Synthetic approaches to 6-substituted 9-(3-azido-3,4-dideoxy-β-d,l-erythro-pentopyranosyl)purines

Methyl 3-azido-2-O-benzoyl-3,4-dideoxy-β-dl-erythro-pentopyranoside (6) was synthesized through two routes in five steps from methyl 2,3-anhydro-4-deoxy-β-dl-erythro-pentopyranoside (1). The first route proceeded via selective azide displacement of the 3-tosyloxy group of methyl 4-deoxy-2,3-di-O-tosyl-α-dl-threo-pentopyranoside, followed by detosylation and benzoylation. The second route consisted, with a better overall yield, in the azide displacement of the mesyloxy group of methyl O-benzoyl-4-deoxy-3-O-methylsulfonyl-α-dl-threo-pentopyranoside (10), obtained by benzylate opening of 1, followed by benzoylation, debenzylation, and mesylation. Compound 6 was transformed into its glycosyl chloride, further treated by 6-chloropurine to give the nucleoside 9-(3-azido-2-O-benzoyl-3,4-dideoxy-β-dl-erythro-pentopyranosyl)-6-chloropurine (13). When treated with propanolic ammonia, 13 yielded 9-(3-azido-3,4-dideoxy-β-dl-erythro-pentopyranosyl)adenine.     

A discussion of microbial genetics in fermentation process development with particular reference to fungi producing high yields of antibiotics

When trying to improve antibiotic processes that are already high yielding, real industrial problems have to be faced. These include the use of organisms with non-ideal growth and recombination cycles, and problems of scale up from the laboratory to the main production plant. Many of the principles derived from academic studies have to be radically modified before they can be applied in the industrial context. These issues are a challenge to those who genuinely wish to contribute to the solution of industrial problems.     

Potentiation of the antagonistic effect of ACTH11-24 on steroidogenesis by synthesis of covalent dimeric conjugates

Covalent dimerization of the adrenocorticotropin fragment ACTH11-24 increases its antagonistic potency on the ACTH-induced steroidogenesis in isolated bovine fasciculata/reticularis cells by 3 orders of magnitude when the C-termini are linked via a 10 A long spacer. This strong potentiation, probably mediated by cross-linking of the receptors, was shown to be dependent on the point of attachment of the monomeric fragment to the spacer, thus providing information about the position of the binding site in the hormonal segment and about the distance of the receptors on the cell surface.     

T wave changes in humans and dogs during experimental dives.

Electrocardiogram (ECG) analysis was performed in three human divers studied at 21 and 23.5 ATA while they breathed various gas mixtures containing H2 and/or He (COMEX HYDRA IX experiment) and in five dogs exposed to 91 ATA of He-O2 or He-N2-O2. In all cases, the O2 partial pressure was slightly higher than its physiological value. These human and animal studies reveal that elevated pressure of different inert gases did not change the resting heart rate or its respiratory fluctuation. However, the T wave amplitude increased in proportion to the gas density in the three divers; this was also found in four of the five dogs studied. Changes in peak T wave configurations were also observed in the dog experiments. Positional changes in QRS or T vectors cannot explain these T wave changes.     

Uptake of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, delivered to cultured human fibroblasts by serum proteins. Lack of evidence for perturbation of LDL catabolism

Etretinate or acitretin are efficiently delivered to cultured human fibroblasts in the presence of low density lipoproteins, high density lipoproteins or human serum albumin. In contrast to acitretin, delivery of etretinate to fibroblasts is more efficiently achieved with human serum albumin than with lipoproteins. The uptake of etretinate and acitretin via low density lipoproteins delivery, does not take place via the low density lipoprotein-receptor endocytotic pathway but mostly through a passive exchange with the plasma membrane. However, in contrast to acitretin, the exchange of etretinate seems to occur alter binding of etretinate-loaded low density lipoproteins to the apolipoprotein B receptors. No differences are observed in binding, internalization and degradation of native, etretinate-loaded low density lipoproteins and acitretin-loaded low density lipoproteins, suggesting that the presence of these retinoids in low density lipoproteins does not alter their processing by the cells. Furthermore, the presence of these retinoids in the cells does not notably affect, under our experimental conditions, the catabolism of native low density lipoproteins.     

Mutations affecting the catalytic activity of Bacillus cereus 5/B/6 beta-lactamase II

Random in vitro mutagenesis of a cloned Bacillus cereus 5/B/6 beta-lactamase II gene was used to select defective genes unable to confer ampicillin or cephalosporin C resistance to Escherichia coli. DNA sequencing of mutant genes identified histidine at position 28 as important to beta-lactamase II function. In addition, the isolation of six identical frameshift mutants established that the carboxyl-terminal end of beta-lactamase II is critical for enzyme function. Random mutagenesis also revealed that His88 (implicated previously as one of 4 residues acting as a zinc ligand) is crucial to enzymatic activity and that a glycine to glutamic acid substitution at position 148 produced a defective beta-lactamase. Oligonucleotide mutagenesis directed at Glu37 and Glu212 suggests that these residues are inconsequential to enzyme function but that histidine at position 28 may be involved in substrate binding or recognition.