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In an effort to prepare complex oligosaccharide derivatives, a series of unexpected alpha glycosides were predominantly formed in the presence of neighboring group participation using imidates or thioglycosides as glycosyl donors under standard glycosylation conditions. The observations are especially suitable in the case of alpha-(1-->3) glycosidic bond formation.
A novel analogue of sialyl Lewis X ganglioside, N-deacetylsialyl Lewis X ganglioside, was synthesized. Methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-trifluoroacetamido-D-glycero-alpha-D-galacto-2-nonulopyranosylonate-(2 --> 3)-2,4,6-tri-O-benzoyl-D-galactopyranosyl trichloroacetimidate was coupled with 2-(trimethylsilyl)ethyl [2-acetamido-6-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-beta-D-glucopyranosyl]-(1 --> 3)-[2,4,6-tri-O-benzyl-beta-D-galactopyranosyl]-(1 --> 4)-2,3,6-tri-O-benzyl-beta-D-galactopyranoside to give the desired pentasaccharide in high yield. The glycosylation of the pentasaccharide acceptor, which was derived from its precursor by removal of the 3-methoxybenzyl group, with the phenyl 1-thioglycoside derivative of L-fucose using N-iodosuccinimide-trifluoromethanesulfonic acid as promoter, produced the hexasaccharide. Proper manipulation of the protecting groups of the hexasaccharide afforded the corresponding glycosyl imidate, which was coupled with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol. Selective reduction of the azido group, N-acylation with octadecanoic acid, and the complete removal of the protecting groups gave the desired N-deacetylsialyl Lewis X ganglioside. L-Selectin bound more strongly to N-deacetylsialyl Lewis X ganglioside than to the sialyl Lewis X ganglioside, whereas E- and P-selectins bound equally well to the two gangliosides.
Combination of a one-pot coupling technique and the use of benzyl ethers as permanent protecting groups offered a short and simple route to dioscin-type saponins. This strategy in combination with a mild reductive opening procedure of the spiroketal function in diosgenin also offered a convenient approach to bidesmosidic furostan type saponins. Me(3)N.BH(3)/AlCl(3) promoted acetal opening of 3-O-TBDMS-protected diosgenin gave the 26-OH acceptor 9 into which a benzylated beta-glucose moiety was introduced by a S(N)2-type imidate coupling. After cleavage of the silyl ether, the 3beta-O-glucose and the 4-O-linked rhamnose of the chacotriose unit were introduced by a NIS/AgOTf-promoted one-pot coupling sequence utilising thioglycoside donors and their different reactivity in different solvents. After removal of a benzoyl group, the same coupling conditions were also used for the coupling of the second 2-O-linked rhamnose unit. The target substance was obtained after cleavage of the protecting benzyl ethers under Birch-type conditions, which did not affect the double bond in the steroid skeleton.
D-Glucosamine can be readily transformed into 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino+ ++) -D-glucopyranose (2). From this intermediate valuable glycosyl donors can be obtained; reaction with ethanethiol in the presence of boron trifluoride etherate afforded ethyl 3,4,6-tri-O-acetyl-2-deoxy-1-thio-2-(2,2, 2-trichloroethoxycarbonylamino)-beta-D-glucopyranoside (4) which gave, upon N-acetylation, the N-acetyl-N-trichloroethoxycarbonyl derivative (5). Selective removal of the 1-O-acetyl group in 2 followed by treatment with trichloroacetonitrile in the presence of base afforded 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)- alpha -D-glucopyranosyl trichloroacetimidate (6). Reaction of 5 with five selectively protected glycosides as glycosyl acceptors in the presence of N-iodosuccinimide/trifluoromethanesulfonic acid as the promoter system furnished the corresponding beta-glycosides in good yields, thus exhibiting the valuable glycosyl donor properties of 5. Reductive removal of the trichloroethoxycarbonyl (Teoc) group afforded the corresponding N-acetyl-protected saccharides in high yields. The imidate 6 reacted with three of the above acceptors in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate to give the beta-linked disaccharides in even better yields. The direct replacement of the N-Teoc group by the N-acetyl group using zinc/acetic anhydride, via the free amines as transient intermediates, adds to the high efficiency and convenience of this methodology.
Seven analogues of the trisaccharide beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3 have been synthesized as potential substrates for glycosyltransferases involved in the chain-termination of N-acetyllactosamine-type N-glycans. These compounds include: 3-O-methyl-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp -(1-->O) (CH2)7CH3, 3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1 -->O) (CH2)7CH3, 3-deoxy-3-fluoro-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-M anp- (1-->O)(CH2)7Ch3, 3-amino-3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Ma np- (1-->O)(CH2)7CH3, beta-D-Gulp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-- >O)(CH2)7CH3, beta-L-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3, and alpha-L-Altp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1- ->O) (CH2)7CH3. All trisaccharides were obtained by condensation of suitably modified glycosyl donors based on imidates or thioglycosides with the same disaccharide acceptor, octyl 3,4,6-tri-O-benzyl-2-O-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D- glucopyranosyl)-alpha-D-mannopyranoside, followed by deprotection.
The first chemical synthesis of cellooctaose by a convergent synthetic method is described. A challenging glycosylation between cellotetraosyl donor 5 and acceptor 7 proceeded in a one-step reaction using a high-vacuum system for anhydrous glycosylation and minimizing imidate side reactions such as hydrolysis and glycosyl fluoride formation. Pivaloyl, allyl, and benzyl protecting groups of cellooctaose derivative 8 were completely removed with SeO2-AcOH, NaOMe-MeOH, and H2/Pd(OH)2-C, respectively. The acetylation after each deprotection step finally led to cellooctaose hexacosaacetate (20), which is useful for purification and structural identification. Finally, the acetyl derivative 20 was deacetylated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 20% MeOH-CH2Cl2 to give pure cellooctaose (21). The analogous synthetic route to the present convergent synthetic design of cellooctaose may be a most promising one that enables us to synthesize cellulose with a defined degree of polymerization (dp).
Expeditious and stereocontrolled syntheses are reported of beta-D-Glc pNAc-(1-->4)-[beta-D-Glc pA-(1-->3)-beta-D-Glc pNAc-(1-->4)]n-beta-D-Glc pA-(1-->OMe), where n = 1, 2, and 3, which represent structural elements of the extracellular polysaccharide hyaluronic acid. Condensation of 4,6-O-benzylidene-3-O-chloroacetyl-2-deoxy-2-trichloroacetamido- alpha-D-glucopyranosyl trichloroacetimidate with methyl (4-methoxyphenyl 2,3-di-O-benzoyl-beta-D-glucopyranosid)uronate gave the disaccharide derivative 9, which was demethoxyphenylated and imidoylated to afford the pivotal disaccharide trichloroacetimidate 7. Condensation of 7 with methanol followed by O-dechloroacetylation gave the acceptor 8. Coupling of 7 with 8 gave the tetrasaccharide derivative 4. O-Dechloroacetylation of 4 followed by condensation with imidate 7 afforded hexasaccharide 5, which was transformed into octasaccharide 6 by a similar two-step procedure. Subsequent O-dechloroacetylation, transformation of the N-trichloroacetyl groups into N-acetyl, debenzylidenation, and saponification of 4-6 afforded the tetra- (1), hexa- (2), and octa-saccharide (3) derivatives in high yields, as their sodium salts.
Chondroitin di-, tri- and tetrasaccharides, as well as their 4-, 6-mono- and 4,6-disulfates as their 4-methoxyphenyl glycosides, were systematically synthesized. Target disaccharides having beta GalNAc-(1-->4)-beta GlcA sequences were obtained starting from the corresponding pivotal chondroitin disaccharide precursor. A trisaccharide intermediate, which was synthesized by coupling of glucuronate imidate with a known disaccharide acceptor, was transformed into the sulfated and non-sulfated chondroitin trisaccharides. Chondroitin tetrasaccharide and the corresponding 4-disulfate, 6-disulfate as well as 4,6-tetrasulfate were also obtained based on the strategy developed above starting from the reported tetrasaccharide having [beta GalN3-(1-->4)-beta GlcA2] sequence.
Sialyl Lewis X ganglioside analogues modified at C-6 of the galactose residue, having 6-O-methoxy, 6-acetamido and 6-amino functional groups, have been synthesized. Treatment of 2-(trimethylsilyl)ethyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5- dideoxy-D-glycero-alpha-D-galacto-2-nonulopyranosylonate)-(2-->3)- 2-O-benzoyl -beta-D-galactopyranoside with trimethyloxonium tetrafluoroborate or Tf2O, followed by NaN3, gave the 6-O-methyl and 6-azido derivatives, respectively, which were converted into their respective methyl 1-thioglycoside derivatives. The glycosyl donors obtained were coupled with 2-(trimethylsilyl)ethyl 2- acetamido-6-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-beta-D-glucopyranosyl - (1-->)-2,4,6-tri-O-benzyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-be nzyl- beta-D-galactopyranoside in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) to give their respective pentasaccharides. The glycosylation of the pentasaccharide acceptors derived from their precursors by removal of the 4-methoxybenzyl group, with phenyl 1-thioglycoside derivative of L-fucose using N-iodosuccinimide-TfOH afforded the corresponding hexasaccharides, which were transformed in good yield, via reductive removal of the benzyl group, the simultaneous transformation of azide to amine and acetamide, Omicron-deacylation and saponification of the methyl ester into the target compounds without the ceramide groups. On the other hand, the proper manipulation of the protecting group of the hexasaccharides, including a transformation of azide into acetamide and trifluoroacetamide, gave the hexasaccharide imidates, which were coupled with (2S,3R,4E)-2-azido-o-O-tert-butyldipenhylsilyl-4-o ctadecene-1,3-diol. Selective reduction of the azido group, N-acylation with octadecanoic acid, and the complete removal of the protecting groups gave the desired sialyl LeX ganglioside analogues.
Glucoconjugates of (+/-)-ibuprofen, (+/-)-alpha-tocopherol (vitamin E), gentisic acid, gallic acid, 2,6-bis(tert-butyl)-4-thiophenol, and N-acetyl-L-cysteine were prepared with the objective of increasing the bioavailability of such antioxidant and anti-inflammatory drugs. The O-glucosides were synthesized using benzylated alpha-D-glucopyranosyl trichloracetimidate as glycosyl donor. For the synthesis of the S-glucosides, the glycosyl donor 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose provided higher yields than the corresponding O-acetylated imidate.
Synthesis applied to prepare compounds 5-15 and 17-22 discussed in this paper has been presented in Scheme 1. Multi-stage preparation techniques were used to obtain 4-aryl-hexahydro 1-4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-dione (16) derivatives, being the starting compounds for further modification. N-Alkylation of the imide group in compounds 1-4 and 16 followed, using 1,4-dibromobutane to yield monobromobutyl derivatives 5-8 and 17. Subsequent condensation of those compounds with appropriate 1-aryl or 1-heteroarylpiperazine led to the final hexahydro- 9-15 and octahydro- 18-22 pyrido[1,2-c]pyrimidine-1,3-dione derivatives. The final products were subjected to screening test to elucidate the affinity to 5-HT1A and 5-HT2A receptors.
Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The chlorides used in the above synthesis can exist in two isomeric forms: chain (18-20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity which was superior than that of acetylsalicylic acid in two different tests. Most of the investigated imides suppressed significantly spontaneous locomotor activity in mice.
A spectrophotometric analysis of the UV-spectrum of 4-methoxy-2-[2-hydroxy-3(4-phenyl-1-piperazinyl)]propyl-2,3-dihydro-6-methyl-1,3-dioxo-1H-pyrrolo[3,4-c]pyridine (I) in 0.01 M HCl was performed by determining the values of specific absorption coefficients at the following analytical wavelengths: 224, 285 and 348 nm. The separation by means of TLC of compound I and of its five decomposition products was also studied. Silica gel coated plates (60 F(254)) were used and the mobile phase was consisted of butanol-acetic acid (1.05 kg/l)-water (80:12:30, v/v/v). The HPLC method (LiChrosorb(R) 100 RP-18 column 250 x 4.0 mm I.D., dp=5 microm; mobile phase: acetonitrile-0.01 M phosphate buffer (H(3)PO(4)+KH(2)PO(4); pH 3) (50:50, v/v-phase A) or (30:70, v/v-phase B) was validated by determination of the following parameters: selectivity, precision, linearity, stability of the analite and LOD as well as LOQ. Kinetic studies of the decomposition process of I in both acidic and alkaline environments indicate instability of the imide group.
Continuing our studies connected with the design of new anxiolytics we have now synthesized a series of new compounds, derivatives of 7,8-benzo-1,3-diazaspiro[4,5]decane-2,4-dione bearing a 4-aryl-1-piperazinylbutyl group attached to the imide nitrogen. One single compound was submitted to the 5-HT1A receptor binding assay and found to display the expected--though rather weak--receptorial affinity.
2-(1-Piperidino)- and 2-(4-methyl-1-piperazinyl)-6-methyl-3,4-pyridinedicarboximides (1, 2) react with N-phenylhydrazine yielding N-phenylamino-3,4-pyridinedicarboximides (7, 8). The same reaction with 1,6-dimethyl-2-oxo-1,2-dihydro- and 2-chloro-6-methyl-3,4-pyridinedicarboximides (3, 17) gives the salts of the corresponding N-phenylpyridopyridazines with phenylhydrazine (13, 18), which transform into N-phenylaminoimides (14, 19) during boiling in 80% acetic acid. Compounds 7, 8 and 14 isomerize to the corresponding 2-phenyl-1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra(1,2,3,4,5,6-hexa) hydropyrido[3,4-d]pyridazines (9, 10, 15) under the influence of heating in alcoholic solution of C2H5ONa or CH3ONa. Only in the case of imide 19 are 2- and 3-phenyl isomers (20 and 21) formed under these conditions. Some of the obtained compounds were pharmacologically active.
An overview of the different heterocyclic NO-releasing compounds is given. Mesoionic heterocycles like sydnone imines are one example. This class is discussed on the synthesis and the mechanism of NO formation from Molsidomine and its first metabolite SIN-1. Furthermore, 1,2,3,4 oxatriazolium olates and imidates are presented in an example of the synthesis of GEA-3175. Heterocyclic N-oxides are another group of compounds capable of NO release under certain conditions. This class is discussed in the example of furoxane carboxamides like CAS-1609, and some SAR-data show the great impact of intramolecular hydrogen bridges on their in vitro activity. Each class of compounds requires different cofactors for NO release: sydnone imines need oxidants like oxygen, furoxanes are converted to NO via reaction with thioles.
As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the 'writhing syndrome' test (5f-1/640 LD50). Some of the structure-activity relationships are also discussed.
The influence of chemical structure of porous polymers on the chromatographic properties of high-performance liquid chromatography columns was studied. Columns were packed with four different porous copolymers: di(methacryloyloxymethyl)naphthalene-divinylbenzene containing ester functional groups, 4,4'-bis(maleimido)diphenylmethane-divinylbenzene with imide groups, di(4,4'-dimethacrylphenyl)sulfone-divinylbenzene which contains sulphonyl groups, and styrenedivinylbenzene with any functional groups. Using the alkyl aryl ketone scale, the retention indices of five homologous series (alkylbenzenes, alkyl aryl ketones, N-alkylanilines, alkyl aryl ethers, alkylbenzoates) and column test compounds (toluene, nitrobenzene, p-cresol, 2-phenylethanol, N-methylaniline) were calculated. Their values were used for comparison of the selectivities of the studied polymeric packings.