Gerard Janssen

Isomerization of polyunsaturated long chain fatty acids by propionibacteria

Summary Nine species of the genus Propionibacterium were studied for in vitro biotransformation of unsaturated long chain fatty acids. P. acnes isomerized the 9- cis -double bond of linoleic acid into a 10- trans -double bond followed by partial reduction of the 12- cis -double bond. This species also isomerized the 9- cis -double bond of γ-linolenic acid, the 10- cis -double bond of 10- cis , 13- cis -nonadecadienoic acid and the 12- cis -double bond of homo-γ-linolenic acid and arachidonic acid. P. freudenreichii subsp. freudenreichii , P. freudenreichii subsp. shermanii, P. acidi-propionici and P. technicum isomerized the 12- cis -double bond of linoleic acid into an 11- trans -double bond partially followed by reduction of the 9- cis -double bond. These species also isomerized the 12- cis -double bond of linolenic acid and y-linolenic acid. P. granulosum, P. avidum, P. jensenii, P. thoenii and P. lymphopbilum did not isomerize unsaturated long chain fatty acids. After prolonged incubation, all strains partially catabolized the long chain fatty acids in the culture medium.

An efficient synthesis and physico-chemical properties of 2'-O-D-ribofuranosylnucleosides, minor tRNA components

ABSTRACT A high yield preparation of 9-(2-O-β-D-ribofuranosyl-β-D-ribofuranosyl)adenine, guanine- and the pyrimidine analogs (cytosine, thymine and uracil base moiety) has been achieved, and the conformational properties of the ring systems were investigated using NMR spectroscopy and X-ray.

Synthesis and Biological Activity of the Mono- and Diamino Analogues of 2′-Deoxyadenosine, Cordycepin, 9-(3-Deoxy-α-D-Threo-Pentofuranosyl)-Adenine (A Structural Component of Agrocin 84) and 9-(2-Deoxy-α-D-Threo-Pentofuranosyl)Adenine

Abstract The mono- and diamino analogues of 9-(2-deoxy-α-D-erythro-pen-tofuranosyl)adenine la, 9-(2-deoxy-α-D-threo-pentofuranosyl)adenine 4a, 9-(3-deoxy-α-D-erythro-pentofuranosyl)adenine 2a and 9-(3-deoxy-α-D-threo-pentofuranosyl)adenine 3a were synthesized by triphenylphosphine reduction of the corresponding azido compounds. The azido group was introduced by a substitution reaction with lithium azide on mesylates or, more directly, by reaction with lithium azide, triphenylphosphine and carbon tetrabromide. Of the newly synthesized compounds, only 3′-amino-2′,3′-dideoxyadenosine proved, albeit slightly, inhibitory to murine leukemia L1210 and mammary carcinoma FM3A, and human B-lymphoblast Raji, T-lymphoblast Molt/4F and T-lymphocyte MT-4 cell proliferation in vitro (50 % inhibitory dose : 43.1-323 μM). None of the compounds inhibited human immunodeficiency virus-induced cytopathogenicity in MT-4 cells.

Sex-linked differences in bile acid metabolism of germfree rats.

Abstract The bile acid composition was investigated in male and female germfree rats. β-Muricholic acid and cholic acid were the major bile acids in both sexes; in addition, 3β-hydroxy-5-cholenoic acid, chenodeoxycholic acid, α-muricholic acid, allochenodeoxycholic acid and allocholic acid were present. Important sex-linked differences in the relative amounts and the sulfation of these substances were observed. β-Muricholic and cholic acid accounted for 61.4 % and 27.7 % of total bile acids in the small intestine of males; females had 38.9 % of β-muricholic acid and 50 % of cholic acid. In females, the bile acid sulfate fraction increased from 1.1 % in the small intestine to 22.3 % in the large intestine; in males these values were 0.2 % and 1.7 %, respectively. A considerable increase in the relative amounts of allochenodeoxycholic and allocholic acid was observed in the cecum and large intestine of the female rat, where more than 70 % of these substances was in the bile acid sulfate fraction. In males these allo-bile acids were mainly in the unsulfated fraction and their relative amounts did not increase in the large intestine.

Specific inhibition of cholesterol absorption by sulfaguanidine

Abstract 1.(1) Feeding of 1% sulfaguanidine to mice on a cholesterol-supplemented diet lowered liver cholesterol concentrations about 50%. This phenomenon was obtained with commercial diet, and with formula diets containing different carbohydrates. 2.(2) Single oral doses of sulfaguanidine proinoted the fecal excretion of simultaneously given 4- 14 C-cholesterol. 3.(3) Fecal excretion of fatty acid was not affected by sulfaguanidine. Fecal excretion of bile salts was slightly depressed. 4.(4) The effect of sulfaguanidine was most pronounced when the drug and cholesterol were fed simultaneously. Prior feeding of sulfaguanidine for 1 week did not alter cholesterol absorption after withdrawal of sulfaguanidine. 5.(5) The inhibition of cholesterol absorption does not depend on the antibacterial action of sulfaguanidine, since it also reduced liver cholesterol in germfree mice. 6.(6) Compounds with chemical structures resembling that of sulfaguanidine were inactive.

Synthesis, enzymatic stability and base-pairing properties of oligothymidylates containing thymidine dimers with different N-substituted guanidine linkages

Reaction of 5′-amino-5′-deoxythymidine 1 with different S,S-dimethyl-N-substituted dithiocarbonimidates 2a–j afforded the N-substituted isothioureas 3a–j which, on further reaction with 3′-amino-3′-deoxythymidine 4 in the presence of AgNO3, led to thymidine dimers 5a–j with different N-substituted guanidine linkages. The dimer with a thiourea linkage (compound 9) was also prepared. Dimers 5a–h were incorporated at different positions in oligothymidylates by using phosphoramidite chemistry. Attempts to incorporate compounds 5i,j and 9 led to complex mixtures. 3′-Protected oligonucleotides showed somewhat higher stability to snake venom phosphodiesterase. Melting experiments revealed that the N-methylsulfonyl-substituted guanidine linkage best mimics the natural phosphodiester bridge. The fluorescence properties of oligonucleotides with dimer 5f were studied in view of its potential use as a non-radioactive label for DNA.

Protection of the Lactam Function of 2′-Deoxyinosine with A 2-(4-Nitrophenyl)-Ethyl Moiety

Abstract The reaction of O-protected inosine with p-nitrophenyl ethanol under Mitsunobu conditions yields a mixture of the 1- and 0° -alkylated derivatives. 2′-Deoxyinosine protected on 06 -, can be synthesized fairly easy from deoxyguanosine with a Mitsunobu reaction followed by reductive deamination.

Preparation and biological evaluation of technetium‐99m‐L,L‐propylenedicysteine

In this study we have investigated the influence of replacement of the ethylene moiety in 99mTc-L,L-ethylenedicysteine (99mTc-L,L-EC) by a propylene moiety on the physical and biological properties. S,S′-dibenzyl-N,N′-1,3-propylenediylbis-L-cysteine was synthesised by reaction of S-benzyl-L-cysteine with 1,3-dichloropropane. The thiol groups were deprotected with sodium in liquid ammonia. The resulting L,L-propylenedicysteine (L,L-PC) was directly labelled with 99mTc at pH 12. Whereas labelling of L,L-ED results in a single radiochemical species, labelling of L,L-PC yields two 99mTc-complexes in a 3/1 ratio, probably two isomers with the central propylene carbon atom syn or anti to the oxotechnetium core. These isomers are stable and do not interconvert at neutral pH. In mice, both isomers of 99mTc-L,L-PC showed a slower urinary excretion and a higher hepatobiliary uptake than 99mTc-L,L-EC. Furthermore, 99Tc-L,L-PC showed some renal retention. In a baboon, both conformers of 99mTc-L,L-PC were excreted rapidly in the urine without visualisation of liver or intestines, but their plasma clearance was only 33.6% of hippuran clearance for isomer A and 25.6% for isomer B, as compared to 75% in the case of 99mTc-L,L-EC. The results indicate that, besides the oxotechnetium-glycine sequence, also the length and orientation of the alkylene bridge between the two amines are important for the interaction of this type of compounds with the renal tubular transport proteins. Copyright

A further study of the bile acids in infants with coprostanic acidemia

The structure of the bile acids in serum of infants with coprostanic acidemia was further investigated. The identity of 3 alpha-hydroxy-5 beta-cholestan-26-oic acid and 3 beta-hydroxy-5-cholesten-26-oic acid was confirmed. The biosynthesis of the 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-C29 dicarboxylic bile acid does not start from beta-sitosterol.

Investigation of the kinetics of degradation of hexopyranosylated cytosine nucleosides using liquid chromatography

Abstract Liquid chromatography was used to follow the degradation of hexopyranosylated cytosine nucleosides in buffers of acid, neutral and alkaline pH and of constant ionic strength. The compounds were found to degrade by hydrolysis to cytosine and/or by deamination to the corresponding uracil nucleosides. Degradation in acid is influenced by the number of sugar hydroxyl groups, presence of sugar double bonds and the type of anomer. Stability of some of the compounds was compared with that of related thymine nucleosides. Temperature studies support a unimolecular mechanism of hydrolysis at pH 1.22.