Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

DNA sequence specificity of a naphthylquinoline triple helix-binding ligand.

We have examined the effect of a naphthylquinoline triplex-binding ligand on the formation of intermolecular triplexes on DNA fragments containing the target sites A6G6xC6T6 and G6A6xT6C6. The ligand enhances the binding of T6C2, but not T2C6, to A6G6xC6T6 suggesting that it has a greater effect on TxAT than C+xGC triplets. The complex with T6C2 is only stable below pH 6.0, confirming the requirement for protonation of the third strand cytosines. Antiparallel triplexes with GT-containing oligonucleotides are also stabilised by the ligand. The complex between G5T5 and A6G6xC6T6 is stabilised by lower ligand concentrations than that between T5G5 and G6A6xC6T6. The ligand does not promote the interaction with GT-containing oligonucleotides which have been designed to bind in a parallel orientation. Although the formation of antiparallel triplexes is pH independent, we find that the ligand has a greater stabilising effect at lower pH, suggesting that the active species is protonated. The ligand does not promote the binding of antiparallel GA-containing oligonucleotides at pH 7.5 but induces the interaction between A5G5 and G6A6xT6C6 at pH 5.5. Ethidium bromide does not promote the formation of any of these triplexes and destabilises the interaction of acridine-linked pyrimidine-containing third strands with these target sites

Kinetic study of the reaction of OH with CH3I revisited

A flash photolysis resonance fluorescence technique has been employed to investigate the kinetics and mechanism of the reaction of OH(X2\textgreekP) radicals with CH3I over the temperature and pressure ranges 295-390 K and 82-303 Torr of He, respectively. The experiments involved time-resolved RF detection of the OH (A2\textgreekS+ → X2\textgreekP transition at \textgreekl = 308 nm) following FP of H2O/CH 3I/He mixtures. The OH(X2\textgreekP) radicals were produced by FP of H2O in the vacuum-UV at wavelengths \textgreekl \textgreater 115 nm using a commercial Perkin-Elmer Xe flash lamp. Decays of OH in the presence of CH 3I are observed to be exponential, and the decay rates are found to be linearly dependent on the CH3I concentration. The measured rate coefficients for the reaction of OH with CH3I are described by the Arrhenius expression kOH+CH3I = (4.1 ± 2.2) × 10 -12 exp [(-1240 ± 200)K/T] cm3 molecule -1s-1. The implications of the reported kinetic results for understanding the CH3I chemistry of both atmospheric and nuclear industry interests are discussed. © 2011 Wiley Periodicals, Inc

Combustion Processes as a Source of High Levels of Indoor Hydroxyl Radicals through the Photolysis of Nitrous Acid

International audienceHydroxyl radicals (OH) are known to control the oxidative capacity of the atmosphere but then influence on reactivity within indoor environments is believed to be of little importance: Atmospheric direct sources of OH include the photolysis of ozone and nitrous acid (HONO) and the ozonolysis of alkenes. It has been argued that the ultraviolet light fraction of the solar spectrum is largely attenuated within indoor environments, thus, limiting the extent of photolytic OH sources. Conversely, the ozonolysis of alkenes has been suggested as the main pathway of OH formation within indoor settings. According to this hypothesis the indoor OH radical concentrations span in the range of only 104 to 108 cm(-3). However, recent direct OH radical measurements within a, school classroom yielded OH radical peak values at moderate light intensity measured at evenings of 1.8 x 106 cm(-3) that Were attributed to the photolysis of HONa In this `work, we report results from chamber experiments irradiated with varying light intensities in order to mimic realistic indoor lighting conditions. The exhaust of a burning candle was introduced in the chamber as a typical indoor source causing a sharp peak of HONO, but also of nitrogen oxides (NOx). The photolysis of HONO yields peak OH concentration values, that for the range of indoors lightning conditions were estimated in the range 5:7 X 10(6) to 1.6 x 107 cm(-3). Excellent agreement exists between OH levels determined by a chemical clock and those calculated by a simple PSS model. These findings suggest that significant OH reactivity takes place at our dwellings and the consequences of this reactivity that is, formation of secondary oxidants ought to be studied hereafter

Redetermination of the rate coefficient for the reaction of O( 1 D) with N 2

International audienc