Thioimidates provide general access to thioamide, amidine, and imidazolone peptide-bond isosteres.

Thioamides, amidines, and heterocycles are three classes of modifications that can act as peptide-bond isosteres to alter the peptide backbone. Thioimidate protecting groups can address many of the problematic synthetic issues surrounding installation of these groups. Historically, amidines have received little attention in peptides due to limitations in methods to access them. The first robust and general procedure for the introduction of amidines into peptide backbones exploits the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. Further, amidines formed on-resin can be reacted to form (4H)-imidazolone heteorcycles which have recently been shown to act as cis-amide isosteres. General methods for heterocyclic installation capable of geometrically restricting peptide conformation are also under-developed. This work is significant because it describes a generally applicable and divergent approach to access unexplored peptide designs and architectures.

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone.

Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of α-chiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.

Fetal Metabolic Alkalosis Resulting from Maternal Vomiting.

We describe a pregnant patient with severe compulsive water ingestion and vomiting that lead to metabolic alkalosis and preterm delivery. A 21-year-old patient was hospitalized multiple times throughout pregnancy for symptoms initially thought to be related to hyperemesis gravidarum. Overtime, it became apparent that the patient induced vomiting by rapidly drinking large volumes of water. At 32 weeks' gestation, rapid ingestion of water caused 3 days of vomiting with findings of hyponatremia, hypokalemia, hypochloremia, metabolic alkalosis, and compensatory respiratory acidosis. Fetal monitoring showed minimal variability and recurrent decelerations; subsequent biophysical profile score of 2/10 prompted urgent cesarean section. A male newborn was delivered and cord blood gases reflected neonatal metabolic alkalosis and electrolyte imbalances identical to those of the mother. Compensatory hypoventilation in both mother and fetus were treated with assisted ventilation. With saline administration and repletion of electrolytes, metabolic alkalosis resolved for both patients within days. Metabolic alkalosis was transplacentally acquired by the fetus. This case demonstrates the development of metabolic alkalosis in a pregnant woman caused by vomiting severe enough to prompt preterm delivery for nonreassuring fetal status. It also demonstrates fetal dependence on both placenta and mother to maintain physiologic acid-base and electrolyte balance.

A General Strategy to Install Amidine Functional Groups Along the Peptide Backbone.

Amidines are a structural surrogate for peptide bonds, yet have received considerably little attention in peptides due to limitations in existing methods to access them. The synthetic strategy developed in this study represents the first robust and general procedure for the introduction of amidines into the peptide backbone. We exploit and further develop the utility and efficiency of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. This work is significant because it describes a generally applicable path to access unexplored peptide designs and architectures for new therapeutics made possible by the unique properties of amidines.

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core.

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

Body temperatures of very low birth weight infants on admission to a neonatal intensive care unit.

OBJECTIVE: Hypothermia occurs frequently in the first minutes after birth in preterm infants. Hyperthermia also occurs, often as a consequence of efforts to provide thermal support. Both hypothermia and hyperthermia are potentially harmful. Our objective was to examine the distribution of admission temperatures of very low birth weight (VLBW) infants, the effect of gestational age on admission temperatures, and the time required for correction of low temperatures. METHODS: Admission axillary temperatures were retrieved from the medical records for all VLBW infants born in our hospital during a 5-year period. The temperatures were classified as severe (<35.0 °C), moderate (35.0-35.9 °C), or mild (36.0-36.4 °C) hypothermia, normothermia (36.5-37.4 °C), or hyperthermia (≥37.5 °C). The relationship between gestational age and admission temperature was examined. In addition, we analyzed the time required for normalization of low temperatures. RESULTS: Overall, 12% of infants were severely hypothermic, 40% moderately hypothermic, 27% mildly hypothermic, 19% normothermic, and 2% hyperthermic. Gestational age was inversely related to hypothermia risk and to the time required for recovery to normothermia. CONCLUSION: Admission hypothermia is common among VLBW infants and is affected by gestational age.

Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation.

OBJECTIVE: To evaluate neonatal survival after prolonged preterm premature rupture of membranes (PROM) in the era of antenatal corticosteroids, surfactant, and inhaled nitric oxide. METHODS: A single-center retrospective cohort study of neonates born from 2002-2011 after prolonged (1 week or more) preterm (less than 24 weeks of gestation) rupture of membranes was performed. The primary outcome was survival to discharge. Neonates whose membranes ruptured less than 24 hours before delivery (n=116) were matched (2:1) on gestational age at birth, sex, and antenatal corticosteroid exposure with neonates whose membranes ruptured 1 week or more before delivery (n=58). Analysis used conditional logistic regression for categorical data and Wilcoxon signed rank test for continuous data. RESULTS: The prolonged preterm PROM exposed and unexposed cohorts had survival rates of 90% and 95%, respectively, although underpowered to assess the statistical significance (P=.313). Exposed neonates were more likely have pulmonary hypoplasia (26/58 exposed, 1/114 unexposed, P<.001), pulmonary hypertension (21/56 exposed, 10/112 unexposed, P<.001), and pulmonary air leak (21/58 exposed, 14/114 unexposed, P<.001). Gestational age at rupture (20.4 weeks exposed, 22.3 weeks unexposed, P=.189), length of rupture (3.7 weeks exposed, 6.4 weeks unexposed, P=.717), and lowest maximal vertical pocket before 24 weeks of gestation (0 cm exposed, 1.4 cm unexposed, P=.114) did not discriminate between survivors and nonsurvivors after exposure to prolonged preterm PROM. CONCLUSION: With antenatal steroid exposure and aggressive pulmonary management, survival to discharge after prolonged preterm PROM was 90%. Pulmonary morbidities were common. Of note, the data were limited to women who remained pregnant 1 week or longer after rupture of membranes.