A dense ring of the trans-Neptunian object Quaoar outside its Roche limit.

Planetary rings are observed not only around giant planets1, but also around small bodies such as the Centaur Chariklo2 and the dwarf planet Haumea3. Up to now, all known dense rings were located close enough to their parent bodies, being inside the Roche limit, where tidal forces prevent material with reasonable densities from aggregating into a satellite. Here we report observations of an inhomogeneous ring around the trans-Neptunian body (50000) Quaoar. This trans-Neptunian object has an estimated radius4 of 555 km and possesses a roughly 80-km satellite5 (Weywot) that orbits at 24 Quaoar radii6,7. The detected ring orbits at 7.4 radii from the central body, which is well outside Quaoar's classical Roche limit, thus indicating that this limit does not always determine where ring material can survive. Our local collisional simulations show that elastic collisions, based on laboratory experiments8, can maintain a ring far away from the body. Moreover, Quaoar's ring orbits close to the 1/3 spin-orbit resonance9 with Quaoar, a property shared by Chariklo's2,10,11 and Haumea's3 rings, suggesting that this resonance plays a key role in ring confinement for small bodies.

Identification of four differently injured victims of the Mangalore air crash disaster.

On the 22nd of May 2010, a Boeing 737-800 aircraft crashed at the Mangalore International Airport killing all but 8 of the 166 people on board. One of the most important roles of the forensic investigation is to identify the victims of the crash. This task was made even more difficult because of the fact that most of the bodies were charred beyond recognition. Four bodies were transported to a mortuary to undergo a postmortem examination, whereas the rest of the victims were examined elsewhere. There is a wide range of methods to identify victims of mass disasters ranging from simple facial recognition to highly complex DNA comparisons. This paper highlights the experience and methods used to describe various types of injuries associated with a plane crash and the methods and techniques used to successfully identify the four victims of the crash. Implications for forensic nurses are discussed.

Antineoplastic agents. 450. Synthesis of (+)-pancratistatin from (+)-narciclasine as relay(1a).

(+)-Narciclasine (2) available in quantity from certain Amaryllidaceae species or by total synthesis was employed as a precursor for a 10-step synthetic conversion (3.6% overall yield) to natural (+)-pancratistatin (1a). The key procedures involved epoxidation of natural (+)-narciclasine (2) to epoxide 6, reduction to diol 8, and formation of cyclic sulfate 12 and its ring opening with cesium benzoate followed by saponification of the benzoate to afford (+)-pancratistatin (1a).

Studies directed towards the refinement of the pancratistatin cytotoxic pharmacophore.

Two deoxy-analogues of the anticancer/antiviral agent pancratistatin containing functionality complementary to the minimum structural pharmacophore were synthesized and subjected to anticancer screening. One of the analogues exhibited selective inhibition of certain tumor cell lines but was significantly less potent than the natural products. The minimum structural pharmacophore has now been refined from eight to three possible structures.

A pinacol rearrangement/oxidation synthetic route to hydroxyphenstatin.

In an attempt to develop biologically active compounds from the inactive trans isomer (3a) of stilbene 1a, after asymmetric dihydroxylation to optically pure (R,R)-diol 8 the unexpected racemic diphenylacetaldehyde (9) was generated via a Pinacol rearrangement. Several derivatives of diphenylacetaldehyde 9 were synthesized (11-15) and reported. Further reaction of aldehyde 9 during desilylation through autoxidative decarbonylation afforded benzophenone 2b, designated hydroxyphenstatin, a potent antitumor and antimitotic agent. Hydroxyphenstatin showed potent inhibition of the tubulin assembly (IC(50) 0.82 microM) and exhibited an ED(50) of 2.5 microg/mL against the P388 lymphocytic leukemia cell line.

Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1, 2-dihydroxy- 1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3' ',4' ',5' '-trimethoxyphenyl)-ethane.

The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).

Reducing risk factors for eating disorders: comparison of an Internet- and a classroom-delivered psychoeducational program.

This controlled trial compared Internet- (Student Bodies [SB]) and classroom-delivered (Body Traps [BT]) psychoeducational interventions for the reduction of body dissatisfaction and disordered eating behaviors/attitudes with a control condition. Participants were 76 women at a private university who were randomly assigned to SB, BT, or a wait-list control (WLC) condition. Measures of body image and eating attitudes and behaviors were measured at baseline, posttreatment, and 4-month follow-up. At posttreatment, participants in SB had significant reductions in weight/shape concerns and disordered eating attitudes compared with those in the WLC condition. At follow-up, disordered behaviors were also reduced. No significant effects were found between the BT and WLC conditions. An Internet-delivered intervention had a significant impact on reducing risk factors for eating disorders.

Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug.

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineoplastic activity, and the benzophenone derivative of combretastatin A-1 was therefore synthesized. The benzophenone, designated hydroxyphenstatin (6a), was synthesized by coupling of a protected bromobenzene and a benzaldehyde to give the benzhydrol with subsequent oxidation to the ketone. Hydroxyphenstatin was converted to the sodium phosphate prodrug (6e) by a dibenzyl phosphite phosphorylation and subsequent benzyl cleavage (6a --> 6d --> 6e). While hydroxyphenstatin (6a) was a potent inhibitor of tubulin polymerization with activity comparable to that of combretastatin A-1 (3a), the phosphorylated derivative (6e) was inactive.

Novel cytotoxic diterpenes from Casearia arborea.

Cytotoxicity-guided fractionation of the dichloromethane-methanol extract of the roots of Casearia arborea yielded five novel clerodane diterpenes, casearborins A-E (1-5), as well as cucurbitacin B. The presence of cucurbitacins glycosides was also detected. The absolute configuration of casearborin E was determined by X-ray crystallography.

Antineoplastic agents 430. Isolation and structure of cribrostatins 3, 4, and 5 from the republic of maldives cribrochalina species.

Continued investigation of cancer-cell growth-inhibitory constituents of the blue marine sponge Cribrochalina sp. has led to discovery of cribrostatins 3 (4a), 4 (5), and 5 (4b) in 10(-5) to 10(-7) % of the wet weight. The structure of cribrostatin 3 (4a) was determined by results of high field (500 MHz) (1)H and (13)C NMR and HRMS interpretations. The same general approach to the structures of cribrostatins 4 (5) and 5 (4b) was completed by X-ray crystal structure determinations. Cribrostatins 3, 4, and 5 provided significant cancer cell line inhibitory activities. Cribrostatins 1 and 2(2) and the newly isolated cribrostatins 3-5 displayed antibacterial and/or antifungal activities.

Isolation and structures of schleicherastatins 1-7 and schleicheols 1 and 2 from the teak forest medicinal tree Schleichera oleosa.

Bioassay (P-388 lymphocytic leukemia cell line)-guided separation of an extract prepared from the bark and stem of the Sri Lankan tree Schleichera oleosa led to the isolation of seven cancer cell growth inhibitory hydroxylated sterols designated schleicherastatins 1-7 (1-7) and two related sterols, schleicheols 1 and 2 (8, 9). The structure of schleicherastatin 1 (1) was completely elucidated by X-ray crystal structure determination. Based upon that defined structure, the remaining new sterol structures were deduced by highfield (300 and 500 MHz) NMR and MS interpretations. In this new series of sterols, hydroxylation at C-22 appears to be important for promoting cancer cell growth inhibition.

Antineoplastic agents. Part 409: Isolation and structure of montanastatin from a terrestrial actinomycete.

A Montana soil actinomycete, Streptomyces anulatus, produced (1 x 10(-2)% yield) a new cancer cell growth inhibitory cyclooctadepsipeptide named montanastatin (1) accompanied by the potent anticancer antibiotic valinomycin (2) in very high (5.1%) yields. Valinomycin but not montanastatin inhibited growth of a number of pathogenic bacteria and fungi. Interpretation of high-field (500 MHz) NMR and high-resolution FAB mass spectral data allowed assignment of the structure cyclo-(D-Val-L-Lac-L-Val-D-Hiv) to montanastatin. Valinomycin (2) was also isolated from actinomycetes cultured from a tree branch and animal feces collected in Malaysia. Streptomyces exfoliatus, isolated from the tree branch, was found to contain valinomycin in 1.6% yield, while the fecal isolate, S. anulatus, gave valinomycin in 0.9% yield.

Antineoplastic agents. 410. Asymmetric hydroxylation of trans-combretastatin A-4.

The South African willow tree Combretum caffrum has yielded a number of potent cancer cell growth inhibitors. The present SAR studies of the antineoplastic agent combretastatin A-4 (1c) were focused mainly on the olefinic bridge to determine the effects on cancer cell growth and, potentially, to better define the combretastatin A-4 binding site on tubulin. The geometric trans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R,2R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihydroxylation conditions. Cancer cell line testing showed the (1S, 2S)-diol 4c to be more potent than its enantiomer 4d. Diol 4c weakly inhibited tubulin polymerization (IC50 = 22 microM, versus 1.2 microM for combretastatin A-4), while 4d was inactive (IC50 > 40 microM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.

Antineoplastic agents. 379. Synthesis of phenstatin phosphate.

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (1b) directed at maintaining the (Z)-stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c --> 3a), and the parent phenstatin (3b) was later synthesized (6a --> 3a --> 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b --> 3c --> 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseriagonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A-4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.

Antineoplastic agents 393. Synthesis of the trans-isomer of combretastatin A-4 prodrug.

The (E)-stilbene isomer (2a) of the (Z)-combretastatin A-4 prodrug (1b) was efficiently prepared from (E)-combretastatin A-4 by a reaction sequence employing phosphorylation (dibenzyl chlorophosphite), cleavage (trimethyliodosilane) of the benzyl ester and reaction of the resulting phosphoric acid with sodium methoxide. The sodium phosphate product (2c) was also found to be an important side-product, presumably from iodine-catalyzed isomerization, when the analogous synthetic route was used to obtain the combretastatin A-4 prodrug (1b). The phosphoric acid precursor of prodrug 1b derived from (Z)-combretastatin A-4 (1a) was converted into a series of metal cation and ammonium cation salts to evaluate effects on human cancer cell growth, antimicrobial activities and solubility behavior.

Antineoplastic agents. 397: Isolation and structure of sesterstatins 4 and 5 from Hyrtios erecta (the Republic of Maldives).

The wide ranging marine sponge Hyrtios erecta is the source of the spongistatins, a new class of macrocyclic lactone antineoplastic agents. Continuation of a detailed investigation of cancer cell growth inhibitory (P388 lymphocytic leukemia) fractions (trace) from H. erecta has revealed the presence (10(-5) to 10(-7)% yield) of cytotoxic pentacyclic sesterterpenes. Employing P388 leukemia and human tumor cell line-guided bioassay techniques, two new moderate inhibitors of cancer cells were isolated and named sesterstatins 4 (1a, P388 ED50 4.9 micrograms/mL) and 5 (1b, DU-145 prostate GI50 1.9 micrograms/mL). Similar to other sesterterpenes, sesterstatin 5 inhibited growth of a Gram-positive bacterium. High field (500 MHz) 2-D NMR techniques were primarily employed for initial structural assignments, and structural assignments were confirmed by X-ray crystal structure determination of sesterstatin 4 (1a) and 5 (1b).

Antineoplastic agents. 362. Isolation and X-ray crystal structure of dibromophakellstatin from the Indian ocean sponge Phakellia mauritiana.

Bioassay-guided isolation procedures using human tumor cell lines led to isolation of dibromophakellstatin (4) from the Republic of Seychelles sponge Phakellia mauritiana. The isolation, X-ray crystal structure elucidation, absolute stereochemistry, and antineoplastic activity have been summarized. P. mauritiana was also found to contain dibromophakellin (1), debromohymenialosine (2), thymidine, deoxyuridine, and thymine.

Isolation and structure of the marine sponge cell growth inhibitory cyclic peptide phakellistatin 1.

A new cell growth inhibitory (P-388 murine leukemia ED50 7.5 micrograms/ml) cycloheptapeptide designated phakellistatin 1 was isolated from two Indo-Pacific sponges, Phakellia costata and Stylotella aurantium. Structural elucidation was accomplished utilizing high field nmr, amino acid analyses, and mass spectral techniques (fab, tandem ms/ms), followed by chiral gas chromatographic procedures for absolute configuration assignments (all S-amino acid units). By these methods phakellistatin 1 [1] was found to be cyclo (Pro-Ile-Pro-Ile-Phe-Pro-Tyr), and this assignment was finally confirmed by an X-ray crystal structure determination.

Isolation and structure of cytostatic steroidal saponins from the African medicinal plant Balanites aegyptica.

Bioactivity-guided separation of a CH2Cl2/MeOH extract of Balanites aegyptica afforded four new cytostatic saponins, named balanitins 4 [1], 5 [2], 6 [3], and 7 [4]. On the basis of enzymatic hydrolyses and glycosidation nmr chemical shifts employing the peracetates, structures 1-4 were established as yamogenin 3 beta-O-beta-D-glucopyranosyl-(1----3)-beta-D-glucopyranosyl-(1----4)-[al pha- L-rhamnopyranosyl-(1----2)]-beta-D-glucopyranoside [1], yamogenin 3 beta-O-alpha-L-rhamnopyranosyl-(1----3)-beta-D-glucopyranosyl-(1----4)- [alpha-L-rhamnopyranosyl-(1----2)]-beta-D-glucopyranoside [2], yamogenin 3 beta-O-beta-D-glucopyranosyl-(1----4)-[alpha-L- rhamnopyranosyl-(1----2)]-beta-D-glucopyranoside [3], and diosgenin 3 beta-O-beta-D-xylopyranosyl-(1----3)-beta-D-glucopyranosyl-(1----4)-[alp ha- L-rhamnopyranosyl-(1----2)]-beta-D-glucopyranoside [4].