Efficient synthesis of an adenosine A2a agonist: glycosylation of 2-haloadenines and an N2-alkyl-6-chloroguanine

A convergent synthesis of adenosine A2a agonist 1 in the form of its maleate salt 2 was achieved. The key step in this approach was the highly selective 9beta-glycosylation reaction between 2-haloadenines or an N(2)-alkyl-6-chloroguanine and a D-ribose derivative containing a 2-ethyltetrazolyl moiety. Glycosylations of other purine derivatives were also examined, and the methods developed provide efficient access to a variety of adenosine analogues such as 2-alkylaminoadenosines, an attractive class of compounds with antiinflammatory activity.     

How dihydrofolate reductase facilitates protonation of dihydrofolate

Dihydrofolate Reductase (DHFR) catalyzes the reduction of dihydrofolate (H2F) to tetrahydrofolate. On the basis of 10-12.5 ns molecular dynamics simulations of two conformations (closed and occluded) of the ternary DHFR/NADPH/H2F complex from Escherichia coli and a free energy perturbation approach, we have calculated the pKa value for the N5 atom in H2F. Our results suggest that the N5 atom in H2F is responsible for the pH dependency of the catalyzed reaction, meaning that DHFR facilitates protonation of H2F by approximately 4 pKa units. The mechanism behind this increase is due to favorable electrostatic interactions between the Asp27 residue and a proton at the N5 atom. The electrostatic interactions are enhanced by a hydrophobic active site, which to a large extent is made hydrophobic by the M20 loop in DHFR. Moreover, we find that the conformation imposed on H2F by DHFR to some extent also favors protonation of the N5 atom. Our results add support to previous findings and suggestions by Callender and co-workers [e.g., Deng, J.; Callender, R. J. Am. Chem. Soc. 1998, 120, 7730-7737] and explain why mutation of Asp27 may lead to severely reduced activity at neutral pH.     

Observations of ion-beam formation in a current-free double layer

With nonperturbative laser-induced fluorescence measurements of ion flow, we confirm numerical simulations of spontaneous electric double-layer (DL) formation in a current-free expanding plasma. Measurements in two different experiments confirm that the DL is localized to the region of rapidly diverging magnetic field. The measurements indicate that the trapped ion population is a single Maxwellian, that the spatial gradient of the energy of ions accelerated through the DL matches the magnetic field gradient, and that DL formation is triggered when the ion-neutral collisional mean-free path exceeds the magnetic field gradient scale length.     

Analog computer simulation of a duffing oscillator and comparison with statistical linearization

We present the results of an analog computer simulation of a Duffing oscillator, i.e. of a damped anharmonic oscillator with a cubic non-linearity driven by Gaussian white noise. The simulations were performed for wide ranges of parameter values. The experimentally obtained spectral densities are compared with those obtained analytically using the method of statistical linearization.     

Differentiability of a convex semigroup on Rn

It is proved that each continuous semigroup {P(t)}_t≥0 of convex operators P(t):Rⁿ→Rⁿ is continuously differentiable with respect to t. This note represents a first step towards a better understanding of semigroups formed by convex operators. We establish the differentiability of a convex semigroup in the finite dimensional case, generalizing a basic result from linear semigroup theory. Our motivation for the study of semigroups of convex operators comes from the theory of Markov decision processes. In [1] and in [2] it was shown that the maximum reward of these processes can be described by a certain nonlinear semigroup. The nonlinear operators are defined as suprema of linear operators (plus a constant), hence they are convex operators. It seems that the convexity assumption keeps its smoothing influence even in the infinite dimensional situation. We hope to discuss this in a future paper.     

The thermal stability of polymethylidenephthalide

Conclusions On the basis of a study of the destructive transformation of polymethylidenephthalide it was found that its decomposition is a radical-chain depolymerization process taking place randomly.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 926–928, April, 1970.