Dimerization of butenolide structures. A biomimetic approach to the dimeric sesquiterpene lactones (+/-)-biatractylolide and (+/-)-biepiasterolide

The biomimetic synthesis of the bisesquiterpene lactones (+/-)-biatractylolide 1 and (+/-)-biepiasterolide 2 via dimerization of the captodative stabilized radical 8 is reported. Atractylon 7 has also been shown to be a possible intermediate during the biosynthesis of biatractylolide 1, biepiasterolide 2, atractylolide 3, and hydroxyatractylolide 4.     

Total synthesis of pyridovericin

The total synthesis of the naturally occurring kinase inhibitor pyridovericin 1 is reported. A flexible and efficient synthesis has been accomplished in good yield from readily available 2,4-dihydroxypyridine. Pyridovericin is a key intermediate in our proposed biomimetic synthesis of pyridomacrolidin 2.     

Self-assembled polymer membrane capsules inflated by osmotic pressure

We fabricate and characterize capsules that are composite membranes, made of a polymer network stabilized by adsorption to colloids and inflated by osmotic pressure from internal free polyelectrolyte; here, poly-l-lysine forms the network and inflates the capsules. To assess these capsules' properties and structure, we deform capsules using microcantilevers and use finite element modeling to describe these deformations. Additional experimental tests confirm the model's validity. These capsules' resilient response to mechanical forces indicates that loading and shear should be good triggers for the release of contents via deformation. The osmotic pressure inflating these capsules has the potential to trigger release of contents via deflation in response to changes in the capsules' environment; we demonstrate addition of salt as a trigger for deflating capsules. Because these capsules have a variety of release triggers available and the technique used to fabricate them is very flexible and allows high encapsulation efficiency, these capsules have very high potential for application in many areas.     

DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles

Cytarabine (1-β-d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is used for the treatment of both acute and chronic myeloblastic leukemias and non-Hodgkin lymphoma. It has a very short plasma half-life and a very low oral bioavailability. To overcome these disadvantages, much effort has been focused on the design of cytarabine prodrugs. In this study, we have synthesized four different cytarabine prodrugs in order to increase the drug lipophilicity and the affinity of the prodrugs toward the biological membranes, as well as the lipophilic carriers. Differential scanning calorimetry was used to study the interaction of cytarabine and its prodrugs with multilamellar vesicles (MLVs) made of dimyristoylphosphatidylcholine (DMPC) and used as a model of biomembranes as well as a lipophilic carrier. The results showed that the 4-N-acetyl-2′,3′-5′-acetyl derivative and the prodrug with short chain fatty acids do not have a significant affinity with MLVs, whereas the prodrugs with long chain fatty acids have a stronger affinity with the MLVs with respect to cytarabine. The entity of the affinity depends on the fatty acids length. The increased affinity could be due to the fatty acid moieties which allow the molecule to insert among the phospholipid molecules. These results provide information on the interaction of these prodrugs with biomembranes and could be useful to design liposomes as carriers for the prodrugs.

     

Anion binding studies of fluorinated expanded calixpyrroles

The anion binding properties of fluorinated calix[n]pyrroles (n = 4-6) in aprotic solvents (acetonitrile and DMSO) and modified reaction conditions allowing for the synthesis and isolation of the hitherto missing dodecafluorocalix[6]pyrrole from the condensation of 3,4-difluoro-1H-pyrrole and acetone are described. In acetonitrile solution containing 2% water, the association constants for the 1:1 binding interaction between octafluorocalix[4]pyrrole and chloride anion obtained with isothermal titration calorimetry (ITC) and (1)H NMR titration methods were found to match reasonably well. As compared to its nonfluorinated congener, octafluorocalix[4]pyrrole was found to display enhanced binding affinities for several representative anions in pure acetonitrile as judged from ITC analyses. Similar analyses of the fluorinated calix[n]pyrroles revealed an increase in the relative affinity for bromide over chloride with increasing macrocycle size, as manifest in a decrease in the binding ratio K(a(Cl))/K(a(Br)). Anion binding studies in the solid state, involving single-crystal X-ray diffraction analyses of the chloride and acetate anion complexes of octafluorocalix[4]pyrrole and decafluorocalix[5]pyrrole, respectively, confirmed the expected hydrogen bond interactions between the pyrrolic NH protons and the bound anions.     

A CSOV study of the difference between HF and DFT intermolecular interaction energy values: the importance of the charge transfer contribution

Intermolecular interaction energy decompositions using the Constrained Space Orbital Variation (CSOV) method are carried out at the Hartree-Fock level on the one hand and using DFT with usual GGA functionals on the other for a number of model complexes to analyze the role of electron correlation in the intermolecular stabilization energy. In addition to the overall stabilization, the results provide information on the variation, with respect to the computational level, of the different contributions to the interaction energy. The complexes studied are the water linear dimer, the N-methylformamide dimer, the nucleic acid base pairs, the benzene-methane and benzene-N2 van der Waals complexes, [Cu+ -(ImH)3]2, where "ImH" stands for the Imidazole ligand, and ImH-Zn++. The variation of the frozen core energy (the sum of the intermolecular electrostatic energy and the Pauli repulsion energy) calculated from the unperturbed orbitals of the interacting entities indicates that the intramolecular correlation contributions can be stabilizing as well as destabilizing, and that general trends can be derived from the results obtained using usual density functionals. The most important difference between the values obtained from HF and DFT computations concerns the charge transfer contribution, which, in most cases, undergoes the largest increase. The physical meaning of these results is discussed. The present work gives reference calculations that might be used to parametrize new correlated molecular mechanics potentials.     

Synthesis and structural characterization of tricarbonyl 1-azahexa-1,3,5-triene iron(0) complexes

Transition Metal Chemistry -     

Anion transfer at a micro-water/1,2-dichloroethane interface facilitated by beta-octafluoro-meso-octamethylcalix[4]pyrrole

The facilitated transfer of four hydrophilic anions, i.e., Cl-, Br-, NO2-, and CH3CO2-, at the micro-water/1,2-dichloroethane interface supported at the tip of a micropipet has been observed successfully using beta-octafluoro-meso-octamethylcalix[4]pyrrole 2 as the receptor. We have also shown for the first time that the dynamics of this process can be studied by micropipet voltammetry. The standard kinetic rate constants (kdegrees) for facilitated anion transfer at such an interface were determined to be (2.11 +/- 0.90) x 10(-2) and (0.75 +/- 0.50) x 10(-2) cm/s in the case of Cl- and CH3CO2-, respectively. These values are much smaller than those associated with the facilitated transfer of analogous alkali metal ions. This difference is thought to reflect a number of underlying factors, including the higher hydration of anions as compared to similar sized cations. Studies such as these are expected to be useful in understanding the mechanism of anion transport at soft interfaces and for the design of yet-improved anion receptors and carriers.     

Poly(methyl methacrylate)s with pendant calixpyrroles: polymeric extractants for halide anion salts

Poly(methyl methacrylate)s containing pendant octamethylcalix[4]pyrrole subunits were prepared and demonstrated to be capable of extracting tetrabutylammonium chloride and fluoride salts from aqueous media.     

Oxidative rearrangements of isobenzofurans: studies toward the synthesis of the ajudazols

We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This methodology has been successfully applied toward the synthesis of ajudazol A.