A new approach to predict the biological activity of molecules based on similarity of their interaction fields and the logP and logD values: application to auxins

The activity of a biological compound is dependent both on specific binding to a target receptor and its ADME (Absorption, Distribution, Metabolism, Excretion) properties. A challenge to predict biological activity is to consider both contributions simultaneously in deriving quantitative models. We present a novel approach to derive QSAR models combining similarity analysis of molecular interaction fields (MIFs) with prediction of logP and/or logD. This new classification method is applied to a set of about 100 compounds related to the auxin plant hormone. The classification based on similarity of their interaction fields is more successful for the indole than the phenoxy compounds. The classification of the phenoxy compounds is however improved by taking into account the influence of the logP and/or the logD values on biological activity. With the new combined method, the majority (8 out of 10) of the previously misclassified derivatives of phenoxy acetic acid are classified in accord with their bioassays. The recently determined crystal structure of the auxin-binding protein 1 (ABP1) enabled validation of our approach. The results of docking a few auxin related compounds with different biological activity to ABP1 correlate well with the classification based on similarity of MIFs only. Biological activity is, however, better predicted by a combined similarity of MIFs + logP/logD approach.     

Thermosonimetry of the phase II/III transition of hexachloroethane

A thermosonimetric study has shown that the Phase II/III polymorphic transition of hexachloroethane emits acoustic signals. This solid-solid phase transition is known to occur by a nucleation-growth process during which a nucleus of the new phase, once formed, grows at the expense of the mother phase to form a complete crystal without fracture. Acoustic emissions from a conditioned multi-crystal sample have been used to study the transition. Acoustic activity correlated well with dilatometric measurements. Frequency analysis on waveforms of many hundreds of individual acoustic emissions revealed marked differences between individual signals. Principal-components analysis on 24 signal features revealed a single dispersed cluster with a highly non-uniform distribution of signals. These experiments provided highly reproducible average power spectra. Time-resolved acoustic power spectra were also generated. These additional types of information cannot be obtained by other techniques.     

Rate constants for the etching of gallium arsenide by atomic chlorine

Known chlorine atom concentrations were prepared in a discharge flow system and used to etch the (100) face of a gallium arsenide single crystal. The etch rate was monitored by mass spectrometry, laser interferometry, and surface proftlometry. In the temperature range from 90 to 160°C the reaction can be described by the rate law $$Etch rate = kP_{Cl} $$ where $$k = 9 \times 10^{(6 \pm 0.5)} \mu m min^{ - 1} Torr^{ - 1} e^{ - 9 \pm 1)kcal/RT} $$      

Seasonal fluctuation of DNA photodamage in marine plankton assemblages at Palmer Station, Antarctica

Ultraviolet radiation-induced DNA damage frequencies were measured in DNA dosimeters and natural plankton communities during the austral spring at Palmer Station, Antarctica, during the 1999-2000 field season. We found that the fluence of solar ultraviolet-B radiation (UV-B) at the earth's surface correlated with stratospheric ozone concentrations, with significant ozone depletion observed because of "ozone hole" conditions. To verify the interdependence of ozone depletion and DNA damage in natural microbial communities, seawater was collected daily or weekly from Arthur Harbor at Palmer Station, Antarctica, throughout "ozone season," exposed to ambient sunlight between 0600 and 1800 h and fractionated using membrane filtration to separate phytoplankton and bacterioplankton populations. DNA from these fractions was isolated and DNA damage measured using radioimmunoassay. Under low-ozone conditions cyclobutane dimer concentrations in bacterioplankton and phytoplankton communities were maximal. DNA damage measured in dosimeters correlated closely with ozone concentrations and UV-B fluence. Our studies offer further support to the theory that stratospheric deozonation is detrimental to marine planktonic organisms in the Southern Ocean.     

The molecular structure of gaseous bis(hexamethydisilylamido)mercury(II), Hg{N(Si(CH3)3)2}2, as determined by electron diffraction

Gaseous bis(hexamethydisilylamido)mercury(II), Hg{N(SiMe₃)₂)₂}₂, has been studied by electron diffraction at a nozzle temperature of ca 390 K.

The diffraction data are consistent with a model consisting only of monomers. By assuming the NHgN chain to be linear and the HgHSi₂ fragments to be planar, an equilibrium conformer with a staggered Si₂NHgNSi₂ skeleton of D_ad-symmetry may be brought into a nice agreement with the observed diffraction data. The relatively large value of the vibrational amplitude of the inter-ligand SiSi distance, 0.26(12) A, indicates that the ligands undergo large amplitude vibrations about the NHgN axis. Steric considerations as well as the magnitude of the rotational barrier as estimated from the diffraction data (ca. 2 kcal mol⁻¹) show that this motion is hindered. A model with an eclipsed, co-planar Si₂NHgNSi₂ backbone of D_adsymmetry could not satisfactorily be brought into agreement with the observed diffraction data.

The values of some relevant key-parameters are: r_a(Hg---N) = 2.01(2) A, r_a(Si---N) = 1.732(9) A, r_a(Si---C) = 1.883(6) A;HgNSi = 116.0(1.0)°, SiNSi = 128.0(2.0)°, NSiC= 111.8(1.2)° and SiCH = 111.0(2.0)°. The trimethylsilyl groups are twisted 25(3)° away from their references positions typified by one Si---C bond of each such group eclipsing the adjacent Hg---N bond, in such a way that the overall symmetry of the model is lowered from D_ad to S₄.     

Synthesis and structural studies of hydrazino-crown ethers and thermodynamic studies of their interaction with transition,and post-transition metal ions and methyl ammonium ion

Hydrazino-crown ethers have been synthesized in only 3 or 4 steps starting from 1,2-diacetylhydrazine. The X-ray crystal structure of protonated hydrazino-19-crown-7 (2) showed that one of the hydrazino nitrogen atoms was directed outside the ring cavity. A solvent methanol molecule is held in the cavity of the host ligand by three hydrogen bonds involving two hydrogen atoms bonded to nitrogens of the ligand and the alcohol hydrogen of the methanol. The logK values for the interaction of2 with CH₃NH ₊ ³ , Ag⁺, Pb²⁺, and Cd²⁺ were much less than those for the interaction of symmetrical triaza-l8-crown-6 (5) with the same cations. Hydrazino-crown2 reduced silver ions to silver metal when a solution of2 and silver ions in DMSO was allowed to stand for several days.     

Length dependent folding kinetics of phenylacetylene oligomers: structural characterization of a kinetic trap

Using simulation to study the folding kinetics of 20-mer poly-phenylacetylene (pPA) oligomers, we find a long time scale trapped kinetic phase in the cumulative folding time distribution. This is demonstrated using molecular dynamics to simulate an ensemble of over 100 folding trajectories. The simulation data are fit to a four-state kinetic model which includes the typical folded and unfolded states, along with an intermediate state, and most surprisingly, a kinetically trapped state. Topologically diverse conformations reminiscent of alpha helices, beta turns, and sheets in proteins are observed, along with unique structures in the form of knots. The nonhelical conformations are implicated, on the basis of structural correlations to kinetic parameters, to contribute to the trapped kinetic behavior. The strong solvophobic forces which mediate the folding process and produce a stable helical folded state also serve to overstabilize the nonhelical conformations, ultimately trapping them. From our simulations, the folding time is predicted to be on the order of 2.5-12.5 mus in the presence of the trapped kinetic phase. The folding mechanism for these 20-mer chains is compared with the previously reported folding mechanism for the pPA 12-mer chains. A linear scaling relationship between the chain length and the mean first passage time is predicted in the absence of the trapped kinetic phase. We discuss the major implications of this discovery in the design of self-assembling nanostructures.     

Cross-linking dendrimers with allyl ether end-groups using the ring-closing metathesis reaction

A third generation Frechet-type dendrimer containing 24 allyl ether end-groups was synthesized, cross-linked using the ring-closing metathesis (RCM) reaction, and the core was removed hydrolytically without significant fragmentation. The results are analogous to those previously reported for homoallyl ether dendrimers (Wendland, M. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1999, 121, 1389-1390) suggesting that the less readily available homoallyl ether dendrimers can be replaced by their allyl ethers analogues in a range of applications.