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Research was conducted to understand the mechanics of adenosine 5'-diphosphate (ADP) ribosyl cyclase substrate recognition and effect of the inhibitors on the process. Results point out to the importance of nicotinamide ribose and the nicotinamide aromatic ring for the enzyme-substrate recognition and modifications in the former inhibits this reaction.

The mechanism of inhibition of myo-inositol 1-phosphate (MIP) synthase by myo-2-inosose 1-phosphate at pH 7.2 was determined by examining the structural features for active site binding in myo-2-inosose 1-phosphate and the contribution of its keto form to these interactions. 2-Deoxy-myo-inositol 1-phosphate (dMIP) was used to evaluate the impact of removing the oxidized reaction center of the enzyme. dMIP reduced its inhibitor potency by 47-fold. Meanwhile, dihydroxyacetone phosphate inhibited MIP synthase activity at 700 muMolar at pH 7.2. These results suggest that active site interactions are essential in inhibiting MIP synthase.

An analysis of two approaches to phosphonomethylate cyclohexene oxide and substituted cyclohexene oxides obtained from quinic acid and myoinositol involved a study of the tradeoff between synthetic simplicity and regioselectivity during oxirane ring opening. Direct phosphonomethylation of the cyclohexene oxides involves the application of boron trifluoride in conjunction with diisopropyl lithiomethanephosphonate.

Research was conducted to examine the hypothesis that a single, active-site base and its conjugate acid mediate all of the non-redox steps separating the substrate from the product. Conformationally restricted (Z)- and (E)-vinylhomophosphonate analogues of the substrate D-glucose 6-phosphate and substrate analogues effectively locked in cyclic, pyranoside forms were synthesized and studied for binding to the active site of myo-inositol 1-phosphate (MIP). Results indicate that MIP synthase exploits the phosphate monoester of 5-keto-D-glucose 6-phosphate to catalyze the intramolecular aldol condensation of the reactive intermediate.

A study was conducted to analyze whether inhibition of myo-inositol 1-phosphate (MIP) synthase in the production of myo-inosotol can be used as alternative to lithium for treatment of manic depression. MIP was reduced through reoxidation of beta-nicotinamide adenine dinucleotide to NAD during the formation of an intermediate of myo-inositol. It is suggested that reduction in consumption of NAD inhibits production of the enzyme. The nature of the interaction of the proposed reaction coordinate intermediate and MIP synthase is discussed.

Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.

In conventional milling, the aleurone layer is combined with the bran fraction. Studies indicate that the bran fraction of wheat contains the majority of the phytonutrients betaine and choline, with relatively minor concentrations in the refined flour. This present study suggests that the wheat aleurone layer ( Triticum aestivum L. cv. Tiger) contains the greatest concentration of both betaine and choline (1553.44 and 209.80 mg/100 g of sample, respectively). The bran fraction contained 866.94 and 101.95 mg/100 g of sample of betaine and choline, respectively, while the flour fraction contained 23.30 mg/100 g of sample (betaine) and 28.0 mg/100 g of sample (choline). The betaine content for the bran was lower, and the choline content was higher compared to previous studies, although it is known that there is large variation in betaine and choline contents between wheat cultivars. The ratio of betaine/choline in the aleurone fraction was approximately 7:1; in the bran, the ratio was approximately 8:1; and in the flour fraction, the ratio was approximately 1:1. The study further emphasizes the superior phytonutrient composition of the aleurone layer.

Six novel diastereomerically pure C-nucleosides have been synthesized from nonchiral starting materials, using the ene/intramolecular Sakurai cyclization reaction demonstrating a simple, general, and stereocontrolled approach to pyranosyl C-nucleosides.

[structure: see text] The synthesis of the bisphosphonate ADP-ribose, in which acetylene has replaced the oxygen of the pyrophosphate linkage, is reported.