Synthesis and anti-tumour, immunomodulating activity of diosgenin and tigogenin conjugates.

A series of novel diosgenin (DSG) and tigogenin (TGG) derivatives with diosgenin or tigogenin steroid aglycons linked to levulinic and 3,4-dihydroxycinnamic acids, dipeptides and various amino acids by an ester bond at the C3-oxygen atom of the steroid skeleton has been synthesized. Diosgenyl esters have been prepared by an esterification reaction (DCC/DMAP) of diosgenin with the corresponding acids. All analogues have been evaluated in vitro for their antiproliferative profile against cancer cell lines (MCF-7, MDA-MB-231, PC-3) and human umbilical vein endothelial cells (HUVEC). Analogue2c (l-serine derivative of TGG), the best representative of the series showed IC50 of 1.5 µM (MCF-7), and induced apoptosis in MCF-7 by activating caspase-3/7. The immunomodulatory properties of six synthesized analogues have been determined by examining their effects on the expression of cytokine genes essential for the functioning of the human immune system (IL-1, IL-4, IL-10, IL-12 and TNF-α). Biological evaluation has revealed that new compounds 4c and 16a do not induce the expression of pro-inflammatory cytokines in THP-1 cells after the lipopolysaccharide (LPS) stimulation. They also stimulate the expression of anti-inflammatory IL-10 that acts stronger than diosgenin itself. An in silico ADME properties(absorption, distribution, metabolism, excretion) study was also performed to predict the pharmacokinetic profile of the synthesized compounds. To shed light on the molecular interactions between the synthesized compounds and the glucocorticoid receptor and the estrogen receptor, 2c, 4c and 16a compounds were docked into the active binding sites of these receptors. The in silico and in vitro data suggested that this new group of compounds might be considered as a promising scaffold for further modification of more potent and selective anticancer and immunomodulatory agents.

Spectral and structural studies of dimethylphenyl betaine hydrate.

Hydrates of betaines can be divided into four groups depending on the interactions of their water molecules with the carboxylate group. Dimethylphenyl betaine crystallizes as monohydrate (1), in which water molecules mediate in hydrogen bonds between the carboxylate groups. The water molecules are H-bonded only to one oxygen atom of the dimethylphenyl betaine molecules and link them into a chain via two O(1W)-H⋯O hydrogen bonds of the lengths 2.779(2) and 2.846(2)Å. The structures of monomer (2) and dimer (4) hydrates in vacuum, and the structure of monomer (3) in an aqueous environment have been optimized by the B3LYP/6-311++G(d,p) approach and the geometrical results have been compared with the X-ray diffraction data of 1. The calculated IR frequencies for the optimized structure have been used for the assignments of FTIR bands, the broad absorption band in the range 3415-3230 cm(-1) has been assigned to the O(1w)-H⋯O hydrogen bonds. The correlations between the experimental (1)H and (13)C NMR chemical shifts (δexp) of 1 in D2O and the magnetic isotropic shielding constants (σcalc) calculated by the GIAO/B3LYP/6-311G++(d,p) approach, using the screening solvation model (COSMO), δexp =a+b σcalc, for optimized molecule 3 in water solution are linear and well reproduce the experimental chemical shifts.

An outbreak of Serratia marcescens associated with the anesthetic agent propofol.

BACKGROUND: In October 1999, 7 patients with postoperative infections caused by Serratia marcescens were identified at a community hospital in Ontario, Canada. We describe the investigation of this outbreak. METHODS: We undertook a case-control study to determine risk factors associated with infection. Case subjects consisted of patients who had undergone surgery and acquired bacteremia or wound infections that, when cultured, grew S marcescens. Control subjects were selected from the cohort of patients who underwent surgery at the same hospital during the outbreak period. Chart reviews were conducted for case and control subjects. Environmental samples were taken from medications and liquids in the operating rooms and from one health care professional who was involved in all the cases. S marcescens isolates were forwarded to a reference laboratory for pulsed field gel electrophoresis. RESULTS: We identified 7 case subjects and 29 control subjects. Five patients had bacteremia and 2 patients had wound infections. Two patients with bacteremia died. All patients with bacteremia or wound infections were exposed to a single anesthetist (anesthetist A) and were administered the anesthetic medication propofol. These patients were more than 40 times more likely to have had anesthetist A administer their anesthetic (OR 41.6, 95% CI 3.6-1120) and 22 times more likely to have received propofol (OR 22, 95% CI 2.1-550) than were control subjects. None of the environmental samples or cultures from anesthetist A were positive for S marcescens. Six of the 7 human isolates had an identical pulsed field gel electrophoresis pattern, and the seventh was untypable. CONCLUSIONS: This outbreak of postoperative infections was very strongly linked to the use of propofol by one anesthetist. Health care professionals must follow strict aseptic techniques when using propofol and should review these techniques regularly.