A new modular indole synthesis. Construction of the highly strained CDEF parent tetracycle of nodulisporic acids A and B

[reaction: see text] Construction of the highly strained CDEF parent tetracycle, a structural motif found only in the potent ectoparasiticidal agents (+)-nodulisporic acids A and B and related congeners, has been achieved via a new modular indole synthesis, exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic. The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted indoles possessing uncommon substitution patterns.     

Indole diterpenoid synthetic studies. Construction of the heptacyclic core of (-)-nodulisporic acid D

[structure: see text] Construction of the heptacyclic core of (-)-nodulisporic acid D, a representative member of a recently discovered class of architecturally complex, ectoparasiticidal indole alkaloids, has been achieved. The modular synthetic strategy comprises an expedient, stereocontrolled synthesis of a tricyclic western hemisphere, in conjunction with union of an eastern hemisphere, exploiting the 2-substituted indole synthetic protocol introduced and developed in our laboratory.     

Design and synthesis of a potent phorboxazole C(11-15) acetal analogue

[structure: see text] We disclose here the design, synthesis, and biological evaluation of simplified Z- and E-C(2-3) alkynyl phorboxazole C(11-15) acetals (+)-7Z and (+)-7E, wherein the Z-isomer proved to be a potent nanomolar cytotoxic agent. Reevaluation of (+)-C(45-46) E-chloroalkenyl phorboxazole A (6) confirms subnanomolar activity across a broad panel of human cancer cell lines.     

Nonlinear approximation using Gaussian kernels

It is well known that nonlinear approximation has an advantage over linear schemes in the sense that it provides comparable approximation rates to those of the linear schemes, but to a larger class of approximands. This was established for spline approximations and for wavelet approximations, and more recently by DeVore and Ron (in press) [2] for homogeneous radial basis function (surface spline) approximations. However, no such results are known for the Gaussian function, the preferred kernel in machine learning and several engineering problems. We introduce and analyze in this paper a new algorithm for approximating functions using translates of Gaussian functions with varying tension parameters. At heart it employs the strategy for nonlinear approximation of DeVore-Ron, but it selects kernels by a method that is not straightforward. The crux of the difficulty lies in the necessity to vary the tension parameter in the Gaussian function spatially according to local information about the approximand: error analysis of Gaussian approximation schemes with varying tension are, by and large, an elusive target for approximators. We show that our algorithm is suitably optimal in the sense that it provides approximation rates similar to other established nonlinear methodologies like spline and wavelet approximations. As expected and desired, the approximation rates can be as high as needed and are essentially saturated only by the smoothness of the approximand.     

Spirastrellolide studies. Synthesis of the C(1)-C(25) southern hemispheres of spirastrellolides A and B, exploiting anion relay chemistry

Construction of the C(1)-C(25) southern fragments of both spirastrellolide A and B are described. Highlights of the syntheses include effective use of the three component anion relay chemistry (ARC) tactic recently introduced by our laboratory, a stereoselective spirocyclization via concomitant Ferrier reaction to elaborate the BC spiroketal and use of two dithiane unions to install the A ring as well as C(22)-C(25) fragment. The synthesis proceeded with longest linear sequences of 33 and 32 steps, respectively for spirastrellolide A and spirastrellolide B.     

Density functional theory for charge transfer: the nature of the N-bands of porphyrins and chlorophylls revealed through CAM-B3LYP, CASPT2, and SAC-CI calculations

While density functional theory (DFT) has been proven to be extremely useful for the prediction of thermodynamic and spectroscopic properties of molecules, to date most functionals used in common implementations of DFT display a systematic failure to predict the properties of charge-transfer processes. While this is explicitly manifest in Rydberg transitions of atoms and molecules and in molecular charge-transfer spectroscopy, it also becomes critical for systems containing extended conjugation such as polyenes and other conducting polymers, porphyrins, chlorophylls, etc. A new density functional, a Coulomb-attenuated hybrid exchange-correlation functional (CAM-B3LYP), has recently been developed specifically to overcome these limitations, and it has been shown to properly predict molecular charge-transfer spectra. Here, we demonstrate that it predicts qualitatively reasonable spectra for porphyrin, some oligoporphyrins, and chlorophyll. However, alternate density functionals developed to overcome the same limitations such as current-density functional theory are shown, in their present implementation, to remain inadequate. The CAM-B3LYP results are shown to be in excellent agreement with complete-active-space plus second-order M?ller-Plesset perturbation theory and symmetry-adapted cluster configuration interaction calculations: These depict the N and higher bands of porphyrins and chlorophylls as being charge-transfer bands associated with localization of molecular orbitals on individual pyrrole rings. The validity of the basic Gouterman model for the spectra of porphyrins and chlorophylls is confirmed, rejecting modern suggestions that non-Gouterman transitions lie close in energy to the Q-bands of chlorophylls. As porphyrins and chlorophylls provide useful paradigms for problems involving extended conjugation, the results obtained suggest that many significant areas of nanotechnology and biotechnology may now be realistically treated by cost-effective density-functional-based computational methods.     

Strategies for protein folding and design

Fundamental challenges in molecular biology can be addressed by using simple models on a lattice, where statistical mechanics and combinatoric techniques can be employed. The basic premise is that it is sensible to test any proposed method on the simplest of models in order to assess their validity before launching a full-scale attack on realistic problems. In this paper we follow this strategy and we present different efficient schemes to perform protein design and to extract effective amino acid interaction potentials.This work was supported in part by INFM, INFN sez. di Trieste, NASA and NATO.     

Equation of Motion of an Electric Charge

The appearance of the time derivative of the acceleration in the equation of motion (EOM) of an electric charge is studied. It is shown that when an electric charge is accelerated, a stress force exists in the curved electric field of the accelerated charge, and in the case of a constant linear acceleration, this force is proportional to the acceleration. This stress force acts as a reaction force which is responsible for the creation of the radiation (instead of the radiation reaction force that actually does not exist at low velocities). Thus the initial acceleration should be supplied as an initial condition for the solution of the EOM of an electric charge.     

Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.     

Phase equilibria, crystal structures, and dielectric anomaly in the BaZrO3-CaZrO3 system

Phase equilibria in the (1−x)BaZrO₃-xCaZrO₃ system were analyzed using a combination of X-ray and neutron powder diffraction, and transmission electron microscopy. The proposed phase diagram features two extended two-phase fields containing mixtures of a Ba-rich cubic phase and a tetragonal, or orthorhombic Ca-rich phase, all having perovskite-related structures. The symmetry differences in the Ca-rich phases are caused by different tilting patterns of the [ZrO₆] octahedra. In specimens quenched from 1650°C, CaZrO₃ dissolves only a few percent of Ba, whereas the solubility of Ca in BaZrO₃ is approximately . The BaZrO₃-CaZrO₃ system features at least two tilting phase transitions, Pm3m→I4/mcm and I4/mcm→Pbnm. Rietveld refinements of the Ba_0.8Ca_0.2ZrO₃ structure using variable-temperature neutron powder diffraction data confirmed that the Pm3m→I4/mcm transition corresponds to a rotation of octahedra about one of the cubic axes; successive octahedra along this axis rotate in opposite directions. In situ variable-temperature electron diffraction studies indicated that the transition temperature increases with increasing Ca-substitution on the A-sites, from approximately −120°C at Ca to 225°C at Ca. Dielectric measurements revealed that the permittivity increases monotonically from 36 for BaZrO₃ to 53 for Ba_0.9Ca_0.1ZrO₃, and then decreases to 50 for Ba_0.8Ca_0.2ZrO₃. This later specimen was the Ca-richest composition for which pellets could be quenched from the single-phase cubic field with presently available equipment. Strongly non-monotonic behavior was also observed for the temperature coefficient of resonant frequency; however, in this case, the maximum occurred at a lower Ca concentration, 0.05?x?0.1. The non-linear behavior of the dielectric properties was attributed to two competing structural effects: a positive effect associated with substitution of relatively small Ca cations on the A-sites, resulting in stretched Ca-O bonds, and a negative effect, related to the distortion of the A-site environment (bond strain relaxation) upon octahedral tilting.