Development of a scalable synthetic route towards a 2,2,6-trisubstituted chiral morpholine via stereoselective hydroalkoxylation

A scalable synthetic route towards a chiral 2,2,6-trisubstituted chiral morpholine, which is a known opioid antagonist, was developed. The synthetic route involves incorporating an aryl group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylation catalyzed by trifluoromethanesulfonic acid. Late stage incorporation of both the aryl and N-alkyl groups make this route suitable for further SAR studies on this molecule.     

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to gamma-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathway may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.     

High-spin states in odd-odd 168Lu

High-spin states of odd-odd ¹⁶⁸Lu were observed up to 18ħ for the first time using the ¹⁵⁹Tb(¹³C, 4nγ)¹⁶⁸Lu reaction at E _13C= 58.5 MeV. γ-γ coincidence, E _γ singles, excitation function, and the DCO ratios were measured. Two rotational bands with signature splitting were populated, among which the lower-energy band is identified as π 7/2⁺[404] ⊗ν 5/2⁺[642] in view of alignment and energy systematics. Received: 27 October 1997     

Statistically Steady Incompressible DNS to Validate a New Correlation for Turbulent Burning Velocity in Turbulent Premixed Combustion

Incompressible 3-D DNS is performed in non-decaying turbulence with single step chemistry to validate a new analytical expression for turbulent burning velocity. The proposed expression is given as a sum of laminar and turbulent contributions, the latter of which is given as a product of turbulent diffusivity in unburned gas and inverse scale of wrinkling at the leading edge. The bending behavior of U _T at higher u′ was successfully reproduced by the proposed expression. It is due to decrease in the inverse scale of wrinkling at the leading edge, which is related with an asymmetric profile of FSD with increasing u′. Good agreement is achieved between the analytical expression and the turbulent burning velocities from DNS throughout the wrinkled, corrugated and thin reaction zone regimes. Results show consistent behavior with most experimental correlations in literature including those by Bradley et al. (Philos Trans R Soc Lond A 338:359–387, 1992), Peters (J Fluid Mech 384:107–132, 1999) and Lipatnikov et al. (Progr Energ Combust Sci 28:1–74, 2002).     

Polymerization and copolymerization of ethene initiated with disiloxane-bridged biscyclopentadienylzirconium complexes and methylaluminoxane

The disiloxane-bridged zirconocene complexes, tetramethyldisiloxanediylbis (cyclopentadienyl)zirconium dichloride and tetramethyldisiloxanediylbis(cyclopentadienyl) dimethylzirconium initiate the homopolymerization of ethene as well as the copolymerization of ethene and α-olefin with a modified methylaluminoxane as cocatalyst. The catalyst systems give resonable activity but the molecular weight of polyethene decreases drastically with increasing polymerization temperature.     

Polymerization of ethene initiated with a mixture of siloxane-bridged mono- and dinuclear zirconocenes

In the polymerization of ethene cocatalyzed with modified methylaluminoxane, the catalyst activities of the siloxane-bridged dinuclear zirconocenes, tetramethyldisiloxanediylbis(cyclopentadienylindenylzirconium dichloride) ( 3 ) and hexamethyltrisiloxanediylbis(cyclopentadienylindenylzirconium dichloride) ( 4 ) were lower than that obtained with the siloxane-bridged mononuclear zirconocene, tetramethyldisiloxanediyldicyclopentadienyldimethylzirconium ( 1 ). On the other hand, weight-average molecular weight M̄_w and ratio of weight- to number-average molecular weights M̄_w/M̄_n of polyethene (PE) obtained with 3 or 4 were higher than those of PE obtained with 1. For a binary mixture of 1/3 or 1/4 , it was found that the obtained PE exhibits a bimodal molecular weight distribution for an appropriate composition of the mixed zirconocenes. M̄_w/M̄_n of PE could be adjusted by changing the relative concentrations of the two zirconocenes.