Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach

The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.     

A finite element method for 3D hydrostatic water flows

In this paper we propose a numerical method for the solution of the “Quasi-3D” hydrodynamic equations. This approach uses a combination of standard linear finite elements along the vertical direction and non-conforming Raviart-Thomas elements in the horizontal planes. We describe, also, a suitable approximation for the convective terms. Received: 17 March 1999 / Accepted: 17 June 1999     

Disinfection of circulating water systems by ultraviolet light and halogenation

Continuous ultraviolet light (u.v.) and chemical disinfection of circulating water systems were evaluated. Direct comparisons of the biocidal effectiveness of u.v. light vs halogenation were tested with Legionella spp and Pseudomonas aeruginosa because of their association with the acquisition of overt clinical disease from water-containing appliances. Findings indicated that six species of Legionella and P. aeruginosa were killed by a moderate level of u.v. radiation. L. pneumophila and other bacteria in a circulating water system were effectively killed by a biocidal u.v. light. However, free chlorine levels needed to kill Legionella, Pseudomonas, and Flavobacterium within 1 min were found to be greater than 4 mg ml^?1. Data from a long-term field trial with u.v. light treatment of evaporative condenser water showed a significant reduction in numbers of bacteria. Ultraviolet disinfection of hospital hydrotherapy whirlpools confirmed the utility of this mode of disinfection under circumstances where chlorination may not be practical for medical reasons. These findings were confirmed during investigations of halogenated or u.v.-treated public hot tub/whirlpools. The effectiveness of routine chemical disinfection for controlling microbial flora in a cooling tower was also evaluated. The 2 month survey indicated that the numbers of bacteria, including Legionella, were not affected by two biocides that were used. The observations made during this investigation support the conclusion that u.v. light disinfection of water-containing systems may be an appropriate alternative or supplement to chemical biocides.