Biochemical and biophysical approaches to improving the anticancer effectiveness of Ara-adenine.

Ara-C at very low dosage has been reported to decrease the host toxicity of ara-AMP or ara-A in combination with 2'-deoxycoformycin, a potent adenosine deaminase inhibitor, while increasing the toxicity to intracerebral L1210 leukemia. The possibility of increasing the selectivity of ara-A by prior administration of ara-C is explored. The importance of deoxynucleoside kinases, some of which may be cancer-induced, in obtaining selective anticancer effects is discussed. The possibility of a conformational basis for the differing degrees of selectivity and activity of various novel arabinosyl nucleosides is evaluated. The levels of cyclic nucleotides, which have opposing effects on leukemia, may possibly be manipulated to interfere with the growth of cancer cells. Approaches to minimizing major metabolic distortions, such as the progressive accumulation of dATP associated with the use of potent adenosine deaminase inhibitors and which limit the therapeutic effects of ara-A, are proposed.

Rate constant of vibrational redistribution in molecules using adiabatic approximation model.

By means of the proposed adiabatic approximation model for vibrational redistribution [Lin, S. H. (1980) Chem. Phys. Lett. 70, 492-499], the calculations of various rate constants caused by different couplings have been given in detail. By two methods it has been demonstrated that the rate constant caused by the Born-Oppenheimer mechanism, corrected by the non-Condon approximation, has the same order of magnitude as that contributed by the anharmonic mechanism. Furthermore, the important effect of molecular rotation on the rate constant based on the Coriolis coupling has been demonstrated.

Optical activity and electronic absorption spectra of some simple nucleosides related to cytidine and uridine: all-valence-shell molecular orbital calculations.

The circular dichroism and electronic absorption of three simple model systems for cytidine and uridine have been measured to 190 nm. The molecular spectral properties (excitation wavelengths, oscillator strengths, rotational strengths, and polarization directions) and electronic transitional patterns were investigated by using wave functions of the entire nucleoside with the goal of establishing the reliability of the theoretical method. The computed electronic absorption quantities were shown to be in satisfactory agreement with experimental data. It was found that the computed optical rotatory strengths of the B2u and E1u electronic transitions and lowest observed n-pi transition are in good agreement with experimental values. Electronic transitions were characterized by their electronic transitional patterns derived from population analysis of the transition density matrix. The theoretical rotational strengths associated with the B2u and E1u transitions stabilize after the use of just a few singly excited configurations in the configuration interaction basis and, hypothetically, are more reliable as indicators of conformation in pyrimidine nucleosides related to cytidine.

Radial distribution function of liquid argon according to significant structure theory.

The significant structure theory of liquids is tested by evaluating the radial distribution function. The calculations are based on face-centered cubic quasi-lattice structure, and the fluctuation in volume is used to describe the thermal displacements of molecules. It is shown that the local structure of liquids has inhomogeneous distributions. The correlation at long ranges becomes negligible because of the fluidized vacancies in our model. The calculations are performed for liquid argon, and the results are in good agreement with experiments.

Reaction kinetics in living systems.

In this report we treat reaction rates, equilibrium theory, and irreversible thermodynamics as different aspects of a single discipline. In biological reactions the rate is ultimately controlled by enzymes and other proteins of complex structure and high molecular weight. The needed formalism can be placed in one-to-one correspondence with appropriate electrical and mechanical networks. An enzyme molecule has zwitter ions anchored in the polypeptide chain, which enable it to distort the substrate by electrostatic polarization. Water weakens the induced or existing polar bonds and so speeds reaction. Several biological processes, such as luminescence, catalysis, nerve excitation, and anesthesia, in which enzymatic reactions play a major part are discussed from this point of view. We also have discussed the energy consumption and coupling effect in living systems. It is likely that a small fraction of bonds can become energy rich through the process of quenching and that unsymmetrical barriers in biological systems act like transistors in making the driving forces more efficient by a valve effect.

Quantum statistical mechanical theory of diffusion and reaction on solid surfaces.

We present the derivation of the general kinetic equations of diffusion and diffusion with interaction (or chemical reaction) on solid surfaces (or in dense media) by using the density matrix method. We indicate several problems to which this formalism applies and, in particular, discuss the damping effect on diffusion.

Anesthetics and high-pressure interaction upon elastic properties of a polymer membrane.

Anesthetics expand cell membranes, and high pressures (about 10-15 MPa) antagonize the anesthetic action. It is also known that inhalation anesthetics expand elastomer membranes. The mechanism of pressure antagonism of anesthetic action on membrane expansion was investigated in the present study with Silastic membranes. Halothane increased the length of Silastic membrane (0.14% per kPa), with an accompanying decrease of Young's modulus (3.7.10(5) Newton/m2 per kPa). High pressure decreased the length of the membrane and increased Young's modulus. The magnitudes of the pressure effect on the length and Young's modulus of the Silastic membrane in the presence of the anesthetic were not identical with those observed in the absence of the anesthetic. In the presence of halothane at pressures common to clinical applications, the bulk modulus of the membrane decreased about 4.6-4.0%. These results suggest that the effects of pressure and anesthetic upon the elastomer may not be completely independent of each other.

Derivation of a formula for the resonance integral for a nonorthogonal basis set.

In a self-consistent field calculation, a formula for the off-diagonal matrix elements of the core Hamiltonian is derived for a nonorthogonal basis set by a polyatomic approach. A set of parameters is then introduced for the repulsion integral formula of Mataga-Nishimoto to fit the experimental data. The matrix elements computed for the nonorthogonal basis set in the pi-electron approximation are transformed to those for an orthogonal basis set by the Löwdin symmetrical orthogonalization.

On the density matrix approach of intramolecular relaxation processes.

In this paper we derive the generalized master equations for the S(1) system coupled with the S(2) system, with the S(1) and S(2) systems embedded in a heat bath. This formalism can be applied to a number of problems like vibrational redistribution, dynamic effect of vibrational relaxation on electronic relaxation in condensed media, etc. In this paper the importance of the memory function associated with a relaxation process is emphasized.

Pressure-anesthetic antagonism on the phase separation of non-ionic surfactant micelles.

An aqueous solution of non-ionic surfactants becomes suddenly turbid when heated to a critical temperature, known as the cloud point, and concomitantly expands the volume. The volume expansion is caused by release of structured water molecules from the hydrophilic polyoxyethyelene moieties. Inhalation anesthetics decreased the cloud-point temperature of hexaoxyethylene dodecyl ether micelles. The concentrations of methoxyflurane, halothane and enflurane causing a 1 degree C depression of the cloud-point temperature were 0.51, 0.71 and 0.78 mmolal, respectively. Hydrostatic pressure increased the cloud-point temperature in the absence and presence of the anesthetics. The change of the apparent molal volume at the cloud point was estimated to be 2.2 cm3/mol in the absence of anesthetics. This value decreased in the presence of the anesthetics, dose dependently. The results indicate that the anesthetics favor dehydration of the hydrophilic surface of the non-ionic surfactant micelles.

Wavelength regulation in rhodopsin: effects of dipoles and amino acid side chains.

The effects of dipoles and aromatic amino acid side-chain models on the absorption and optical activity of the rhodopsin chromophore were calculated by using perturbation theory, and the results were compared with those of a Pariser-Parr-Pople calculation for the unperturbed system. The interaction was assumed to result from purely electrostatic interactions. It was concluded that the side chains of phenylalanine and tryptophan should have no important effects. However, the charge separation in tyrosine is sufficient to cause substantial electrostatic perturbation; in fact, the effect of tyrosine is large enough to approximately many of the spectral properties of rhodopsin quantitatively. This is encouraging because the use of aromatic amino acid side-chain analogs probably provides a better physical model than the use of isolated full charges, except in the case of the counterion to the protonated Schiff base.

A theory of distortion of the reaction zone.

A cylindrical detonating explosive behaves like a non-Newtonian viscous fluid emerging from a cylindrical pipe. The expression for non-Newtonian viscous flow has been applied to detonating explosives. The resultant fit to emerging flame fronts from detonation is excellent for a wide variety of detonating explosives both for transients (at various times) and for steady state. The quantities k'(lambda/lambda(1))(2/B) and 1/B and the rate constant k' increase abruptly at a time supporting a change in mechanism from deflagration to detonation in the transient during initiation. All of these parameters are temperature sensitive, indicating an abrupt temperature increase as a condition or indicator in the deflagration-to-detonation transition. Furthermore, a straight line results when log particle velocity u is plotted against log radial distance r, indicating that, for the explosives studied, the hyperbolic cosine wave front can be replaced by a parabolic wave front within the accuracy of the available experimental data.

A theoretical study of resonance Raman scattering from molecules: High pressure effect.

The main purpose of this paper has been to study the high pressure effect on the resonance Raman scattering (RRS) of molecules in a dense medium. In deriving the RRS cross section under high pressure, a different approach from that presented in the previous papers has been used, and the resulting expression for the RRS cross section can be used to treat both pressure and temperature effects.

Temperature and pressure dependence of viscosity of quantum liquid He according to significant structure theory.

Both solid-like and gas-like flow structures are considered in the calculation of viscosity of liquid (4)He using the significant structure theory of liquids. The predominance of quantum mechanical zero-point motion over that arising from thermal excitation is taken into account for the solid-like motion of molecules. The viscosity of liquid (4)He under its own vapor pressure calculated over its whole temperature range is in reasonably good agreement with experimental data. The pressure dependence of viscosity also was obtained. The calculation does not yield good results at high densities where the free jumping of molecules into the nearest neighboring vacancies through the kinetic zero-point motion is no longer plausible.

Application of the Eyring-Stover survival theory to soil-related functions.

The fit of the Eyring-Stover statistical survival theory was found to be precise when applied to diverse soil-related functions.

Calculations of the circular dichroism of adenosine derivatives constrained in the syn form.

The rotational strengths of the four longer wavelength transitions, B(2u), B(1u), and the two E(1u), of adenosine derivatives constrained in the syn form have been investigated theoretically and experimentally. The theory combines a complete neglect of differential overlap version S (CNDO/S) description of the base with a generalized bond exciton method by means of a matrix method. Rotational strength wheels for these transitions showing the rotational strength as a function of the glycosidic rotational angles are presented and sector rules discussed. Similar sector rules are predicted for purine nucleoside derivatives containing the 6-amino substituent, regardless of heteroatom content at positions 1 or 3 of the base. The sector rules for the B(2u) rotational strength of purine nucleosides lacking the 6-amino substituent are strongly influenced by aza substitution. The circular dichroism spectra of 3-deazaadenosine, 8-(alpha-hydroxyisopropyl)-adenosine, and other purine nucleosides having a strong preference for the syn conformation are presented and compared with the theoretical results.

Surface activities of tertiary amine local anesthetics at air/water interface in the presence and absence of phospholipid monolayers.

Adsorption of procaine and tetracaine to the dipalmitoyl phosphatidylcholine monolayers at the air/water interface is analyzed in terms of two types of interaction: (1) between the phospholipid molecules and the ligand molecules, and (2) among the ligand molecules themselves. The presence of the phospholipid monolayer increases the surface concentration of the anesthetics. The interaction energy, omega AB, between the phospholipid molecules and the anesthetic molecules at the interface accounts for this excess adsorption. The values were --2.95 kT for procaine and --2.99 kT for tetracaine where k is the Boltzmann constant and T = 298 K. The adsorption of the local anesthetics to the interface was cooperative. The interaction energy, omega AA, between the anesthetics molecules on the surface determines the cooperativity. The values were --0.056 kT for procaine and --0.397 kT for tetracaine, where T = 298 K. This parameter determines the slope of the curve plotted relating the surface concentration (gamma) and the logarithm of the bulk concentration (log C). When (omega AA/kT) greater than or equal to 1, the adsorption follows the phase-transition. A parameter KA, which is related to the difference of the free energy of anesthetics between the surface and the bulk molecules, locates the take-off point of the adsorption curve at the log C axis. The values were 2.15 x 10(3) for procaine and 7.00 x 10(3) for tetracaine. In spite of the general assumption that the difference in the clinical potency among local anesthetics are attributable to their lipid solubility, the present results showed that the phospholipid-anesthetic interaction energies for procaine and tetracaine were similar. The larger surface concentration of tetracaine than procaine at the same bulk concentration was due to the combined effect of KA and omega AA. KA represents the tendency of the anesthetic molecules to escape from the hydrogen-bonded water phase, and omega AA determines the cooperativity factor causing these molecules to aggregate at the interface. It was also observed that the charged forms of the anesthetics have non-zero surface activities.

Similarity and differences between conditions for initiation and failure of detonation.

A theory is proposed to study the sensitivity of cylindrical explosives. Using the equations governing the conservation of mass, energy, and momentum, the equation of state, and Newtonian mechanics, we have derived the expression D = D(o)e(-a2/d), in which the apparent length of the reaction zone, a, takes into account burned and unburned explosive and pressure release through the back and sides of the reaction zone. D is the detonation velocity and d is the diameter of the cylindrical charge. From the observed D(1/d) curves and critical energy values, we can interpret failure and other phenomena associated with detonation.

Elementary transition state theory of the Soret and Dufour effects.

The elementary transition state approach has been used to obtain a simple model theory for the Soret effect (thermal diffusion) and the Dufour effect. The flow of heat in the Dufour effect is identified as the transport of the enthalpy change of activation as molecules diffuse. The theory as now formulated applies only to thermodynamically ideal mixtures of substances with molecules of nearly equal size. The results of the theory conform to the Onsager reciprocal relationship. When the results were fit to data on thermal diffusion for two liquid systems, a close fit was obtained and yielded reasonable values of between 2 and 3 kcal mol(-1) for enthalpy changes of activation and differences between the entropy changes of activation for the two components of between 0 and 1 cal K(-1) mol(-1).