First total synthesis of (-)-ichthyothereol and its acetate.

The first and stereoselective total syntheses of (-)-ichthyothereol (1) and its acetate ((+)-2) were achieved by incorporation of the two chiral centers of diethyl L-tartrate. The starting diethyl L-tartrate was converted into trans-2-ethynyl-3-hydroxytetrahydropyran 14 in a stereoselective manner via the endo mode cyclization of the epoxy-alkyne derivative 12. The alcohol 12 was then transformed into (E)-iodoolefin derivative 15, which was exposed to a coupling reaction with 1-tributylstannyl-1,3,5-heptyne (19), derived from the corresponding 1-trimethylsilyl-1,3,5-heptyne (18), under Stille conditions to produce the all-carbon framework of the target natural products. Chemical modification of the coupled product 20 under conventional conditions completed the first total synthesis of (-)-ichthyothereol (1) and its acetate ((+)-2).

A 21-aminosteroid, U-74006F, attenuates endotoxin-induced lung injury in awake sheep.

The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor.

The sequence of 5,037 amino acids composing the ryanodine receptor from rabbit skeletal muscle sarcoplasmic reticulum has been deduced by cloning and sequencing the complementary DNA. The predicted structure suggests that the calcium release channel activity resides in the C-terminal region of the receptor molecule, whereas the remaining portion constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum and the transverse tubule.

2-Mercaptoethanol acts as a potentiating factor of interleukin-2-dependent lymphocyte proliferation.

An interleukin-2 (IL-2) dependent cell line which could be grown continuously with crude concanavalin A-stimulated rat or mouse spleen cell culture supernatant could not survive for over 48 hr in the culture medium supplemented with partially purified or recombinant IL-2. The cell growth was restored by adding another factor obtained from the same crude culture supernatant. This potentiating activity which was physicochemically inseparable from serum albumin was also obtained from the culture medium containing 2-mercaptoethanol (2-ME) and incubated at 37 C for 24 hr without the spleen cells. By further experiments, it was demonstrated that 2-ME itself had the potentiating activity on the IL-2-dependent proliferation of this cell line and cysteine mediated the activity of 2-ME. The cells could not enter S-phase in the absence of 2-ME even in the presence of IL-2.