Latrunculin analogues with improved biological profiles by "diverted total synthesis": preparation, evaluation, and computational analysis

Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of "latrunculin-like" compounds, in which all characteristic structural elements of these macrolides were subject to pertinent molecular editing. Although all previously reported derivatives of 1 and 2 were essentially devoid of any actin-binding capacity, the synthetic compounds presented herein remain fully functional. One of the designer molecules with a relaxed macrocyclic backbone, that is compound 44, even surpasses latrunculin B in its effect on actin while being much easier to prepare. This favorable result highlights the power of "diverted total synthesis" as compared to the much more widely practiced chemical modification of a given lead compound by conventional functional group interconversion. A computational study was carried out to rationalize the observed effects. The analysis of the structure of the binding site occupied by the individual ligands on the G-actin host shows that latrunculin A and 44 both have similar hydrogen-bond network strengths and present similar ligand distortion. In contrast, the H-bond network is weaker for latrunculin B and the distortion of the ligand from its optimum geometry is larger. From this, one may expect that the binding ability follows the order 1 >/= 44 > 2, which is in accord with the experimental data. Furthermore, the biological results provide detailed insights into structure/activity relationships characteristic for the latrunculin family. Thus, it is demonstrated that the highly conserved thiazolidinone ring of the natural products can be replaced by an oxazolidinone moiety, and that inversion of the configuration at C16 (latrunculin B numbering) is also well accommodated. From a purely chemical perspective, this study attests to the maturity of ring-closing alkyne metathesis (RCAM) catalyzed by a molybdenum alkylidyne complex generated in situ, which constitutes a valuable tool for advanced organic synthesis and natural product chemistry.     

Total synthesis and evaluation of the actin-binding properties of microcarpalide and a focused library of analogues

A comparative investigation shows that hydroxylated 10-membered lactones modeled around the fungal metabolites microcarpalide (1) and pinolidoxin (2) are endowed with selective actin-binding properties. Although less potent than the marine natural product latrunculin A, which represents the standard in the field, nonenolides of this type are significantly less toxic and accommodate substantial structural editing. Most notable is the fact that even an intramolecular transesterification with formation of a hydroxylated butanolide skeleton does not annihilate their microfilament disrupting capacity. This finding calls for a reinvestigation of the biological profile of other fungal metabolites that embody a similar motif. Microcarpalide (1) serving as the calibration point for this comparative study was prepared by total synthesis based on ring-closing metathesis (RCM) as the key step. The chosen route favorably compares to previous approaches to this target and provides further support for the notion that the (E,Z)-configuration of a medium-sized cycloalkene can be controlled by proper choice of the catalyst as previously outlined by our group. 9-epi-Microcarpalide 26 and furanone 27 as representative examples of the "natural productlike" compounds investigated herein have been characterized by crystal structure analysis.     

Hydrophobic interaction chromatography of proteins IV. Kinetics of protein spreading

Adsorption of proteins on surfaces of hydrophobic interaction chromatography media is at least a two-stage process. Application of pure protein pulses (bovine serum albumin and beta-lactoglobulin) to hydrophobic interaction chromatography media yielded two chromatographic peaks at low salt concentrations. At these salt concentrations, the adsorption process is affected by a second reaction, which can be interpreted as protein spreading or partial unfolding of the protein. The kinetic constants of the spreading reaction were derived from pulse response experiments at different residence times and varying concentrations by applying a modified adsorption model considering conformational changes. The obtained parameters were used to calculate uptake and breakthrough curves for spreading proteins. Although these parameters were determined at low saturation of the column, predictions of overloaded situations could match the experimental runs satisfactorily. Our findings suggest that proteins which are sensitive to conformational changes should be loaded at high salt concentrations in order to accelerate the adsorption reaction and to obtain steeper breakthrough curves.     

Electrically conducting ion tracks in diamond-like carbon films for field emission

Electrically conducting channels in an insulating carbon matrix were produced by 140-MeV Xe ion irradiation. The high local energy deposition of the individual ions along their pathes causes a rearrangement of the carbon atoms and leads to a transformation of the insulating, diamond-like (sp³-bonding) form of carbon into the conducting, graphitic (sp²-bonding) configuration. The conducting ion tracks are clearly seen in the current mapping performed with an atomic force microscope (AFM). These conducting tracks are of possible use in field emission applications. Received: 4 May 1999 / Accepted: 5 May 1999 / Published online: 1 July 1999     

On the dynamics of circulating monocable aerial ropeways

We investigate the dynamics of a hauling rope modelled as an inextensible completely flexible string and calculate the first natural frequencies. Furthermore we discuss the sensitivity of the model on the operating speed of the ropeway. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Zur formelmäßigen Berechnung der Zuordnung von schwingungsspektroskopischen Frequenzen

For Analytical Calculation of Assignments of Vibrational Spectroscopic Frequencies Using the normal coordinate treatment we calculate assignments of vibrational spectroscopic frequencies of the systems X₃ ( D _3h) and X₄ ( T d) and partially of the systems XY₄ ( D _4h) and XY₆ ( O _h).     

Convenient Synthesis of N-Trimethylsilylaminotitanium Trichlorides

Bis(N-trimethylsilylamino)plumbylenes 1 {[Me₃Si(R)N]₂Pb with R = ^tBu ( a ), Me₃Si ( b ), 9-(9-borabicyclo[3.3.1]nonyl) ( c )} react smoothly with an excess of TiCl₄ to give PbCl₂ and N-trimethylsilylaminotitanium trichlorides 3 a – c . In contrast, the analoguous reaction of the corresponding stannylenes 2 a – c leads to mixtures containing unidentified Ti^III compounds, the amides 3 a or 3 b , bis[bis(trimethylsilyl)amino]titanium dichloride 4 b and bis(amino)tin dichlorides 5 a – c . The crystal structure of 3 a was determined by X-ray structural analysis. Compound 3 a is a dimer in the solid state with distorted trigonal pyramidal surroundings of the titanium atoms. Each titanium atom bears two μ²-Cl ligands which are in axial (d_Ti–Cl = 250.7(1) pm) and equatorial positions (d_Ti–Cl = 247.0(1) pm) and two terminal chloro ligands, one in axial (d_Ti–Cl = 228.0(1) pm) and one in equatorial position (d_Ti–Cl = 221.1(1) pm). The equatorial Ti–N bonds are short (183.8(2) pm).