The interactions of microtubules with most compounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind microtubules, which suggests that other factors are involved in their cellular effects. The binding constants of epothilones, eleutherobin, discodermolide, sarcodictyins, 3,17beta-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-triene, and dictyostatin to the paclitaxel site; the critical concentrations of ligand-induced assembly; and their cytotoxicity in carcinoma cells have been measured, and correlations between these parameters have been determined. The inhibition of cell proliferation correlates better with the binding enthalpy change than with the binding constants, suggesting that large, favorable enthalpic contribution to the binding is desired to design paclitaxel site drugs with higher cytotoxicity.

A flexible and modular approach was used in the convergent and highly stereocontrolled synthesis of the antimitotic agent dictyostatin. This first total synthesis establishes its full stereochemistry and should be amenable to producing useful quantities and designed analogues of this molecule, whose conformation closely resembles that of discodermolide (see overlayed structures).

We report a full account of our work towards the total synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon (pinaceae). Pseudolaric Acid B (1a) is an antifungal and antifertility agent. Furthermore, its capacity of inhibiting tubulin polymerization makes it a lead compound for cancer therapy. Herein, we describe the use of a Ru or Rh catalyzed [5+2] intramolecular cycloaddition reaction of an alkyne and a vinylcyclopropane for the construction of the polyhydroazulene core of the molecule. Our first unsuccessful strategy towards the introduction of the quaternary center based on an epoxide opening with cyanide led to the discovery of a new TBAF mediated isomerization of 1,4 diene to 1,3 diene and a vinylogous eliminative opening of an epoxide to form a dienol. Our second strategy, based on the cyclization of an alkoxycarbonyl radical upon a diene system, succeeded in forming the quaternary center. Detailed studies showed the dependence of this underutilized approach for the synthesis of lactones from substrate structure and reaction conditions. In the late stage of the synthesis, the unique capacity of cerium organometallic reagents to add onto sensitive sterically hindered ketone was demonstrated. The easy formation of an oxo-bridged derivative was the major hurdle for the completion of the synthesis and showcased the intriguing reactivity of the complex core of the pseudolaric acids.

--Zusammenfa~ongThe Approximate Dirichlet Domain Decomposition Method. Part I: An Algebraic Approach. We present a new approach to the construction of Domain Decomposition (DD) preconditioners for the conjugate gradient method applied to the solution of symmetric and positive definite finite element equations. The DD technique is based on a non-overlapping decomposition of the domain ~2 into p subdomains connected later with the p processors of a MIMD computer. The DD preconditioner derived contains three block matrices which must be specified for the specific problem considered. One of the matrices is used for the transformation of the nodal finite element basis into the approximate discrete harmonic basis. The other two matrices are block preconditioners for the Dirichlet problems arising on the subdomains and for a modified Schur complement defined over all nodes on the coupling boundaries between the subdomains. The relative spectral condition number is estimated. Relations to the additive Schwarz method are discussed. In the second part of this paper, we will apply the results of this paper to two-dimensional, symmetric, second-order, elliptic boundary value problems and present numerical results performed on a transputer-network. AMS

Electrical synapses (gap junctions) rapidly transmit signals between neurons and are composed of connexins. In neurons, connexin36 (Cx36) is the most abundant isoform; however, the mechanisms underlying formation of Cx36-containing electrical synapses are unknown. We focus on homocellular and heterocellular gap junctions formed by an AII amacrine cell, a key interneuron found in all mammalian retinas. In mice lacking native Cx36 but expressing a variant tagged with enhanced green fluorescent protein at the C-terminus (KO-Cx36-EGFP), heterocellular gap junctions formed between AII cells and ON cone bipolar cells are fully functional, whereas homocellular gap junctions between two AII cells are not formed. A tracer injected into an AII amacrine cell spreads into ON cone bipolar cells but is excluded from other AII cells. Reconstruction of Cx36–EGFP clusters on an AII cell in the KO-Cx36-EGFP genotype confirmed that the number, but not average size, of the clusters is reduced – as expected for AII cells lacking a subset of electrical synapses. Our studies indicate that some neurons exhibit at least two discriminatory mechanisms for assembling Cx36. We suggest that employing different gap-junction-forming mechanisms could provide the means for a cell to regulate its gap junctions in a target-cell-specific manner, even if these junctions contain the same connexin.