 4,4′-methylenebis(phenyl isocyanate)13 and 1,3,5-benzene triisocyanate20 afforded the corresponding dendritic molecules possessing 6 or 9 peripheral functional groups. Functional group conversions on the dendritic molecules have been successfully carried out, including hydrogenation of the terminal nitro to the corresponding amine and cleavage of the methoxy ether to give the corresponding phenol.

Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds ( 2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat α 1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human α 1- and α 2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the α 2- versus the α 1-ARs, affinities being the least at the α 1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six α-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human α 1A- and α 2A-AR subtypes indicate that a basic functional group is important for optimum binding to the α 1- and α 2A-adrenergic receptors.

Epoxidation–cyclization of rosewood oxides

AbstractThe epoxidation reaction of linalool by MCPBA led to two furanoid oxides (35.7 and 37.0%), known as rosewood oxides, two pyranoid oxides (2.4 and 1.9%) and four rosewood epoxide derivatives. Reaction with BF3‐MeOH of the epoxidized cis‐furanoid oxide allowed the isolation of a new bicyclic compound [2‐(methoxymethyl)‐1,4,4‐trimethyl‐3,8‐dioxabicyclo(3.2.1)octane], whereas the epoxidized trans‐furanoid oxide led to a new monocyclic diol methoxy ether [2‐(1‐hydroxy‐2‐methoxyethyl)‐5‐(1‐hydroxy‐1‐methylethyl)‐2‐methyltetrahydrofuran]. 2D‐NMR analyses were used for structure determination. Copyright © 2004 John Wiley & Sons, Ltd.

Analysis of the end groups of poly(methyl methacrylate)

Methyl methacrylate polymerization by potassium hydride results in macromolecules with the methyl starting group. A side-reaction occurs during the process leading to potassium methoxide. It serves as the second initiator of the polymerization and gives macromolecules with the methoxy starting group. All macromolecules possess the methine group at the chain end after protonation. Potassium alkalide K - , K + (15-crown-5) 2 produces various active centres in the initial step of the polymerization. It results in macromolecules with the methyl, ethyl, methoxy and vinyl ether starting groups. However, the majority of macromolecules are formed on the species with two active centres. The termination reaction takes place during the polymerization, therefore, not all chains have the methine end group after protonation.

A new environmentally stable protective group for deep UV resists: Methoxy(tetrahydropyranyl) ether

Deep UV photoresists are designed to be used in the manufacturing of highly integrated chips (>16 Mbit). They differ from the conventional photoresists in their principal chemistry. The vast majority of positive deep UV resists are based on protected poly(hydroxystyrene) resins and photochemical acid generators (PAG). They rely on photochemically induced acid-catalyzed reactions (chemical amplification) to generate the desired pattern and meet the high-sensitivity requirements. It turned out that the type of the acid labile protective group is of paramount importance for the performance of the resists. It has to be stable enough not to be cleaved by the weakly acidic phenol at room temperature, but has to be labile enough to be cleaved readily even at the top of the resist where portions of the generated acid may be neutralized by airborne bases. Selection criteria for useful groups and the performance of the very well suited protective group methoxy(tetrahydropyran) are described in this paper. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 208–216, 2000

Carbocyclic α-amino acids: asymmetric synthesis of all four 1-amino-2-hydroxycyclohexanecarboxylic acids

Starting from racemic 2-methoxycyclohexanone and ( S)- or ( R)-1-phenylethylamine, respectively, the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acid are obtained via an asymmetric Strecker synthesis with ee values ranging from 87 to 98%. Their stereochemistry is established by NMR methods and by X-ray analyses. Hydrogenolysis of a benzylic C–N bond by conc. sulphuric acid as well as cleavage of a methoxy ether by conc. HCl are two intriguing reactions which are observed within the five-step procedure described herein.

Synthesis of the equine estrogen metabolites 2-hydroxyequilin and 2-hydroxyequilenin.

Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols which are further oxidized to electrophilic/redox active o-quinones which have the potential to both initiate and promote the carcinogenic process. In this investigation, we have synthesized potential metabolites of equilin and equilenin, 2-hydroxyequilin and 2-hydroxyequilenin, respectively, as well as their methyl ether metabolites. These compounds were synthesized from commercially available optically pure equilin via a practical and efficient approach; five steps gave 2-methoxyequilin from which 2-hydroxyequilin was prepared by BBr3-catalyzed demethylation in one step. Similarly, treating 2-methoxyequilin with SeO2 followed by demethylation with BBr3 produced 2-hydroxyequilenin. The structures of the catechols as well as those of their methoxy ethers were unambiguously characterized by one-dimensional and two-dimensional NMR experiments, including 1H, 13C, APT, COSY, HMBC, and HMQC as well as mass spectrometry.

Synthesis of Enantiomerically Pure Thiocrown Ethers Derived from 1,1'-Binaphthalene-2,2'-diol.

Synthetic methodology is given for the preparation of two different types of thiocrown ethers from optically pure 1,1'-binaphthalene-2,2'-diol (10). The conceptually simplest approach starts from optically pure 10 itself, which is alkylated (4 equiv of K(2)CO(3) in DMF at 110 degrees C) with 2-chloroethanol followed by mesylation to provide 2,2'-bis(2-(mesyloxy)ethoxy)-1,1'-binaphthyl (14). When allowed to react with ethane-1,2-dithiol, propane-1,3-dithiol, 1,4,7-trithiaheptane, 1,4,8,11-tetrathiaundecane, 2,2-dimethylpropane-1,3-dithiol, 2-(mercaptomethyl)-1-propene-3-thiol, and 1,2-benzenedithiol in the presence of Cs(2)CO(3) in DMF at 60 degrees C the corresponding thiocrown ethers 22-25, 28, 30, and 32 are formed in 30-54% yields. Test reactions were carried out to establish that no racemization occurs during alkylation under these conditions. Reaction of optically pure 10 with tetrahydropyranyl (THP)-protected 3-chloropropanol under similar conditions for the preparation of 14 proceeded more sluggishly but cleanly. Removal of the THP protecting groups afforded 2,2'-bis(3-bromopropoxy)-1,1'-binaphthyl (20), which on reaction with propane-1,3-dithiol, 1,5,9-trithianonane, 2,2-dimethylpropane-1,3-dithiol, 2-(mercaptomethyl)-1-propene-3-thiol, and 1,2-bis(mercaptomethyl)benzene provided the respective thiocrown ethers 26, 27, 29, 31, and 33 in 24-68% yields. Another class of thiocrown ethers was prepared from optically active 10, which was converted via ortho-lithiation to 3,3'-bis(bromomethyl)-2,2'-dimethoxy-1,1'-binaphthyl (39) by means of methylation (K(2)CO(3)/CH(3)I), ortho-lithiation followed by formylation (n-C(4)H(9)Li/N,N,N',N'-tetramethylethylenediamine (TMEDA)/ether followed by DMF and H(2)O workup) followed by reduction (NaBH(4)) followed by bromination (PBr(3) in C(5)H(5)N). Reaction (Cs(2)CO(3) in DMF at 60 degrees C) with 1,4,7-trithiaheptane, 1,4,8-trithiaoctane, 1,4,7,10-tetrathiadecane, 1,4,8,11-tetrathiaundecane, and 1,5,10,14-tetrathiatetradecane afforded the corresponding thiocrown ethers 40-44 in 40-75% yields. Despite repeated attempts using a wide range of reagents, demethylation of the methoxy ether functionalities failed. Attempts to prepare the free phenol derivatives of the latter type of crown ethers by oxidative coupling of two naphthol units failed.

1- O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine—A methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism

Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1–100 μM 1- O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH 3) induced platelet aggregation but 1- O-hexadecyl- sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH 3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH 3 (0.1 μM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [ 3H]WEB 2086 showed that Et-16-OCH 3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH 3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 μM Et-16-OCH 3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 μM. Thus, this study shows that Et-16-OCH 3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.

Reaction of C60 with Benzocyclobutenol: Expeditious Route to Fullerene Adducts

Reaction of C 60 with benzocyclobutenol (2a) and its methoxy ether (2b) in refluxing toluene gave 1,9-dihydrofullerene cycloadducts (3a) and (3b) in 59% and 50% yields, respectively. The alcohol was converted to pyranyl ether (4), acrylate (5), p-vinylbenzoate (6) and acid succinate esters (7) in good yields under very mild conditions. The adducts exist as two interconverting boat conformers. Acrylate (5) and p-vinylbenzoate (6) should be used for polymerization studies. Acid (7) shows enhanced solubility in polar solvents

Corner attack on exo- and endo-tricyclo[3.2.1.02,4]octane by deuteron and mercuric ions

Reaction of endo-tricyclo(3.2.1.0{sup 2,4})octane (1) with deuteron in methanol-d{sub 1} gave a mixture (62:38) of methoxy ethers 3b and 4b from cleavage of the most substituted cyclopropane bond. The reaction proceeds by attack of deuterium at the corner of the cyclopropane. Trapping of the intermediate cation 5b is competitive with rearrangement to the nonclassical cation 6b. Reaction of exo-tricyclo(3.2.1.0{sup 2,4})octane (2) under similar conditions gave methoxy ether 11b, which results from rupture of an external cyclopropyl bond, and methoxy ether 12b formed from rupture of the internal cyclopropyl bond with inversion at the site of both electrophilic and nucleophilic attack. Reaction of hydrocarbon 1 with mercuric acetate in methanol gave 4-endo-(acetoxymercurio)-2-endo-methoxybicyclo(3.2.1)octane (3c) from attack of the mercuric ion at the corner of the cyclopropane and nucleophilic attack by methanol with inversion without skeletal rearrangement. Similar reaction of the exo hydrocarbon 2 gave product 12c from internal bond rupture without molecular rearrangement and with inversion of configuration at the site of electrophilic and nucleophilic attack. In addition an almost equal quantity of 11c, a product of rupture of the external cyclopropyl bond, was formed. The stereochemistry of mercuric ion and deuteron attack at C2 at the corner of the cyclopropane ringmore » of 1 and 2 is rationalized by consideration of the symmetry and energy of the molecular orbitals involved. 31 refs., 4 figs.« less