The proposed structures of phenolic compounds isolated from Piper betle L. differ from those of the compounds obtained by total synthesis.

We describe the syntheses of phenolic compounds, 4-[(1E, 3E, 5E)-6-(4-octyloxyphenyl)hexa-1,3,5-trien-1-yl]benzene-1,2-diol (1) and 3-(n-dodecyloxy) phenol (2), isolated from Piper betle. The triene moiety of 4-[(1E, 3E, 5E)-6-(4-octyloxyphenyl)hexa-1,3,5-trien-1-yl]benzene-1,2-diol was formed via two different methods, the Horner-Wadsworth-Emmons reaction and the McMurry coupling reaction. The spectral data of synthesized compounds show differences with those of reported as the naturally occurring compounds.

Synthesis and biological activity of (±)-7,3',4'-trihydroxyhomoisoflavan and its analogs.

Acetylcholinesterase (AChE) inhibitors and neurite outgrowth promoters are thought to alleviate the symptoms of degenerative brain disorders, such as Alzheimer's disease. We designed and synthesized a series of homoisoflavonoids based on the structure of natural homoisoflavan isolated from Dracaena cambodiana dragon's blood. The homoisoflavonoids were then evaluated as AChE inhibitors and neurite outgrowth promoters. The catechol structure of the homoisoflavan B rings was important for AChE inhibition, and some of the homoisoflavonoids significantly promoted neurite outgrowth induced by nerve growth factor (NGF).

Peripheral gabapentin regulates mosquito allergy-induced itch in mice.

The antipruritic activity of gabapentin, an anticonvulsant, was studied in a mouse model of allergic itch. In mice sensitized by an extract of the salivary glands of the mosquito (ESGM), an intradermal injection of ESGM elicited scratching and increased peripheral nerve firing. Oral or intradermal administration of gabapentin at the ESGM injection site inhibited ESGM-induced scratching and peripheral nerve firing. However, gabapentin did not affect histamine-induced scratching. The distributions of immunoreactivity to the voltage-dependent calcium channel α2δ-1 subunit, a site of gabapentin action, and the histamine H1 receptor differed in the mouse dorsal root ganglia. The α2δ-1 subunit was mainly found in neurons that were 15-20 µm in diameter, whereas the H1 receptor was mainly in 20-30 µm neurons. In addition, α2δ-1 subunit immunoreactivity co-localized with that of transient receptor potential vanilloid 1 (TRPV1). These results suggest that gabapentin regulates allergic itch by acting on the calcium channel α2δ-1 subunit in peripheral TRPV1-positive neurons.

Structure-activity relationships of flavanones, flavanone glycosides, and flavones in anti-degranulation activity in rat basophilic leukemia RBL-2H3 cells.

The incidence of type I allergies, which are associated with mast cell degranulation and local inflammation, is increasing, and new treatments are needed. To date, structure-activity relationships of flavonoids in their degranulation-inhibiting activity have not been systematically characterized. In the current study, the degranulation-inhibiting activity of a series of flavonoids was evaluated. The following three observations were made: (1) the activity disappears when a sugar moiety is introduced into the A ring of the flavanone; (2) the activity depends on the number of hydroxyl groups on the B ring; (3) the activity is markedly enhanced when a double bond is introduced into the C ring. The information obtained in the current study may guide the development of a therapy for type I allergies.

The structure proposed for apteniol D is different from that of the compound obtained by total synthesis.

We describe the synthesis of 4,4'-oxyneolignan, the proposed structure for naturally occurring apteniol D. The diphenyl ether moiety in 4,4'-oxyneolignan was formed via classical Ullmann ether synthesis using excess copper powder in N,N-dimethylacetamide. The spectral data of synthesised apteniol D show differences compared to those of naturally occurring apteniol D.

Synthesis and degranulation-inhibiting activities of the proposed apteniols B, C, and G.

The synthesis of compounds with the structures proposed for the oxyneolignan apteniols B, C, and G is described. The diphenyl ether skeletons of the proposed apteniols were formed via Ullmann ether synthesis. In particular, the spectral data for the synthesized apteniols B, C, and G did not agree with those previously reported for the isolated compounds. Furthermore, the synthesized proposed apteniol B did not show degranulation-inhibiting activity, while the prepared proposed apteniols C and G exhibited activities considerably weaker than that of the methyl ester of proposed apteniol A.

Syntheses and biological activities of the proposed structure of apteniol A and its derivatives.

We describe the syntheses of the proposed structure of diphenyl ether oxyneolignan, apteniol A and its derivatives. The diphenyl ether moiety of proposed apteniol A was formed via Ullmann ether synthesis, but the spectral data of the synthesized apteniol A did not agree with that in previous studies. The dimethyl ester derivative of the proposed apteniol A was found to enhance neurite outgrowth in PC12 cells and inhibit antigen-induced degranulation in RBL-2H3 cells.

A new route to diverse 1-azasugars from N-Boc-5-hydroxy-3-piperidene as a common building block.

A new general method for the synthesis of a variety of 1-azasugars with a nitrogen atom at the anomeric position is described. The readily available chiral N-Boc-5-hydroxy-3-piperidene 3 is transformed to isofagomine (2), homoisofagomine (13), and 5'-deoxyisofagomine (14) via stereoselective epoxidation and regioselective ring-cleavage in a highly stereocontrolled manner. In addition, the synthesis of all four stereoisomers of 3,4,5-trihydroxypiperidines (18-21) classified as 1-azasugar-type glycosidase inhibitors was stereoselectively achieved from the (chiral) piperidene 3.

Biological properties of D- and L-1-deoxyazasugars.

L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyidonojirimycin (ido-DNJ) were prepared according to prior methods for the d-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although d-DNJ and d-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the nM range, l-DNJ and l-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the muM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. d-manno-DNJ is known as a much better inhibitor of alpha-l-fucosidase than alpha-mannosidase, while l-allo-DNJ was a better inhibitor than d-manno-DNJ of alpha-mannosidase. l-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-l-fucosidase with a K(i) value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-l-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. d-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC(50) = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while d-DNJ inhibiting alpha-glucosidase (IC(50) = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although l-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC(50) = 64 microM), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.

Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block.

[reaction: see text] A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 1-3 was carried out via the use of 4 in a highly stereocontrolled mode.

Suppression by gabapentin of pain-related mechano-responses in mice given orthotopic tumor inoculation.

In this study, we examined whether several types of non-opioid agents would inhibit the pain-related responses of melanoma-bearing mice. Orthotopic inoculation with melanoma into the hind paw induced marked tactile allodynia and mechanical hyperalgesia. A peroral injection (p.o.) of gabapentin (100-300 mg/kg) inhibited the allodynia and hyperalgesia, without effects on gross behaviors. An intraperitoneal injection (i.p.) of ketamine hydrochloride (30 mg/kg) produced partial inhibition in allodynia and hyperalgesia and prostate posture at 15 min after injection. Diclofenac sodium (10 and 30 mg/kg, i.p), mexiletine hydrochloride (20 mg/kg, i.p.), clonidine hydrochloride (0.1 mg/kg, i.p.) and suramin (100 mg/kg, i.p.) were without effects on allodynia and hyperalgesia. Subcutaneous injections of baclofen (3 mg/kg) and N(G)-nitro-L-arginine methyl ester (100 mg/kg) were also without effects. Repeated administration of gabapentin (150 mg/kg, p.o.) produced constant inhibitions, suggesting no analgesic tolerance. Gabapentin may be useful for the management of cancer pain.

Asymmetric synthesis of the four possible fagomine isomers.

The asymmetric synthesis of fagomine and its congeners 1-4 has been achieved by catalytic ring-closing metathesis (RCM). The synthesis involved the construction of the piperidene-type chiral building block 5 followed by dihydroxylation, starting from the d-serine-derived Garner aldehyde 6.

A novel C(2)-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester as a promising chiral building block for piperidine-related alkaloids.

C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]

Dermorphin and deltorphin heptapeptide analogues: replacement of Phe residue by Dmp greatly improves opioid receptor affinity and selectivity.

The usefulness of 2,6-dimethylphenylalanine (Dmp) as a Phe surrogate in two opioid peptides, dermorphin (DM) and deltorphin II (DT), was investigated. Compared to DM, [L-Dmp(3)]DM (1) showed a 170-fold increase in mu affinity and only a 4-fold increase in delta affinity, resulting in a 40-fold improvement in mu receptor selectivity. Compared to DT, [L-Dmp(3)]DT (3) showed a 22-fold increase in delta affinity and somewhat of a loss in mu affinity, and consequently a marked (75-fold) improvement in delta receptor selectivity. The D-Dmp replacement, however, resulted in a great loss in receptor selectivity in each of the peptides. The specific receptor interactions of 1 and 3 were confirmed by in vitro bioassays. Analogues 1 and 3 seem to be useful as pharmacological tools for the study of opioid systems.

1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline: a novel and chemoselective tert-butoxycarbonylation reagent.

[reaction: see text] The use of 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) as tert-butoxycarbonylation reagent for aromatic and aliphatic amine hydrochlorides and phenols in the absence of a base has been demonstrated. The reactions proceed chemoselectively in high yield under mild conditions.