Polymer-aided stereodivergent synthesis (PASS): a new concept for the discrete preparation of optical antipodes.

[structure: see text]. A new concept for the discrete preparation of optical antipodes is reported. The approach makes use of a cyclization/cleavage procedure that has been applied to polymer-supported quasi-meso compound 1, containing a polymeric leaving group and a regular leaving group. Two-directional cyclization leads to the formation and separation of quasi-enantiomers 2 and 3 simultaneously, with one being immobilized and one free in solution. Treatment of 2 and 3 with appropriate nucleophiles gives discrete enantiomers 4 and 5.

Clathration-induced asymmetric transformation of cefadroxil.

[structure: see text] The cephalosporin antibiotic Cefadroxil can be epimerized at the alpha-carbon of its amino acid side chain using pyridoxal as the mediator. By clathration with 2,7-dihydroxynaphthalene, the desired diastereomer can be selectively withdrawn from the equilibrating mixture of epimers. In this way, an asymmetric transformation of Cefadroxil can be accomplished. This opens the possibility of the production of Cefadroxil starting from racemic p-hydroxyphenylglycine, in contrast to the current industrial synthesis that employs the D-amino acid in enantiopure form.

A new synthesis of p-hydroxy phenylglycine and some analogues from p-benzoquinone

[reaction: see text] A new route to p-hydroxy phenylglycine and N-substituted analogues has been developed starting from p-benzoquinone. 1,2-Addition of methyl lithioacetate to p-benzoquinone and subsequent quenching of the oxygen anion with methyl chloroformate, followed by an elimination-addition reaction with an appropriate amine, resulted in the desired amino acid derivatives. A diastereoselectivity of 60% was achieved using 8-phenylmenthyl acetate as the chiral auxiliary.

A critical account on the inception of Striga seed germination.

The seeds of the parasitic weed Striga germinate in response to stimulants exuded by the roots of host plants and some nonhost plants. Literature data are summarized that support the view that strigolactones induce germination of parasitic weed seeds via a receptor-mediated mechanism. The suggestion by Lynn et al. that the strigol D-ring is solely responsible for germinating Striga seeds via a redox reaction was based on hypothesized structural similarities between the natural compound dihydrosorgoleone (SXSg) and the strigol D-ring. Experiments have shown that the mechanistic connection between SXSg and the strigol D-ring is not valid, and therefore the proposed redox mechanism for the induction of Striga seed germination by strigolactones does not hold.

Dose-response of seeds of the parasitic weeds Striga and Orobanche toward the synthetic germination stimulants GR 24 and Nijmegen 1.

Striga and Orobanche seeds germinate in response to a host-derived germination stimulant. Dose-response curves of the synthetic strigolactone analogues GR 24 and Nijmegen 1 were determined, and their activities were compared to that of the naturally occurring stimulant sorgolactone. Typical sigmoidal curves were obtained. ED(50) values for GR 24 were in the order of 10(-)(9)-10(-)(8) mol/L; for Nijmegen 1 these values were 3 orders of magnitude higher. Both synthetic stimulants are appreciably active at low concentrations and merit investigation as agents for the suicidal germination approach (i.e., treatment of the soil with stimulant in the absence of a host).

The origin of excessive daytime sleepiness in the Prader-Willi syndrome.

The polygraphically recorded sleep-wake continuum of 21 Prader-Willi syndrome (PWS) patients was compared with that of 19 normal people. In the Prader-Willi group, excessive daytime sleepiness (EDS) is found in 95% of subjects, and rapid eye movement (REM) sleep disorders occur in 52%. These two features were significantly different from the normal group of subjects. No indications were found for the presence of the apnoea syndrome. The REM sleep disorders are: sleep onset rapid eye movements (SOREM), REM sleep in naps, many arousals during REM sleep, and a significant decrease in total REM sleep. These disturbances in the Prader-Willi group, combined with the presence of EDS and sometimes of cataplexy, are likely to be expressions of a narcoleptic syndrome although this was not sustained by the HLA-DR2 expression above normal. The quality of life of PWS subjects can be improved in some cases by treating them as narcoleptic patients.

The influence of various amphiphilic phosphates on in vitro caries lesion formation in human dental enamel.

Some newly designed surface-active phosphates were investigated with respect to their capacity to inhibit caries lesion formation in vitro. On the labial or buccal surfaces of sound human third molars, windows were prepared for investigation. One half of each window was treated with the test compound at pH values of 7.5, 5.5, or 3.5. The other half served as a control. Both halves were demineralized and the generated caries lesions in both parts were compared by means of quantitative microradiography. Mono-, bis- and trisphosphates differed only marginally in their effect on the demineralization. The compounds diminished the demineralization down to 30% of that of untreated enamel. Per molecule at least one long alkyl chain (more than 12 C atoms) was required for achieving decreased demineralization, indicating the importance of a low surface tension. The results suggest that some of the tested compounds have promising properties for their use as anticaries agents, especially when applied in combination with fluoride.

The effect of 2-O-stearoyl-glycerol 1,3-bisphosphate on the demineralization of dental enamel in vitro.

Parts of the buccal and lingual enamel surfaces of sound human third molars were treated with a test compound, and the non-treated parts served as control. After the treatment both parts were demineralized, and the artificial caries lesions were analyzed by means of quantitative microradiography. Treatment during only 1 minute with an aqueous solution of 1.5 mmol/l of the surface active compound 2-O-stearoyl-glycerol 1,3-bisphosphate (Glydip) resulted in a decrease in the rate of enamel demineralization by about 60%. When Glydip was dissolved in a toothpaste/water slurry it inhibited the demineralization by about 30%. When the enamel was covered by a salivary pellicle prior to the application of the slurry, the inhibition of the demineralization disappeared. However, when Glydip was applied in an aqueous solution, the presence of a salivary pellicle did not interfere with the decreasing effect of Glydip on the demineralization. It is concluded that Glydip has promising properties for its use as an anti-caries agent, in combination with fluoride.

In vitro remineralization of caries lesions treated with surface-active phosphates.

Intact human enamel was demineralized in vitro to obtain artificial caries lesions. Part of the lesions was then treated with different surface-active compounds and remineralized with a remineralizing solution. The other part of the lesions was de- and remineralized in the same way, but was not treated with a surface-active compound. The results indicate that none of the surface-active compounds do affect the remineralization of the caries lesions. Possible applications of the tested compounds in combination with fluoride, for the prevention of dental caries, are discussed.

Effect of 2-O-stearoyl glycerol-1,3-bisphosphate on in vitro demineralization of dental root surfaces.

The effect of 2-O-stearoyl glycerol-1,3-bisphosphate (Glydip) on caries lesion formation in root surfaces of sound human third molars was investigated in vitro. For this purpose parts of the root surfaces were treated with Glydip. Adjacent parts of the surfaces were not treated and served as control. Lesions were obtained by demineralization with an acetate buffer of pH 5.0. It was found that Glydip had no inhibiting effect on the rate of lesion formation. Additionally, pretreatments were performed with lauryl sulphate, a chloroform-methanol mixture, an aqueous solution of sodium hypochlorite, and collagenase prior to the treatment with Glydip to enhance the accessibility of the tissue for Glydip. None of these pretreatments or combinations of them revealed an inhibiting effect of Glydip on the rate of caries lesion formation. This result is in contrast to the effect of Glydip on the demineralization of enamel.

Effects of surface-active compounds on the demineralization of dental enamel.

Slices of bovine enamel and intact human enamel were treated with (a) a two-step treatment consisting of phytate followed by hexadecyl amine, or (b) 2-O-stearoylglycerol-1,3-diphosphate (Glydip), or (c) phosphatidic acid. The effect of these agents on the rate of caries lesion formation and on the permeability of dental enamel was quantitatively determined. Glydip had the most pronounced effect on lesion formation and showed a strong inhibiting effect on the rate of demineralization, combined with a reduction of the permeability. The results indicate that at least a part of the effect of Glydip on the demineralization was caused by a reduction of the rate of dissolution of the enamel mineral. The reduction in permeability may have had an additional effect.

Glutathione conjugation and bacterial mutagenicity of racemic and enantiomerically pure cis- and trans-methyl epoxycinnamates.

This paper describes the ability of racemic, and enantiomerically pure cis- and trans-methyl epoxycinnamates (methyl 3-phenyl-2,3-epoxy-propanoates) to undergo glutathione conjugation and subsequent excretion as mercapturic acid and on the mutagenicities of these epoxy esters in the Ames assay. In incubation mixtures containing rat liver cytosol (9,000 g), the decrease of glutathione due to the epoxy esters occurred enzymatically. The highest glutathione depletion was found for the cis-epoxy cinnamic esters. Adult male rats administered a single i.p. dose of racemic trans- and cis-epoxy cinnamates (0.7 mmol/kg, n = 4) excreted thioethers in urine. Higher urinary thioether excretion was found after the cis-epoxy ester dosing. The structures of the thioether metabolites isolated from the urinary extracts were identified by TLC and confirmed by synthesis and mass spectrometry (FAB+). The thioethers appeared to be hydroxy mercapturic acids. The N-alkylating potential of the racemic epoxy esters was determined using 4-(p-nitrobenzyl)pyridine (= NBP). The trans-epoxy ester appeared to react much better with NBP than the cis-compound. Mutagenic effects of racemic trans-epoxy cinnamate as well as the enantiomerically pure trans-epoxy cinnamates were observed in the Ames test with S. typhimurium strains TA1535, TA1537, TA1538 and TA100 without metabolic activation. No mutagenic responses were detected using any of the epoxy cinnamates with S9 activation. By comparing the mutagenicity and the enzymatically catalyzed glutathione conjugation it follows that the activity of the respective enantiomeric methyl cinnamates goes in the opposite order. Glutathione conjugation plays a protective role in the detoxication in living organism of the potentially toxic methyl epoxy cinnamates.

Substrate specific sulfatase activity from hair follicles in recessive X-linked ichthyosis.

Recessive X-linked ichthyosis (RXLI) has its biochemical basis in a defect of the enzyme steroid sulfatase. Since several studies have reported a simultaneous deficiency of arylsulfatase C and steroid sulfatase it has been hypothesized that both enzymes are identical. In human hair follicles, however, hydrolytic activity for 4-methylumbelliferone sulfate, the substrate for arylsulfatase C, is found, while dehydroepiandrosterone sulfate is not hydrolyzed at all. These findings suggested the possible existence of two different enzymes. In the present paper structure-activity studies and molecular energy calculations are used for the demonstration that the remaining sulfatase activity in hair follicles of RXLI patients can be explained on the basis of the assumption that the enzyme has not lost its total function but has become less efficient.

Inhibition of ADP-ribosylation increases X-ray-induced chromosomal damage in mouse testis and bone-marrow cells in vivo.

The effect of 3-aminobenzamide (3AB) treatment on chromosomal radiosensitivity of mouse spermatogonial stem cells and bone-marrow cells was studied using various doses of X-rays. The results show that 3AB increases the induction of reciprocal translocations in slowly cycling spermatogonia as well as the frequency of chromosomal aberrations in actively dividing bone-marrow cells. The experiments indicate that both types of tissue are suitable to study the ability of inhibitors of ADP-ribosylation to modulate chromosome-breaking damage induced by ionizing radiation in vivo.

Disposition of disodium azodisalicylate in healthy subjects. A possible new drug for inflammatory bowel disease.

The disposition of disodium azodisalicylate and salicylazosulfapyridine was studied in 6 healthy volunteers. After a single oral dose (1.0 g disodium azodisalicylate; 2.3 g salicylazosulfapyridine) maximum serum concentrations of the intact compound ranged between 1.4 and 6.8 mumol/L and 32 and 114 mumol/L, respectively. Mean residence time and serum half-life of disodium azodisalicylate were considerably longer than those of salicylazosulfapyridine, probably because of a higher apparent volume of distribution. Both compounds were largely split by colonic bacteria and comparable amounts of the active moiety, (acetyl-)5-aminosalicylic acid, were recovered in feces. During long-term ingestion of disodium azodisalicylate (1.0 g/day) it took 6-19 days to reach a steady state. Serum concentrations of disodium azodisalicylate at steady state were low: 2.2-8.4 mumol/L. The serum half-life was 6-10 days. It is concluded that the disposition of disodium azodisalicylate is similar, in important respects, to that of salicylazosulfapyridine. Disodium azodisalicylate, therefore, deserves therapeutic trial.