Synthesis and biological evaluation of novel macrocyclic paclitaxel analogues

[reaction: see text] This work describes the synthesis of two novel macrocyclic taxoid constructs by ring-closing olefin metathesis (RCM) and their biological evaluation. Computational studies examine conformational profiles of 1 and 2 for their fit to the beta-tubulin binding site determined by electron crystallography. The results support the hypothesis that paclitaxel binds to microtubules in a "T" conformation.     

Room temperature operation of a deep etched buried heterostructure photonic crystal quantum cascade laser

High power single mode quantum cascade lasers with a narrow far field are important for several applications including surgery or military countermeasure. Existing technologies suffer from drawbacks such as operation temperature and scalability. In this paper we introduce a fabrication approach that potentially solves simultaneously these remaining limitations. We demonstrate and characterize deep etched, buried photonic crystal quantum cascade lasers emitting around a wavelength of 8.5 μm. The active region was dry etched before being regrown with semi‐insulating Fe:InP. This fabrication strategy results in a refractive index contrast of 10% allowing good photonic mode control, and simultaneously provides good thermal extraction during operation. Single mode emission with narrow far field pattern and peak powers up to 0.88 W at 263 K were recorded from the facet of the photonic crystal laser, and lasing operation was maintained up to room temperature. The lasing modes emitted from square photonic crystal mesas with a side length of 550μm, were identified as slow Bloch photonic crystal modes by means of three‐dimensional photonic simulations and measurements.

     

Rotational-echo double-resonance NMR distance measurements for the tubulin-bound Paclitaxel conformation

The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of numerous research efforts, since the inability of polymerized tubulin to form crystals precludes structure proof by X-ray crystallography. Likewise, although the alpha,beta-tubulin dimer structure has been solved by electron crystallography, the 3.7 A resolution is too low to permit direct determination of either ligand conformation or binding pose. In this article, we present experimental results from 2H{19F} REDOR NMR that provide direct confirmation that paclitaxel adopts a T-shaped conformation when it is bound to tubulin.