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Syntheses of the title glycosides are described. The critical O-glycosylations were carried out in the presence of boron trifluoride etherate with a high degree of alpha-selectivity.
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The methylating agents methyl methanesulphonate (MMS) and N-methyl N'-nitro-N-nitrosoguanidine (MNNG), administered by single i.p. injection in mice failed to yield thymic lymphoma at doses around 60% of the LD50 values, in contrast to MNUA which gives a high yield of tumours by this route. Comparison of the tissue distribution and mode of DNA methylation by these agents showed a positive correlation with ability to methylate the 0-6 atom of guanine in DNA of the target tissues thymus and bone marrow and tumorigeneis. MMS gave a low yield of this product due to its relatively low Sn1 reactivity but was able to methylate DNA extensively at other sites in the target tissues and other organs examined. MNNG despite its ability to methylate 0-6 of guanine in DNA in vitro to the same relative extent as the potent carcinogen MNUA, methylated DNA of thymus and bone marrow to a very small extent in vivo but was able to methylate DNA in certain other tissues nearer the site of i.p. injection. These findings contrast with the general relatively extensive methylation of 0-6 of guanine in DNA of the target tissues and other organs by N-methyl-N-nitrosourea (MNUA).
1. In neutral aqueous solution N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) yields salts of nitrocyanamide as u.v.-absorbing products. With cysteine, as found independently by Schulz & McCalla (1969), the principal product is 2-nitràminothiazoline-4-carboxylic acid. Both these reactions liberate the methylating species; thiols enhance the rate markedly at neutral pH values. An alternative reaction with thiols gives cystine, presumably via the unstable S-nitrosocysteine. 2. Thiols (glutathione or N-acetylcysteine) in vitro at about the concentration found in mammalian cells enhance the rate of methylation of DNA markedly over that in neutral solution. 3. Treatment of cultured mammalian cells with MNNG results in rapid methylation of nucleic acids, the extent being greater the higher the thiol content of the cells. Rodent embryo cells are more extensively methylated than mouse L-cells of the same thiol content. Cellular thiol concentrations are decreased by MNNG. Proteins are less methylated by MNNG than are nucleic acids. 4. Methylation of cells by dimethyl sulphate does not depend on cellular thiol content and protein is not less methylated than nucleic acids. Methylation by MNNG may therefore be thiol-stimulated in cells. 5. Both in vitro and in cells about 7% of the methylation of DNA by MNNG occurs at the 6-oxygen atom of guanine. The major products 7-methylguanine and 3-methyladenine are given by both MNNG and dimethyl sulphate, but dimethyl sulphate does not yield O(6)-methylguanine. Possible reaction mechanisms to account for this difference between these methylating agents and its possible significance as a determinant of their biological effects are discussed.
Syntheses of p-trifluoroacetamidophenyl glycosides of the haptenic pentasaccharide and the non-reducing disaccharide unit of the title pentasaccharide are reported. The synthesis of the terminal N-formylkansosamine unit started from methyl 6-deoxy-2,3-O-isopropylidene-alpha-L-lyxo- hexopyran-4-uloside which, after C-3 methylation, was transformed into a glycosyl donor [3-O-benzyl-4-N-benzylformamido-4,6-dideoxy-3-C-methyl-2-O-methyl- alpha,beta-L-mannopyranosyl trichloroacetimidate (20), and used for the synthesis of p-trifluoroacetamidophenyl (4-formamido-4,6-dideoxy-3-C-methyl-2-O-methyl-alpha-L-mannopyranosyl)- (1-->3)-6-deoxy-2-O-methyl-alpha-D-mannopyranoside (29). Ethyl (3-O-benzyl-4-N-benzylformamido-4,6-dideoxy-3-C-methyl-2-O-methyl- alpha-L-mannopyranosyl)-(1-->3)-4-O-benzyl-6-deoxy-2-O-methyl-1-thio- alpha-D-mannopyranoside (31), prepared by glycosylation of ethyl 4-O-benzyl-6-deoxy-2-O-methyl-1-thio-alpha-D-mannopyranoside with 20, served as glycosyl donor in a 2 + 3 block synthesis of the title pentasaccharide.
A study has been made of the unscheduled DNA synthesis (UDS) induced in early spermatid stages of the mouse by methyl nitrosourea (MNU), a methylating agent that reacts predominantly by an SN1 type mechanism. In comparison with methyl methanesulfonate (MMS), a methylating agent that reacts predominantly by an SN2 mechanism, MNU induced more UDS by a factor of about 1.4. This result was in line with chemical dosimetry studies carrie out with both chemicals, which showed that 4 h after treatment with MNU, testicular DNA was methylated about 1.5 times more than it was 4 h after treatment with MMS. The UDS response in the spermatids fell off rapidly in the first half-day after treatment with either MNU or MMS. However, from 0.5 to 3 days after treatment the UDS response decreased with a t1/2 of 2.4 days after MNU treatment, but 1.2 days after MMS treatment. Chemical dosimetry studies with 3H-labeled MNU and MMS showed that the pattern of methylation produced in the developing sperm was different for each chemical and was generally correlated with the corresponding pattern of induced dominant-lethal mutations. However, on the basis of equal sperm-head methylation, MNU is as much as 17 times more effective than MMS in producing dominant lethals. It is suggested that more methylation by MNU at the O-6 position of guanine or phosphate groups in DNA in the developing germ cells may account for MNU's greater effectiveness in inducing dominant lethals. Greater methylation of these sites by MNU than by MMS might also account for the differences observed in the UDS response of the spermatids to these chemicals.
3-Ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (13), a bioisostere of amlodipine, was prepared by the reaction of ethyl 4-(2-hydroxyethoxy)acetoacetate (11) with methyl 2-(2,3-dichlorobenzylidene)acetoacetate (12) and NH4OAc. Compound 13 was elaborated to the target product 3-ethyl 5-methyl 1,4-dihydro-2-[2- [(1-methyl-1,4-dihydropyridyl-3-carbonyloxy)ethoxy]methyl]- 6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (16). The C-2 CH2OCH2CH2OH compound (13, IC50 = 6.56 x 10(-9) M) was about 44-fold more active as a calcium channel antagonist than the reference drug nimodipine (IC50 = 1.49 x 10(-8) M), but 4-fold less potent than felodipine (IC50 = 1.45 x 10(-9) M). Compound 16, possessing the 1-methyl-3-pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent calcium channel antagonist (IC50 = 2.99 x 10(-8) M) than the parent compound 13. Compounds 13, 16, felodipine and nimodipine are highly lipophilic (Kp = 227, 344, 442 and 187, respectively). The C-2 CH2OCH2CH2OH compound (13) exhibited equipotent anticonvulsant activity to nimodipine in the maximal electroshock (MES) anticonvulsant screen. Unlike nimodipine, 13 provided modest protection in the subcutaneous metrazol (scMet) anticonvulsant screen. In contrast, compound 16 was inactive in both the MES and scMet screens.
1. This paper deals with the identification of three O-methyl sugars in lipopolysaccharides isolated from strains of the Gram-negative photosynthetic family Rhodospirillaceae. In addition to the previously described 3-O-methyl-l-xylose, a second O-methyl sugar was encountered in the lipopolysaccharide of Rhodopseudomonas viridis F, namely 3-O-methyl-d-mannose. The lipopolysaccharides of two strains of Rhodopseudomonas palustris (strain 1e5 and 8/1) contain two O-methylsugars, 4-O-methyl-d-xylose and 3-O-methyl-6-deoxy-d-talose (d-acovenose). 4-O-Methyl-d-xylose, but not 3-O-methyl-6-deoxy-d-talose, could be identified in the lipopolysaccharides of the strains K/1 and 2/2 of the same species. 2. The O-methyl sugars described in this communication were isolated by paper chromatography and identified by g.l.c., paper chromatography, high-voltage electrophoresis and mass spectrometry. Besides the genuine sugars, their alditol acetates and their demethylated (parental) forms were investigated. Optical rotation measurements and, in one case, enzymic reactions were used to establish the optical configuration of the sugars under investigation.
The authors used the compounds 2-methyl-3)2-phenyl-3-methyl tetrahydroxasino)-propiophenone hydrochloriad (code PsI) and 1-phenoxycarboxy-1-phenyl-2-methyl-3 (2-phenyl-3-methyl-tetrahydroxasino-propan hydrochlorid(code P3) and carried out the following studies: influence of tripamine, corasol and strichnine seizures 1-phenoxycarboxy--1-phenyl-2-methyl--3 (2-phenyl--3-methyl-tetrahydroxasino) propar hydrochlor (Code P8) in white mice, effect on the hypertensive action of reserpine in white rats, investigations on the analeptic action in urethanized cats as well as on the analgetic effect, examined both by the test of "hot plate" and the method of Hendreshot-Forsaith. The examined compounds, administered in a dose of 1/6 of LD50, showed analgetic effect weaker than that of the preparations Morphinum hydrochloricum and Analigin, but their analeptic effect was less manifested that of of corasol. Similar to MAO-inhibitor-oproniazid although in smaller degree the compound PS1 potentiated tripamine seizures and inverted the hypotensive effect of Reserpine into hypertensive.
Four out of the eight possible stereoisomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine, 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and the corresponding iodomethylates have been synthesised. They were formally derived from hybridisation of potent though unselective agonists studied before, such as 1,3-dioxolane 1 and 1,3-oxathiolane 2, with the structure of nicotine. It was expected that, by exalting the molecular complexity of the parent compounds, in particular through stereochemical complication in the proximity of the critical cationic head of the molecule, the chance to find agonists able to discriminate among cholinergic receptors subtypes would increase. The relative and absolute configuration of the compounds obtained has been established by means of NMR spectroscopy and X-ray crystallography. In preliminary studies, their binding affinity has been evaluated on rat brain nicotinic and muscarinic receptors. While none of the compounds showed any nicotinic affinity up to the dose of 10 microM, most of the iodomethylates were endowed with promising affinity for the muscarinic receptors.
5-methyl-2-(4-methylphenyl)-7,8-dihydro-6H-cyclopenta[g]pyrazolo[1,5-a]pyrimidine, C17H17N3, 2-(4-chlorophenyl)-5-methyl-7,8-dihydro-6H-cyclopenta[g]pyrazolo[1,5-a]pyrimidine, C16H14ClN3, and 2-(4-bromophenyl)-5-methyl-7,8-dihydro-6H-cyclopenta[g]pyrazolo[1,5-a]pyrimidine, C16H14BrN3, are isostructural; in each compound, the molecules are linked into chains by a single C-H...pi(arene) hydrogen bond. Molecules of 2-(4-methoxyphenyl)-5-methyl-7,8-dihydro-6H-cyclopenta[g]pyrazolo[1,5-a]pyrimidine, C17H17N3O, are linked by a single C-H...N hydrogen bond into chains, which are themselves linked into sheets by a pi-pi stacking interaction.
Molecules of methyl 4-[(5-methyl-1H-pyrazol-3-yl)amino]-3-nitrobenzoate, C12H12N4O4, (I), exhibit a polarized (charge-separated) structure in the nitroaniline portion. The molecules are linked into chains of edge-fused R(2)2(16) and R(2)2(22) rings by a combination of N-H...O(carbonyl) and C-H...O(nitro) hydrogen bonds. Methyl 1-(5-methyl-1H-pyrazol-3-yl)-1H-benzimidazole-5-carboxylate, C13H12N4O2, (II), which is readily formed from (I) by reduction followed by ring formation, crystallizes with Z' = 2 in the space group P-1. Each of the two independent molecular types is linked into sheets of R(4)4(28) rings by a combination of N-H...N and C-H...O(carbonyl) hydrogen bonds.
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Starting from two previously studied muscarinic full agonists, characterized by a 1,3-dioxolane ((+)-1) and a 1,3-oxathiolane ((+)-2) cycle, two new series of muscarinic ligands were designed, obtained by the steric complication of the parent compounds produced by freezing the aminoalkyl chain into a pyrrolidine ring. Both tertiary amines and the corresponding iodomethyl derivatives were synthesised and studied, and several compounds of the series which behaved as muscarinic agonists have been selected, on the basis of preliminary binding experiments on rat cortex homogenates, for the present work. Results are presented obtained from testing the affinity of the selected compounds against cloned human muscarinic receptors expressed in CHO cells, in order to evaluate subtype selectivity. Their functional activity on classical models of M1-M4 receptors, in guinea pig and rabbit tissues is also reported. With respect to parent compounds, the new molecules present some selectivity toward hm2 receptors; fair M2 selectivity is also evident in functional studies, where these compounds behave as partial agonists. Among the other compounds of the series (2S, 4'R, 2'S)-1,1-dimethyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidinium iodide (-)-3 and (2R, 5'S, 2'S)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine (+)-5 present a promising pharmacological profile. Compound (-)-3 shows modest hm2 selectivity in binding experiments but a clearcut M2 selectivity in functional tests, where it behaves as a weak antagonist on M1 and M4 subtypes, as a weak full agonist on the M3 subtype and as a potent partial agonist on M2 subtype. Tertiary amine (+)-5 presents a quite similar profile but appears more interesting since, lacking a permanent charge on the nitrogen atom, it may represent an interesting tool to study CNS muscarinic receptors. Our results confirm that sterical complication of parent compounds (+)-1 and (+)-2 produces more selective muscarinic agonists.
The methyl-accepting chemotaxis proteins (MCPs) are integral membrane proteins that undergo reversible methylation during adaptation of bacterial cells to environmental attractants and repellents. The numerous methylated forms of each MCP are seen as a pattern of multiple bands on polyacrylamide gels. We have characterized the methylation sites in MCPI by analyzing methyl-accepting tryptic peptides. At least two different tryptic peptides accept methyl esters; one methyl-accepting peptide contains methionine and lysine and may be methylated a maximum of four times. The second methyl-accepting tryptic peptide contains arginine and may be methylated twice. Base-catalyzed demethylations of tryptic peptides and analysis of the charge differences between the different methylated forms of MCPI show that MCPI molecules may be methylated a total of six times. The two methyl esters on the methyl-accepting arginine peptide appear to be preferentially methylated in most of the forms of MCPI in attractant-stimulated cells. The ability to acquire six methylations on MCPI allows the bacterial cells to adapt to a broad range of attractant and repellent concentrations.
Reaction of DNA with the carcinogens N-methyl-N-nitrosourea and N-nitroso-N,N-dimethylamine produces several methylated species including the premutagenic O6-methylguanine. The mechanism of methylation is believed to be through a methanediazonium ion. We have studied the mechanism of methylation of DNA by these carcinogens by analyzing the stereochemistry of the methyl transfer. DNA was methylated in vitro by (R)- and (S)-N-[2H1,3H]methyl-N-nitrosourea and in vivo by (R)- and (S)-N-[2H1,3H]methyl-N-methyl-N-nitrosamine and (R)- and (S)-N-[2H1,3H]methyl-N-nitrosourea. 7-Methylguanine, 3-methyladenine, O6-methylguanine, and the methylated phosphate backbone were isolated. The methyl groups were converted into acetic acid, and the stereochemistry was analyzed. The identity of the nucleophile did not influence the stereochemistry of the methylation reaction. It was found that the methyl group was transferred with an average of 73% inversion and 27% retention of configuration. The most likely mechanism for the retention of configuration is through multiple methylation events in which nucleophiles which initially react with the methanediazonium ion react as electrophiles with DNA.
This report describes the chemical synthesis of six new bile acid analogs, namely, 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid (7 beta-methyl-cholic acid), 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid (7 alpha-methyl-ursocholic acid), 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid (7 xi-methyl-deoxycholic acid), 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-7-en-24-oic acid, 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid, and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid. The carboxyl group of the starting material 3 alpha,12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid was protected by conversion to its oxazoline derivative. A Grignard reaction of the bile acid oxazoline with CH3MgI followed by acid hydrolysis gave two epimeric trihydroxy-7-methyl-cholanoic acids and three dehydration products. The latter were purified by silica gel column chromatography and silica gel-AgNO3 column chromatography of their methyl ester derivatives. Catalytic hydrogenation of 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid gave 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid. The configuration of the 7-methyl groups and the position of the double bonds were assigned by proton nuclear magnetic resonance spectroscopy and the chromatographic and mass spectrometric properties of the new compounds. These compounds were synthesized for the purpose of exploring new and potentially more effective cholelitholytic agents. The hydrophilic bile acids 7 beta-methyl-cholic acid and 7 alpha-methyl-ursocholic acid are of particular interest because they should be resistant to bacterial 7-dehydroxylation.