Discovery of (E)-9,10-dehydroepothilones through chemical synthesis: on the emergence of 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B as a promising anticancer drug candidate

We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.     

Effect of repetition nanoindentation of GaN epilayers on a‐axis sapphire substrates

In this work, gallium nitride (GaN) epilayers were deposited on a‐axis sapphire substrate by means of metal organic chemical vapor deposition (MOCVD). Berkovich nanoindentation was used to explore the repetition pressure‐induced impairment of the GaN film. The observation of load‐displacement vs stress‐strain curves concludes that basal slip is implicated in the deformation on the A plane GaN. The increase in the hardness (H) and elastic modulus (E) was determined from cyclic nanoindentation, and resulted in a crack due to the formation of incipient slip bands and/or the to‐and‐fro motion of mobile dislocation. It is indicated that the generation of individual dislocation and residual deformation of the GaN films are showed by CL mapping analysis. From the morphological studies, it is revealed that the crack was found by means of atomic force microscope (AFM) technique at nine loading/reloading cycles even after the indentation beyond the critical depth on the residual indentation impression. Copyright © 2010 John Wiley & Sons, Ltd.     

Optical properties of chiral nematic side‐chain copolymers bearing cholesteryl and azobenzene building blocks

Thermotropic chiral nematic (N*) side‐chain copolymers (CPs) bearing cholesteryl and azobenzene units were synthesized to investigate the structure–property relationships of the acrylates of the chiral, achiral, and photochromic monomers of free radical polymerization‐derived polymers. The polar effect of chlorine substitution on the benzene ring of the chiral monomer (M3*) widened the mesophase transition temperature only at the monomer level, but no remarkable effect on the mesomorphic, optical or thermochromism of the corresponding CPs was observed. An examination of the CPs prepared using differential scanning calorimetry and hot‐stage polarizing microscopy showed that all the CPs exhibited a cholesteric nematic phase (N*), and increasing the content of the cholesteryl units in the CPs displayed only the N* phase over a much wider temperature range. On cooling from the isotropic melt of N* CPs, selective reflections of visible light that changed from short to long wavelengths were observed. The photolysis of CPs revealed that CP1 – CP4 undergo reversible photoisomerization and that CP5 and CP6 undergo irreversible photoisomerization. The rate of isomerization depends on the type (? N?N? , ? CH?CH? , and both) and content of photochromic units in the CPs. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Quantitation ofAcidothermus cellulolyticus E1 endoglucanase andThermomonospora fusca E3 exoglucanase using enzyme-linked immunosorbent assay (ELISA)

Two distinct quantitative indirect ELISAs were developed to determine the concentration of recombinant cellulase enzymes in culture filtrates. A monoclonal antibody (E1P7) was used as the primary antibody in developing an ELISA specific forAcidothermus cellulolyticus E1 endoglucanase. Likewise, a polyclonal rabbit serum (Ab684) was used to develop an ELISA specific forThermomonospora fusca E₃ exoglucanase. Dose-response curves indicated a dynamic range for both assays between 0.01 and 0.08 μg/mL (1–8 ng/assay) when purified enzymes were used as standards. These assays have been used to estimate concentrations of secreted recombinant E1 and/or E₃ in culture supernatants ofStreptomyces lividans strain TK24 in which the corresponding genes have been cloned and expressed.     

Improved nonaqueous capillary electrophoresis for tetracyclines at subparts per billion level

A NACE method with laser-induced fluorescence detection was modified for sensitive detection of 4 tetracyclines (TCs) in biological samples and feeds. The changes in injection mode, injection times, id of capillary, excitation wavelength, and the use of surfactant and sample stacking technique all contributed to improved LODs of TCs to sub-ng/mL level. With the optimized conditions, the instrumental LODs could reach 1.33 ng/mL for chlorotetracycline (CTC) and 13.3 ng/mL for TC, oxytetracycline (OTC), and doxycycline (DC), an improvement of 10-100-fold over past studies. A simple SPE procedure was further developed for the extraction and concentration of TCs in plasma, urine, feed, and milk. Taken together, the instrumental LOD and feasible SPE concentration factors the overall LODs for CTC could reach 65 pg/mL in feed and milk and 260 pg/mL in plasma and urine. Detection limits for TC, OTC, and DC at sub-ng/mL level were also achieved. The modified CE-LIF method was found to be less complicated and more sensitive than the best current methods using UV or LIF detection, and has been applied successfully to assess oral absorption of DC in swine and chickens and to confirm suspected TC-positive bovine serum samples.     

New Diarylheptanoids and Kavalactone from Alpinia katsumadai Hayata

Two new diarylheptanoids, katsumains A ( 1 ) and B ( 2 ), and one new kavalactone, katsumadain ( 3 ), together with the three known compounds (4E,6E)‐1,7‐diphenylhepta‐4,6‐dien‐3‐one ( 4 ), (5R,6E)‐1,7‐diphenyl‐5‐hydroxyhept‐6‐en‐3‐one ( 5 ), and cardamonin ( 6 ), were isolated from the seeds of Alpinia katsumadai Hayata . Their structures were elucidated mainly by spectroscopic methods (1D‐ and 2D‐NMR) and by mass spectrometry (HR‐ESI‐MS). Besides, the erroneous nomenclatures for (+)‐linderatin and (+)‐neolinderatin as given in [10] [11] were corrected to be 2′,4′,6′‐trihydroxy‐3′‐[(3R,4R)‐4‐isopropyl‐1‐methylcyclohex‐1‐en‐3‐yl]dihydrochalcone for (+)‐linderatin and 2′,4′,6′‐trihydroxy‐3′,5′‐bis[(3R,4R)‐4‐isopropyl‐1‐methylcyclohex‐1‐en‐3‐yl]dihydrochalcone for (+)‐neolinderatin, respectively.     

Substitution Reactions of Sulchemfonylated Sulfolenes with the Carbanion of Dimethyl Malonate

The reactions of 4-alkyl-4-(phenylsulfonyl)-2-sulfolenes with excess carbanion of dimethyl malonate in refluxing THF have been studied. The substitution reaction takes place at the 3-position via an addition-elimination process so that 3,4-disubstituted 2-sulfolenes are obtained. These products are isomerized to the corresponding3-sulfolenes under basic conditions.     

Bicyclo[2.2.2]octene-based "crab-like" molecules: synthesis, complexation, luminescence properties, and solid-state structures

[structure, reaction: see text] The U-shaped, multifunctionalized tetraetheno-bridged dicyclopenta[b,i]anthracenediol 10 was synthesized to serve as a platform molecule. The molecule was prepared from the Diels-Alder adduct 5a of tricycloundecatriene 3 and bicyclo[2.2.2]octene-fused p-benzoquinone 4. Functionalization of 10 to construct crab-like molecules was achieved via the base-promoted bis-O-alkylation of two endo-oriented hydroxyl groups at termini in 10 with the following alkyl halides: allyl, propagyl, and benzyl bromides; 1-bromo- and 1-iodo-4-(bromomethyl)benzene; 9-(bromomethyl)anthracene; 1-(bromomethyl)pyrene; and isomeric bromomethylpyridines. Single-crystal X-ray structures were obtained for bis-phenyl (21) and bis-pyrenyl (25) crabs, and for the silver(I) complex (32 and 33) crabs. The silver(I) complex 32 from bis-o-pyridyl crab 30 is a [2+2] dimeric dimetallocyclophane, and 33 from bis-m-pyridyl crab 29 is a [1+1] metallo-bridged cyclophane. The self-assembled intramolecular pi-stacking of pyrenyl rings in 25 with an interplanar distance of 3.40 A and the consequent pi-pi interactions were revealed by the X-ray crystal structure and its luminescence property.