Furazans in Medicinal Chemistry.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.

Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation.

Coffee consumption has been correlated with a decreased risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD), but the mechanism by which coffee may provide neuroprotection in humans is not fully understood. We hypothesized that compounds found in brewed coffee may elicit neuroprotective effects by inhibiting the aggregation of amyloid-beta (Aß) and tau (AD) or α-synuclein (PD). Three instant coffee extracts (light roast, dark roast, decaffeinated dark roast) and six coffee components [caffeine (1), chlorogenic acid (2), quinic acid (3), caffeic acid (4), quercetin (5), and phenylindane (6)] were investigated for their ability to inhibit the fibrillization of Aß and tau proteins using thioflavin T (ThT) and thioflavin S (ThS) fluorescence assays, respectively. Inhibition of Aß and α-synuclein oligomerization was assessed using ELISA assays. All instant coffee extracts inhibit fibrillization of Aß and tau, and promote α-synuclein oligomerization at concentrations above 100 µg/mL. Dark roast coffee extracts are more potent inhibitors of Aß oligomerization (IC50 ca. 10 µg/mL) than light roast coffee extract (IC50 = 40.3 µg/mL), and pure caffeine (1) has no effect on Aß, tau or α-synuclein aggregation. Coffee components 2, 4, and 5 inhibit the fibrillization of Aß at 100 µM concentration, yet only 5 inhibits Aß oligomerization (IC50 = 10.3 µM). 1-5 have no effect on tau fibrillization. Coffee component 6, however, is a potent inhibitor of both Aß and tau fibrillization, and also inhibits Aß oligomerization (IC50 = 42.1 µM). Coffee components 4 and 5 promote the aggregation of α-synuclein at concentrations above 100 µM; no other coffee components affect α-synuclein oligomerization. While the neuroprotective effect of coffee consumption is likely due to a combination of factors, our data suggest that inhibition Aß and tau aggregation by phenylindane 6 (formed during the roasting of coffee beans, higher quantities found in dark roast coffees) is a plausible mechanism by which coffee may provide neuroprotection. The identification of 6 as a dual-inhibitor of both Aß and tau aggregation is noteworthy, and to our knowledge this is the first report of the aggregation inhibition activity of 6.

Sequential Functionalizations of Carbohydrates Enabled by Boronic Esters as Switchable Protective/Activating Groups.

Processes for site-selective, sequential functionalizations of carbohydrate derivatives are described. In these processes, a tricoordinate boronic ester initially serves as a protective group for a sugar-derived 1,2- or 1,3-diol motif, permitting functionalization of free OH groups. In a second step, addition of a Lewis base generates a tetracoordinate adduct, which serves as an activating group, enabling functionalization of one of the boron-bound oxygen atoms by a second electrophile. By combining an initial acylation, alkylation, or glycosylation step with an amine-mediated glycosylation of the boronic ester, a variety of selectively protected di- and trisaccharide derivatives can be accessed in an operationally simple fashion without purification of intermediates. This Lewis base-triggered switching of behavior from "latent" to "active" nucleophile is a unique feature of boronic esters relative to other protective groups for diol moieties in carbohydrate chemistry.

Boronic esters as protective groups in carbohydrate chemistry: processes for acylation, silylation and alkylation of glycoside-derived boronates.

Procedures for selective installation of acyl, silyl ether and para-methoxybenzyl (PMB) ether groups to glycoside substrates have been developed, employing phenylboronic esters as protected intermediates. The sequence of boronic ester formation, functionalization and deprotection can be accomplished with only a single purification step, and the boronic acid component can be recovered and reused after deprotection. Key advances include the identification of reaction conditions for installation of PMB groups in the presence of boronic esters, and the use of the 'phase switching' protocol developed by Hall and co-workers as an efficient method for boronic ester cleavage. The relatively mild conditions for boronate deprotection are tolerant of several functional groups, including esters, silyl ethers, ketals and thioglycosides.

O-Aryl-Glycoside Ice Recrystallization Inhibitors as Novel Cryoprotectants: A Structure-Function Study.

Low-molecular-weight ice recrystallization inhibitors (IRIs) are ideal cryoprotectants that control the growth of ice and mitigate cell damage during freezing. Herein, we describe a detailed study correlating the ice recrystallization inhibition activity and the cryopreservation ability with the structure of O-aryl-glycosides. Many effective IRIs are efficient cryoadditives for the freezing of red blood cells (RBCs). One effective cryoadditive did not inhibit ice recrystallization but instead inhibited ice nucleation, demonstrating the significance of inhibiting both processes and illustrating the importance of this emerging class of cryoprotectants.

Organoboron-Promoted Regioselective Glycosylations in the Synthesis of a Saponin-Derived Pentasaccharide from Spergularia ramosa.

Organoboron-mediated regioselective glycosylations were employed as key steps in the total synthesis of a branched pentasaccharide from a saponin natural product. The ability to use organoboron activation to differentiate OH groups in an unprotected glycosyl acceptor, followed by substrate-controlled reactions of the obtained disaccharide, enabled a streamlining of the synthesis relative to a protective group-based approach. This study revealed a matching/mismatching effect of the relative configuration of donor and acceptor on the efficiency of a regioselective glycosylation reaction, a problem that was solved through the development of a novel boronic acid-amine copromoter system for glycosyl acceptor activation.

Small molecule ice recrystallization inhibitors enable freezing of human red blood cells with reduced glycerol concentrations.

In North America, red blood cells (RBCs) are cryopreserved in a clinical setting using high glycerol concentrations (40% w/v) with slow cooling rates (~1°C/min) prior to storage at -80°C, while European protocols use reduced glycerol concentrations with rapid freezing rates. After thawing and prior to transfusion, glycerol must be removed to avoid intravascular hemolysis. This is a time consuming process requiring specialized equipment. Small molecule ice recrystallization inhibitors (IRIs) such as ß-PMP-Glc and ß-pBrPh-Glc have the ability to prevent ice recrystallization, a process that contributes to cellular injury and decreased cell viability after cryopreservation. Herein, we report that addition of 110 mM ß-PMP-Glc or 30 mM ß-pBrPh-Glc to a 15% glycerol solution increases post-thaw RBC integrity by 30-50% using slow cooling rates and emphasize the potential of small molecule IRIs for the preservation of cells.