Unconventional MBE Strategies from Computer Simulations for Optimized Growth Conditions

We investigate the influence of step edge diffusion (SED) and desorption on Molecular Beam Epitaxy (MBE) using kinetic Monte-Carlo simulations of the solid-on-solid (SOS) model. Based on these investigations we propose two strategies to optimize MBE growth. The strategies are applicable in different growth regimes: During layer-by-layer growth one can exploit the presence of desorption in order to achieve smooth surfaces. By additional short high flux pulses of particles one can increase the growth rate and assist layer-by-layer growth. If, however, mounds are formed (non-layer-by-layer growth) the SED can be used to control size and shape of the three-dimensional structures. By controlled reduction of the flux with time we achieve a fast coarsening together with smooth step edges.Comment: 19 pages, 7 figures, submitted to Phys. Rev.

Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 μCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0–2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities

Synthesis of furano-epothilone D

The total synthesis of furano-epothilone D by a convergent route is reported. The key fragments are available on a large scale to provide sufficient material for biological evaluation. The approach involves a palladium-catalyzed coupling that generates a highly functionalized aldehyde which is connected in a stereoselective aldol reaction to yield the framework of furano-epothilone D. Finally, a macrolactonization provides furano-epothilone D