Isosteres of ester derived glucose uptake inhibitors

Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.     

Orotidine Monophosphate Decarboxylase——A Fascinating Workhorse Enzyme with Therapeutic Potential

Orotidine 50-monophosphate decarboxylase(ODCase) is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 50-monophosphate(OMP) to uridine 50-monophosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved Dx Kxx Dx motif is present in all the groups,depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodouridine, a potential antimalarial agent.     

Hyperproduction of Orotic Acid and Orotidine by Mutants of Bacillus subtilis

The fatty acid composition of lipids in various organs and in the stomach contents of two species of frigate mackerel, Auxis rocheri and Auxis thazard, related to the tuna species was determined. Docosahexaenoic acid was the dominant unsaturated fatty acid accounting for 20% or more of the total fatty acids in all organs of the two frigate mackerel species (mean ±S.D.: 22.6 ± 6.0% for rocheri, 28.0 ± 4.3% for A. thazard), while the fatty acids in lipids from their stomach contents were comparatively low (1.5–13.0% for A. rocheri, 15.4–16.5% for A. thazard). It is suggested that the high content of DHA in the lipids of tuna species is a general characteristic.     

Enzymatic Production of Ribavirin from Orotidine by Erwinia carotovora AJ 2992

Microorganisms that produce ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide; virazole^®) directly from orotidine and 1,2,4-triazole-3-carboxamide (TCA) were screened from our stock cultures. Of the 425 strains, Erwinia carotovora AJ 2992 was found to possess potent ribavirin-producing ability, from orotidine and TCA. In the presence of intact cells of E. carotovora AJ 2992, 183 mm ribavirin was produced from 300 mm orotidine and 300 mm TCA on 48 hr reaction.     

Orotidine 5'-monophosphate decarboxylase: transition state stabilization from remote protein-phosphodianion interactions

Mutants of orotidine 5'-monophosphate decarboxylase containing all possible single (Q215A, Y217F, and R235A), double, and triple substitutions of the side chains that interact with the phosphodianion group of the substrate orotidine 5'-monophosphate have been prepared. Essentially the entire effect of these mutations on the decarboxylation of the truncated neutral substrate 1-(β-d-erythrofuranosyl)orotic acid that lacks a phosphodianion group is expressed as a decrease in the third-order rate constant for activation by phosphite dianion. The results are consistent with a model in which phosphodianion binding interactions are utilized to stabilize a rare closed enzyme form that exhibits a high catalytic activity for decarboxylation.     

Isosteres of natural phosphates. 5. The preparation of phosphotidylcholine,phosphotidylethanolamine and phosphotidylglycerol

Isosteric phosphonate analogues of phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol have been prepared in which the normal oxygen atom of the phosphate ester linkage in the glycerol backbone of the molecule has been replaced by a methylene group. These have been prepared by the coupling of the previously reported phosphotidic acid (isosteric analogue of phosphatidic acid) with the appropriate protected hydroxyl compound mediated by trichloroacetonitrile. In all cases, racemic materials have been isolated; for the analogue of phosphatidylglycerol, a mixture of two enantiomeric pairs is isolated.     

Isosteres of natural phosphates. 6. The preparation and properties of Lysophosphotidic acid

We herein report the first chemical synthesis of phosphonic acid analogues of lysophosphatidic acid. The racemic isosteric analogues, 4-acyloxy-3-hydroxybutyl-1-phosphonic acids, of lyso-phosphatidic acid were prepared by both catalytic and hydride reductions of the 4-acyloxy-3-oxobutyl-1-phosphonic acids, a general method for the preparation of the latter having been reported previously. The lysophosphatidic acids have been found to substrates for lysophosphatidic acid acyl transferase, and may be acylated chemically to yield phosphotidic acids. The latter reaction is of use in the preparation of differentially acylated phosphatidic acids.     

Impact of Atmospheric Sulfur Deposition on Sulfur Metabolism in Plants: H2S as Sulfur Source for Sulfur Deprived Brassica oleracea L.

Brassica oleracea L. was rather insensitive to atmospheric H₂S: growth was only negatively affected at ≥0.4 μl I^?1. Shoots formed a sink for H₂S and the uptake rate showed saturation kinetics with respect to the atmospheric concentration. The H₂S uptake rate was high in comparison with other species, which may reflect the high sulfur need of Brassica. The net uptake of sulfate by roots of hydroponically grown plants was substantially reduced after one week of exposure to 0.25 μl l^?1 H₂S, indicating that plants switched in part from sulfate to H₂S as sulfur source for plant growth. Plants were sulfur deficient after two weeks of sulfur deprivation, illustrated by reduced growth, which was more pronounced for shoots than for roots, and in enhanced shoot dry matter content. The latter could for the greater part be attributed to enhanced levels of soluble sugars and starch. Sulfur deficiency was further characterized by a low pigment content, extremely low levels of sulfate and water-soluble non-protein thiols, and by enhanced levels of nitrate and free amino acids, particularly in the shoots. Furthermore, sulfur deficient plants contained a lower total lipid content in shoots, whereas its content in roots was unaffected. The level of sulfolipids was decreased in both roots and shoots. When sulfur deprived plants were exposed to 0.25 μl I^?1 H₂S for one week, all sulfur deficiency symptoms were abolished and growth was restored. Furthermore, plants were able to grow with 0.4 μl I^?1 H₂S as the sole sulfur source. Water-soluble non-protein thiol content was enhanced in both shoots and roots of H₂S exposed plants, irrespective of the sulfate supply to the roots, whereas plants grown with H₂S as sole sulfur source contained very low sulfate levels. The interaction between atmospheric and pedospheric sulfur nutrition in plants is discussed.     

Synthesis of Cyclopropane Isosteres of the Antiepilepsy Drug Vigabatrin and Evaluation of their Inhibition of GABA Aminotransferase

The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; γ-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5'-phosphate (PLP)-dependent enzyme γ-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M. and Silverman, R. B. (1991) J. Am. Chem. Soc. 113, 9341–9349), a Michael addition pathway (Scheme 2, pathway a) and an enamine pathway (Scheme 2, pathway b). Analogs of vigabatrin with a cyclopropyl or cyanocyclopropyl functionality in place of the vinyl group (2–5) were synthesized as potential inactivators of GABA-AT that can inactivate the enzyme only through a Michael addition pathway, but they were found to be only weak inhibitors of the enzyme.     

Relations between Hydrogen and Sulfur Metabolism in Purple Sulfur Bacteria

Microbiology - The review considers the role of purple sulfur bacteria in the global cycles of hydrogen and sulfur, as well as the ecology and physiology of these bacteria in relation to the...     

Sulfur soil testing

A wide range of extractants have been used to extract S from soils but correlations with plant response have generally been poor. Direct evidence that ester sulfates contribute to plant S supply lead to the development of the 0.25 M KCl extract heated at 40°C for 3 hours. Sequential extraction showed that this extractant removed 5.9% of ester sulfates from unfertilised soil. Support of the efficacy of the extract was obtained using specific radioactivity data from plants and soil extract.     

Effect of Sulfur Nutrition on the Redistribution of Sulfur in Vegetative Soybean Plants

Soybean (Glycine max L.) plants were grown with sulfate at 2 (S2) or 20 [mu]M (S20) and treated with [35S]sulfate between d 36 and 38. Growth was continued with or without 20 [mu]M sulfate (i.e. S2 -> S0, S2 -> S20, etc.). When the leaves of S20 -> S20 plants were 70% expanded, they exported S and 35S label from the soluble fraction, largely as sulfate, to new expanding leaves. However, 35S label in the insoluble fraction was not remobilized. Very little of the 35S label in the soluble fraction of the leaves of S20 -> S0 plants was redistributed; most was incorporated into the insoluble fraction. The low levels of S remobilization from the insoluble fraction were attributed to the high level of N in the nutrient solution (15 mM). Most of the 35S label in S2 plants at d 38 occurred in the soluble fraction of the roots. In S2 -> S0 plants the 35S label was incorporated into the insoluble fraction of the roots, but in S2 -> S20 plants 35S label was rapidly exported to leaves 3 to 6. It was concluded that the soluble fraction of roots contains a small metabolically active pool of S and another larger pool that is in slow equilibrium with the small pool.     

Sulfur Assimilation and the Role of Sulfur in Plant Metabolism: A Survey

Sulfur occurs in two major amino-acids, cysteine (Cys) and methionine (Met), essential for the primary and secondary metabolism of the plant. Cys, as the first carbon/nitrogen-reduced sulfur product resulting from the sulfate assimilation pathway, serves as a sulfur donor for Met, glutathione, vitamins, co-factors, and sulfur compounds that play a major role in the growth and development of plant cells. This sulfur imprinting occurs in a myriad of fundamental processes, from photosynthesis to carbon and nitrogen metabolism. Cys and Met occur in proteins, with the former playing a wide range of functions in proteins catalysis. In addition, the sulfur atom in proteins forms part of a redox buffer, as for glutathione, through specific detoxification/protection mechanisms. In this review, a survey of sulfur assimilation from sulfate to Cys, Met and glutathione is presented with highlights on open questions on their respective biosynthetic pathways and regulations that derived from recent findings. These are addressed at the biochemical and molecular levels with respect to the fate of Cys and Met throughout the plant-cell metabolism.     

The Origin of Strain Effects on Sulfur Redox Electrocatalyst for Lithium Sulfur Batteries

Introducing strain is considered an effective strategy to enhance the catalytic activity of host material in lithium-sulfur batteries (LSB). However, the introduction of strain through chemical methods often inevitably leads to changes in chemical composition and phase structure, making it difficult to truly reveal the essence and root cause of catalytic activity enhancement. In this paper, strain into MoS₂ is introduced through a simple heat treatment and quenching. Experimental research and theoretical analysis show that the strain raises parts of antibonding orbitals in Mo─S bonds above the Fermi level and weakens Li─S and S─S bonds, resulting in tight anchoring and accelerating the conversion for lithium polysulfides (LiPSs). The cells based on the MoS₂ with high strain delivers an initial discharge specific capacity as high as 1265 mAh g⁻¹ under 0.2 C and a low average capacity fading of 0.041% per cycle during 1500 cycles under 1 C. This research work deeply reveals the origin of strain effects in the reaction process of LSB, providing important design principles and references for the rational design of high-performance catalytic materials in the future.