Quantitative structure-activity relationship study of new potent and selective antagonists at the 5-HT(1A) and adrenergic alpha(1d) receptors: Derivatives of spiroethyl phenyl(substituted)piperazine

The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT(1A) and adrenergic alpha(1d) receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT(1A) receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pK(i) values 10.57 and 10.12 respectively. For the adrenergic alpha(1d) receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series.     

Indoloxypropanolamine analogues as 5-HT(1A) receptor antagonists

Analogues of pindolol, 1-(1H-indol-4-yloxy)-3-isopropylamino-propan-2-ol, were synthesized and evaluated as 5-HT(1A) receptor antagonists. The structural features required for optimal binding to the 5-HT1A receptor are as follows: S-2-propanol linker, 4-indoloxy substituent, and a large lipophilic cyclic amine substituent.     

5-Alkylated thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists

We prepared analogs of potent thiazolidinone-based follicle-stimulating hormone (FSH) agonists 1, that is, 3 that contained an additional 5-alkyl substituent. This extra substituent was added to reduce synthetic problems that arose during preparation of analogs of 1. These compounds (3) were evaluated in a Chinese hamster ovary (CHO) cell line that expressed recombinant human FSH receptor (FSHR) and a luciferase reporter gene regulated by a cAMP response element (CRE). Selected compounds were also tested on a CHO-cell line that over expressed the FSHR for the ability to induce cAMP production. When the 5-alkyl substituent was a methyl group as in analog 16a, similar FSH activity (i.e., EC(50) = 51 nM, 100% efficacy relative to hFSH) to the analogous 5-hydrogen series compound (e.g., 2) was observed; thus, proving that a small 5-alkyl substituent was well tolerated. New derivatives of 3, in which the potentially hydrolytically labile secondary amide function of 1 (-CONH-) was modified to other moieties (e.g., -CH(2)NH-, -CH(2)S-, and -CH(2)OCONH-), were also prepared and evaluated. These congeners (namely 21, 22, and 24) also displayed good potency in the CRE-luciferase assay.     

1-Alkoxycarbonyl-3-halogenoazetidin-2-ones as elastase (PPE) inhibitors

A series of 1-alkoxycarbonyl-3-halogenoazetidin-2-ones, designed as potential suicide inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). All the compounds were transient inhibitors, their activity depending mainly on the nature of the halogen substituent: bromo- and iodo- derivatives are more active (K_i 2–22 μM) than 3-chloroazetidinones (K_i 20–150 μM). The lipophilicity of the N-1 substituent appeared to exert a slightly positive effect.     

Structural and conformational properties of (Z)-beta-(1-naphthyl)- dehydroalanine residue

To understand how chemical structure of beta-substituted alpha, beta-dehydroalanine (particularly size and pi conjugation of beta substituent) affects conformational property, x-ray crystallographic analysis was performed on Boc-Ala-Delta(Z) Nap-Val-OMe [Boc: t-butoxycarbonyl; Delta(Z) Nap: (Z)-beta-(1-naphthyl)dehydroalanine; OMe: methoxy] having the naphthyl group as a bulky beta substituent. Single crystals were grown by slow evaporation from an ethanol solution in the triclinic space group P1 with a = 9.528 (3) A, b = 12.410(4) A, c = 5.975(2) A, alpha = 96.77(3) degrees, beta = 102. 81(2) degrees, gamma = 88.74(3) degrees, V = 684.1(4) A3, and Z = 1. Phase determination was carried out by a direct method (SHELEXS), and the final structure was refined to R = 8.1% and R(w) = 9.0% for 1964 observed reflections. The bond lengths and bond angles of the Delta(Z)Nap residue, characterized by a sp(2) hybridized C(alpha) atom, did not differ from those of other dehydroresidues such as Delta(Z) Phe, Delta(Z) Leu, and DeltaVal essentially. The peptide backbone took a type II beta-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), similar to di- or tripeptides containing a Delta(Z) Phe or Delta(Z) Leu residue in the second positions. Here the naphthyl group was found to be nonplanar [chi(2) = 55(1) degrees ] relative to the C(alpha)==C(beta)==C(gamma) plane. The nonplanarity was supported by conformational energy calculation. The molecular packing was stabilized by two kinds of intermolecular hydrogen bonds and van der Waals interactions. Naphthyl groups were arranged in a partially overlapped face-to-face orientation with a center-to-center distance of 5.97 A. For additional information, peptide Boc-(Ala-Delta(Z) Nap-Leu)(2)-OMe was synthesized and its solution conformation was investigated by (1)H-NMR spectroscopy. The hexapeptide showed the tendency to form a 3(10)-helical conformation in solution essentially. Conformational properties of Delta(Z) Nap residue, characterized by a type II beta-turn and 3(10)-helix, were supported by a conformational energy contour map of the Delta(Z)Nap residue.     

Synthesis of putative metabolites of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (ED-71)

1alpha,25-Dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (ED-71), an analog of active vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is under phase III clinical trials in Japan for the treatment of osteoporosis and bone fracture prevention. Since ED-71 has a substituent at the 2beta-position of the A-ring, it is recognized that the metabolic pathway of ED-71 might be more complicated than 1,25(OH)(2)D(3) because of metabolism at the 2beta-position substituent in addition to the inherent metabolism of the side chain. To clarify the metabolism of hydroxypropoxy substituent of the 2beta-positon and a combination of metabolism between side chain and 2beta-positon, four putative metabolites of ED-71 have been prepared as authentic samples. The metabolites at the 2beta-positon, the methyl ester derivative considered as an ester standard of the oxidized metabolite and the tetraol derivative as the truncated metabolite were synthesized from alpha-epoxide, a key intermediate of ED-71 synthesis. The combination metabolites between side chain and 2beta-positon, the 24(S)- and 24(R)-pentaols were synthesized using Trost's convergent method.     

Design and synthesis of acyclic triaryl (Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors

A group of acyclic 2-alkyl-1,1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC(50) = 0.014 microM), and an extremely selective [COX-2 selectivity index (SI) > 7142], COX-2 inhibitor that showed superior anti-inflammatory (AI) activity (ID(50) = 2.5 mg/kg) relative to celecoxib (ID(50) = 10.8 mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC(50) = 2.4 microM; COX-2 IC(50) = 0.03 microM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID(50) = 4.1mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO(2)Me substituent of (Z)-13b inserts deep inside the 2 degrees -pocket of the COX-2 active site, where one of the O-atoms of SO(2) group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(120), Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)-olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2.     

Bivalent ligand approach on 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine: synthesis and binding affinities for 5-HT(7) and 5-HT(1A) receptors

We here report on the synthesis and binding properties at 5-HT(7) and 5-HT(1A) receptors of ligands 3-12, that were designed according to the 'bivalent ligand' approach. Two moieties of the 5-HT(7)/5-HT(1A) ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (1) were linked through their 3-methoxy substituent by polymethylene chains of variable length, with the aim to increase the affinity for 5-HT(7) receptor and the selectivity over 5-HT(1A) receptors. In the best cases, the dimers showed affinities for 5-HT(7) receptors as high as the monomer with no improvement in selectivity. Some dimers displayed 5-HT(1A) receptor affinities slightly higher than monomer 1.     

Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere

A group of celecoxib analogues in which the para-SO(2)NH(2) substituent on the N(1)-phenyl ring was replaced by a para-sulfonylazido (SO(2)N(3)) 4, or a meta-SO(2)N(3) 8, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO(2)N(3) substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a) having a meta-SO(2)N(3) substituent (COX-1 IC(50) >100microM; COX-2 IC(50)=5.16microM; COX-2 selectivity index >19.3) is a selective COX-2 inhibitor. A molecular modeling (docking) study showed that the SO(2)N(3) group of 8a inserts deep inside the secondary pocket of the COX-2 binding site. The SO(2)N(3) moiety of 8a can undergo a dual H-bonding interaction via one of its SO(2) oxygen-atoms, and an electrostatic (ion-ion) interaction via the terminal azido (N(3)) nitrogen-atom, to the guanidino NH(2) of Arg(513) in the secondary pocket of COX-2. These observations indicate that an appropriately positioned SO(2)N(3) moiety is a novel alternative bioisostere to the traditional SO(2)NH(2) and SO(2)Me pharmacophores present in selective COX-2 inhibitors, that are only capable of H-bonding interactions with the COX-2 isozyme, for use in drug design.     

The molecular crystal structure and self-assembly behavior of 6(I)-O-(3-nitrophenyl)cyclomaltoheptaose

The mono-modified beta-cyclodextrin derivative, 6(I)-O-(3-nitrophenyl)cyclomaltoheptaose{mono[6-O-(3-nitrophenyl)]-beta-cyclodextrin} was synthesized, and its crystal structure was determined by single-crystal X-ray analysis. The crystal structure suggests that the 3-nitrophenyl substituent group is inserted into the adjacent beta-cyclodextrin cavity from the secondary hydroxyl side, and the molecules are stacked along the twofold screw axis to form an infinite one-dimensional polymeric chain.     

Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A(1) and A(2A) receptor ligands

The synthesis of N-(un)substituted-phenylalkylpyrimido[2,1-f]purinediones was performed starting with 7-(3-chloropropyl)-8-bromotheophylline and 7-(3-chloropropyl)-8-bromo-1,3-dipropylxanthine. Compounds with unsubstituted or substituted ethylene spacer to an aromatic ring were synthesized. Additionally variations in the spacer-elongation of the linker containing more than two atoms, introduction of a double bond or heteroatoms were performed. Physicochemical properties of the synthesized compounds were described. The obtained compounds envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were also investigated for the affinity to the A(2B) and A(3) receptor subtypes. It was stated that phenylethyl pyrimido[2,1-f]purinediones and their analogs with variations of the ethylene spacer (substituted or extended) exhibit micromolar or submicromolar affinity for A(2A) ARs (adenosine receptors); for example compound 2Ac with p-hydroxy substituent displayed a K(i) value of 0.23 microM at the rat A(2A) receptor. In comparison to the previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones compounds with a shorter spacer, phenethyl derivatives were optimal for A(2A) AR. The kind of substituent at the aromatic ring was important for the affinity. Oxygen and nitrogen atoms in the spacer resulted frequently in a slight decrease of the A(2A) AR affinity, introduction of more heteroatoms into the spacer-in carbamates-caused distinctly negative effect on the activity. In this series of compounds more frequently the adenosine A(1) activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with K(i) value of 0.62 microM at the rat A(2A) AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A(1) and A(2A) ARs. It was concluded that for the activity at adenosine A(1) and A(2A) receptors lipophilicity, steric effects along with the molecule's electrostatic surface properties had greatest value. Chosen compounds were evaluated in vivo as anticonvulsants in MES, scMet tests and examined for neurotoxicity. Contrary to previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones, all tested compounds were inactive as anticonvulsants.     

Design and synthesis of (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes and (Z)-1-(4-azidophenyl)-1,2-diphenylalk-1-enes: novel inhibitors of cyclooxygenase-2 (COX-2) with anti-inflammatory and analgesic activity

A group of novel (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)oct-1-ene (8d) as a highly potent (IC50=0.03 microM), and an extremely selective [COX-2 SI (selectivity index)>3,333], COX-2 inhibitor that showed good anti-inflammatory (AI) activity (ID50=2.8 mg/kg). A molecular modeling (docking) study showed that the p-MeSO2NH group present in (Z)-8d inserts deep inside the 2 degrees-pocket of the COX-2 binding site, it undergoes a hydrophobic interaction with Ala516 and Gly519, and one of the O-atoms of the MeSO2 group participates in a weak hydrogen bonding interaction with the NH2 of Arg513 (distance= 3.85 angstroms). Similar in vitro COX-1/COX-2 enzyme inhibition studies showed that the azido compound 1-(4-azidophenyl)-1,2-diphenyloct-1-ene (9c) is also a potent and selective COX-2 inhibitor (COX-2 IC50=0.11 microM: SI>909) that exhibits good AI activity (ID50=5.0 mg/kg). A docking experiment to determine the orientation of (Z)-9c within the COX-2 binding site showed that the linear p-N3 group inserts into the COX-2 2 degrees-pocket, where it undergoes an ion-ion (electrostatic) interaction with Arg513. Structure-activity data acquired indicate that an olefin having either a C-1 p-MeSO2NH-phenyl, or a p-N3-phenyl, substituent, that is, cis to a C-2 unsubstituted phenyl substituent, in conjunction with C-1 unsubstituted phenyl and C-2 alkyl substituents, provides a novel template to design acyclic olefinic COX-2 inhibitors.     

Novel 3-O-carbamoyl erythromycin A derivatives (carbamolides) with activity against resistant staphylococcal and streptococcal isolates

A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2 Å resolution).     

The temperature response of C(3) and C(4) photosynthesis

We review the current understanding of the temperature responses of C(3) and C(4) photosynthesis across thermal ranges that do not harm the photosynthetic apparatus. In C(3) species, photosynthesis is classically considered to be limited by the capacities of ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco), ribulose bisphosphate (RuBP) regeneration or P(i) regeneration. Using both theoretical and empirical evidence, we describe the temperature response of instantaneous net CO(2) assimilation rate (A) in terms of these limitations, and evaluate possible limitations on A at elevated temperatures arising from heat-induced lability of Rubisco activase. In C(3) plants, Rubisco capacity is the predominant limitation on A across a wide range of temperatures at low CO(2) (<300 microbar), while at elevated CO(2), the limitation shifts to P(i) regeneration capacity at suboptimal temperatures, and either electron transport capacity or Rubisco activase capacity at supraoptimal temperatures. In C(4) plants, Rubisco capacity limits A below 20 degrees C in chilling-tolerant species, but the control over A at elevated temperature remains uncertain. Acclimation of C(3) photosynthesis to suboptimal growth temperature is commonly associated with a disproportional enhancement of the P(i) regeneration capacity. Above the thermal optimum, acclimation of A to increasing growth temperature is associated with increased electron transport capacity and/or greater heat stability of Rubisco activase. In many C(4) species from warm habitats, acclimation to cooler growth conditions increases levels of Rubisco and C(4) cycle enzymes which then enhance A below the thermal optimum. By contrast, few C(4) species adapted to cooler habitats increase Rubisco content during acclimation to reduced growth temperature; as a result, A changes little at suboptimal temperatures. Global change is likely to cause a widespread shift in patterns of photosynthetic limitation in higher plants. Limitations in electron transport and Rubisco activase capacity should be more common in the warmer, high CO(2) conditions expected by the end of the century.     

2-(N-acyl) and 2-N-acyl-N(6)-substituted analogues of adenosine and their affinity at the human adenosine receptors

A series of 2-(N-acyl) and 2-(N-acyl)-N(6)-alkyladenosine analogues have been synthesized from the intermediate 2-amino-6-chloroadenosine derivatives (2b and 7) and evaluated for their affinity at the human A(1), A(2A), and A(3) receptors. We found that 2-(N-acyl) derivatives of adenosine showed relatively low affinity at A(2A) and A(3) receptors, while the N(6)-cyclopentyl substituent in 4h and 4i induced high potency [A(1) (K(i))=20.7 and 31.8 nM respectively] at the A(1) receptor and resulted therefore in increased selectivity for this subtype. The general synthetic methods and their binding studies are presented herein.     

Conformational preferences of hypermodified nucleoside lysidine (k2C) occurring at "wobble" position in anticodon loop of tRNA(Ile)

Conformational preferences of hypermodified nucleoside, 4-amino-2-(N(6)-lysino)-1-(beta-D-ribofuranosyl) pyrimidinium (Lysidine or 2-lysyl cytidine), usually designated as k(2)C, have been investigated theoretically by the quantum chemical perturbative configuration interaction with localized orbitals (PCILO) method. The zwitterionic, non-zwitterionic, neutral, and tautomeric forms have been studied. Automated geometry optimization using molecular mechanics force field (MMFF), semi-empirical quantum chemical PM3, and ab initio molecular orbital Hartree-Fock SCF quantum mechanical calculations have also been made to compare the salient features. The predicted most stable conformations of zwitterionic, non-zwitterionic, neutral, and tautomeric form are such that in each of these molecules the orientation of lysidine moiety (R) is trans to the N(1) of cytidine. The preferred base orientation is anti (chi = 3 degrees ) and the lysine substituent folds back toward the ribose ring. This results in hydrogen bonding between the carboxyl oxygen O(12a) of lysine moiety and the 2'-hydroxyl group of ribose sugar. In all these four forms of lysidine O(12a)...H-C(9) and O(12b)...H-N(11) interactions provide stability to respective stable conformers. Watson-Crick base pairing of lysidine with A is feasible only with the tautomeric form of usual anti oriented lysidine. This can help in recognition of AUA codon besides in avoiding misrecognition of AUG.     

Synthesis and biological data of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters, a new series of A1-adenosine receptor (A1AR) ligands.

The synthesis of a new family of A1-adenosine receptor (A1AR) ligands 3a-n has been performed in a straightforward way. Affinity data at A1AR, A2AAR and A3AR in bovine membranes show that these new compounds bind the A1AR in a selective way over A2AAR and A3AR and one of them (3j) presents a very high affinity, probably due to the phenethylamine substituent at C-4.     

Synthesis of amphiphilic photochromic benzo-15(18)-crown-5(6)-ethers and their properties in monolayers

New amphiphilic photochromic benzo-15(18)-crown-5(6) ethers (APC) differing in the position of the octadecyl substituent and the size of the crown cavity were synthesized. The compounds form stable monolayers in the air/water and air/alkaline metal salt solution interfaces. The results of the pressure isotherm measurements, atomic force microscopy (AFM), and electronic spectroscopy show that the structure of the monolayers formed depends on the structure of the parent APC and the nature of the cation in salt solutions. The area per molecule of APC in the monolayer (specific area) is the smallest on the water surface and increases by 20-40% on the aqueous subphase surface with an increasing concentration of salts therein to indicate the formation of APC complexes with the metal cations. When the hydrophobic aliphatic substituent is displaced from position 3 to position 5 of the benzothiazole ring, the specific area on the surface of water and subphases decreases twofold, which indicates the compactization of the monolayer on this modification. A reversible E-Z-photoisomerization of APC was found in the monolayers formed in the salt solution/air interface. The features of the reaction are defined by the specific organization of the amphiphilic molecules in the monolayer and by the nature of the cation.     

Translocation of the 5-alkoxy substituent of 2,5-dialkoxyarylalkylamines to the 6-position: effects on 5-HT(2A/2C) receptor affinity

Positional modification of 2,5-dimethoxyamphetamine analogues has been studied. Specifically, the 5-alkoxy substituent was translocated to the 6-position of the phenyl nucleus. Methoxy groups were also constrained by incorporation into appended dihydrofuran and furan rings. 2,6-Dimethoxy-4-methylamphetamine had an approximately 3-fold lower affinity for the 5-HT(2A) receptor compared to the parent 2,5-dimethoxy-4-methylamphetamine (DOM). The rigid compound based on the 2,3,5,6-tetrahydrobenzo[1,2-b;5,4-b']difuran nucleus and the aromatic analogue containing the benzo[1,2-b;5,4-b']difuran nucleus possessed an approximate 7- and 27-fold increase in affinity, respectively, compared to 2,6-dimethoxy-4-methylamphetamine, the non-rigid, positional isomer.     

A concise and practical synthesis of antigenic globotriose, alpha-D-Gal-(1-->4)-beta-D-Gal-(1-->4)-beta-D-Glc

A concise and practical synthesis of the antigenic globotriose, alpha-D-Gal-(1-->4)-beta-D-Gal-(1-->4)-beta-D-Glc (13), was achieved by coupling of a monosaccharide donor, 3-O-allyl-2-O-benzoyl-4,6-O-benzylidene-alpha-D-galactopyranosyl trichloroacetimidate (4) with a disaccharide acceptor, p-methoxyphenyl 2,3,6-tri-O-benzoyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-benzoyl-beta-D-glucopyranoside (8), followed by deprotection. In spite of the existence of a C-2-ester substituent capable of neighboring-group participation in the donor, the coupling gave exclusively the alpha-linkage in satisfactory yield. The acceptor 8 was readily obtained from selective 3-O-benzoylation of the galactosyl ring of p-methoxyphenyl 2,6-di-O-benzoyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-benzoyl-beta-D-glucopyranoside (7), which was prepared from p-methoxyphenyl beta-D-lactoside (5) via isopropylidenation, benzoylation, and deisopropylidenation. Donor 4 was obtained from p-methoxylphenyl 3-O-allyl-2,4,6-tri-O-benzoyl-beta-D-galactopyranoside (1) via selective 4,6-di-O-debenzoylation, oxidative removal of 1-O-MP, benzylidenation, and trichloroacetimidate formation.